Gianvi

Follow the patient instructions provided with your medicine. Ask your doctor or pharmacist if you do not understand these instructions. Missing a pill increases your risk of becoming pregnant.

If you miss one active pill, take two pills on the day that you remember. Then take one pill per day for the rest of the pack.

If you miss two active pills in a row in Week 1 or 2, take two pills per day for two days in a row. Then take one pill per day for the rest of the pack. Use back-up birth control for at least 7 days following the missed pills.

If you miss two active pills in a row in Week 3, throw out the rest of the pack and start a new pack the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that day.

If you miss three active pills in a row in Week 1, 2, or 3, throw out the rest of the pack and start a new pack on the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that day.

If you miss two or more pills, you may not have a period during the month. If you miss a period for two months in a row, call your doctor because you might be pregnant.

If you miss a reminder pill, throw it away and keep taking one reminder pill per day until the pack is empty. You do not need back-up birth control if you miss a reminder pill.

Many drugs can interact with birth control pills and make them less effective, which may result in pregnancy. Ethinyl estradiol can also affect blood levels of certain other drugs, making them less effective or increasing side effects. This includes prescription and over-the-counter medicines, vitamins, and herbal products.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Breast pain or tenderness
• headache, severe and throbbing
• heavy non-menstrual vaginal bleeding
• irregular menstrual periods
• nausea
• normal menstrual bleeding occurring earlier, possibly lasting longer than expected

Less common

• Longer or heavier menstrual periods
• unusual tiredness or weakness
• vomiting

Incidence not known

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• difficulty with breathing
• dizziness
• fever
• headache
• itching
• loss of appetite
• pain in the chest, groin, or legs, especially the calves
• rash
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• sudden, unexplained shortness of breath
• unpleasant breath odor
• unusual tiredness or weakness
• vision changes
• vomiting of blood
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Crying
• decreased interest in sexual intercourse
• delusions of persecution, mistrust, suspiciousness, and/or combativeness
• false or unusual sense of well-being
• inability to have or keep an erection
• irritability
• loss in sexual ability, desire, drive, or performance
• mental depression
• quick to react or overreact emotionally
• rapidly changing moods
• weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How to Take Gianvi

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, Gianvi must be taken exactly as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered.

How to Start Gianvi

Instruct the patient to begin taking Gianvi 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 Gianvi use, instruct the patient to take one light pink Gianvi daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one light pink Gianvi daily for 24 consecutive days, followed by one white inert tablet daily on Days 25 through 28. Gianvi 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. Gianvi can be taken without regard to meals. If Gianvi is first taken later than the first day of the menstrual cycle, Gianvi 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 Gianvi use, instruct the patient to take one light pink Gianvi daily, beginning on the first Sunday after the onset of her menstrual period. She should take one light pink Gianvi daily for 24 consecutive days, followed by one white inert tablet daily on Days 25 through 28. Gianvi 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. Gianvi can be taken without regard to meals. Gianvi 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 Gianvi 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 Gianvi 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 Gianvi daily for seven consecutive days.

When switching from a different birth control pill

When switching from another birth control pill, Gianvi 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, Gianvi should be started when the next application would have been due. When switching from an injection, Gianvi should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Gianvi 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 Gianvi, instruct the patient to continue taking Gianvi 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 Gianvi 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 Gianvi 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 Gianvi no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Gianvi 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 Gianvi for 7 consecutive days.

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.

Do not prescribe Gianvi to women who are known to have the following:

• Renal impairment • Adrenal insufficiency • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)] • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)] • Have cerebrovascular disease [see Warnings and Precautions (5.1)] • Have coronary artery disease [see Warnings and Precautions (5.1)] • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)] • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] • Have uncontrolled hypertension [see Warnings and Precautions (5.5)] • 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)]

Thromboembolic Disorders and Other Vascular Problems

Stop Gianvi 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 Gianvi 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]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 Gianvi at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Gianvi 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 Gianvi 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

Gianvi 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. Gianvi 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 Gianvi 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 Gianvi 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 Gianvi 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 Gianvi. 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.

Headache

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

Based on patient diaries from two contraceptive clinical trials of Gianvi, 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 Gianvi 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.

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)].

Depression

Women with a history of depression should be carefully observed and Gianvi 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.

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.

Oral Contraceptive Clinical Trial

In the primary contraceptive efficacy study of Gianvi (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 Gianvi in women 35 years of age or younger during cycles in which no other form of contraception was used.

Premenstrual Dysphoric Disorder Clinical Trials

Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the effectiveness of Gianvi 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 Gianvi 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 Gianvi 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 Gianvi 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 Gianvi 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 Gianvi, compared to 30.0 points in women taking placebo.

Acne Clinical Trials

In two multicenter, double-blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received Gianvi 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
	Gianvi	Placebo	Gianvi	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

Guide for Using Gianvi

WARNING TO WOMEN WHO SMOKE Do not use Gianvi if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

Birth control pills help to lower the chances of becoming pregnant when taken as directed. They do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

What Is Gianvi?

Gianvi is a birth control pill. It contains two female hormones, a synthetic estrogen called ethinyl estradiol and a progestin called drospirenone.

The progestin drospirenone may increase potassium. Therefore, you should not take Gianvi if you have kidney, liver or adrenal disease because this could cause serious heart and health problems. Other drugs may also increase potassium. If you are currently on daily, long-term treatment for a chronic condition with any of the medications below, you should consult your healthcare provider about whether Gianvi is right for you, and during the first month that you take Gianvi, you should have a blood test to check your potassium level.

• NSAIDs (ibuprofen [Motrin, Advil], naproxen [Aleve and others] when taken long-term and daily for treatment of arthritis or other problems) • Potassium-sparing diuretics (spironolactone and others) • Potassium supplementation • ACE inhibitors (Capoten, Vasotec, Zestril and others) • Angiotensin-II receptor antagonists (Cozaar, Diovan, Avapro and others) • Heparin • Aldosterone antagonists

Gianvi may also be taken to treat premenstrual dysphoric disorder (PMDD) if you choose to use the Pill for birth control. Unless you have already decided to use the Pill for birth control, you should not start Gianvi to treat your PMDD because there are other medical therapies for PMDD that do not have the same risks as the Pill. PMDD is a mood disorder related to the menstrual cycle. PMDD significantly interferes with work or school, or with usual social activities and relationships with others. Symptoms include markedly depressed mood, anxiety or tension, mood swings, 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 may include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly before menstruation starts and go away within a few days following the start of the period. Diagnosis of PMDD should be made by healthcare providers.

You should only use Gianvi for treatment of PMDD if you:

Have already decided to use oral contraceptives for birth control, and

Have been diagnosed with PMDD by your healthcare provider.

Gianvi has not been shown to be effective for the treatment of premenstrual syndrome (PMS), a less serious set of symptoms occurring before menstruation. If you or your healthcare provider believe you have PMS, you should take Gianvi only if you want to prevent pregnancy; and not for the treatment of PMS.

Gianvi may also be taken to treat moderate acne if all of the following are true:

• Your healthcare provider says it is safe for you to use Gianvi. • You are at least 14 years old. • You have started having menstrual periods. • You want to use a birth control pill to prevent pregnancy.

How Well Does Gianvi Work?

Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.

Based on the results of one clinical study, 1 to 2 women out of 100 women, may get pregnant during the first year they use Gianvi.

The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.

How Do I Take Gianvi?

1. Be sure to read these directions before you start taking your pills or anytime you are not sure what to do.

2. The right way to take the pill is to take one pill every day at the same time in the order directed on the package. Preferably, take the pill after the evening meal or at bedtime, with some liquid, as needed. Gianvi can be taken without regard to meals.

If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. See "WHAT TO DO IF YOU MISS PILLS” below.

3. Many women have spotting or light bleeding at unexpected times, or may feel sick to their stomach during the first 1-3 packs of pills.

If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it does not go away, check with your healthcare provider.

4. Missing pills can also cause spotting or light bleeding, even when you make up these missed pills.

On the days you take two pills, to make up for missed pills, you could also feel a little sick to your stomach.

5. If you have vomiting (within 3 to 4 hours after you take your pill), you should follow the instructions for "WHAT TO DO IF YOU MISS PILLS." If you have diarrhea or if you take certain medicines, including some antibiotics and some herbal products such as St. John's Wort, your pills may not work as well.

Use a back-up method (such as condoms and spermicides) until you check with your healthcare provider.

6. If you have trouble remembering to take the pill, talk to your healthcare provider about how to make pill-taking easier or about using another method of birth control.

7. If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

Before You Start Taking Your Pills

1. Decide What Time of Day You Want to Take Your Pill

It is important to take Gianvi in the order directed on the package at the same time every day, preferably after the evening meal or at bedtime, with some liquid, as needed. Gianvi can be taken without regard to meals.

2. Look at Your Pill Pack – It has 28 Pills

The Gianvi pill pack has 24 light pink pills (with hormones) to be taken for 24 days, followed by 4 white pills (without hormones) to be taken for the next four days.

3. Also look for:

a) Where on the pack to start taking pills,

b) In what order to take the pills (follow the arrows)

4. Be sure you have ready at all times (a) another kind of birth control (such as condoms and spermicides) to use as a back-up in case you miss pills, and (b) an extra, full pill pack.

When To Start the First Pack of Pills

You have a choice for which day to start taking your first pack of pills. Decide with your healthcare provider which is the best day for you. Pick a time of day which will be easy to remember.

Day 1 Start:

1. Take the first light pink pill of the pack during the first 24 hours of your period.

2. You will not need to use a back-up method of birth control, since you are starting the Pill at the beginning of your period. However, if you start Gianvi later than the first day of your period, you should use another method of birth control (such as a condom and spermicide) as a back-up method until you have taken 7 light pink pills.

Sunday Start:

1. Take the first light pink pill of the pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

2. Use another method of birth control (such as a condom and spermicide) as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). This also applies if you start Gianvi after having been pregnant, and you have not had a period since your pregnancy.

When You Switch From a Different Birth Control Pill

When switching from another birth control pill, Gianvi should be started on the same day that a new pack of the previous birth control pill would have been started.

When You Switch From Another Type of Birth Control Method

When switching from a transdermal patch or vaginal ring, Gianvi should be started when the next application would have been due. When switching from an injection, Gianvi should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Gianvi should be started on the day of removal.

What to Do During the Month

1. Take one pill at the same time every day until the pack is empty.

Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. When you finish a pack of pills, start the next pack on the day after your last white pill. Do not wait any days between packs.

What to Do if You Miss Pills

If you miss 1 light pink pill of your pack:

  1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take two pills in one day.   2. You do not need to use a back-up birth control method if you have sex.

If you miss 2 light pink pills in a row in Week 1 or Week 2 of your pack:

  1. Take two pills on the day you remember and two pills the next day.   2. Then take one pill a day until you finish the pack.   3. You could become pregnant if you have sex in the 7 days after you restart your pills. You must use another birth control method (such as a condom and spermicide) as a back-up for those 7 days.

If you miss 2 light pink pills in a row in Week 3 or Week 4 of your pack:

  1. If you are a Day 1 Starter:   Throw out the rest of the pill pack and start a new pack that same day.   If you are a Sunday Starter:   Keep taking one pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day.   2. You could become pregnant if you have sex in the 7 days after you restart your pills. You must use another birth control method (such as a condom and spermicide) as a back-up for those 7 days.   3. You may not have your period this month but this is expected. However, if you miss your period two months in a row, call your healthcare provider because you might be pregnant.

If you miss 3 or more light pink pills in a row during any week:

  1. If you are a Day 1 Starter:   Throw out the rest of the pill pack and start a new pack that same day.   If you are a Sunday Starter:   Keep taking 1 pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day.   2. You could become pregnant if you have sex in the 7 days after you restart your pills. You must use another birth control method (such as condoms and spermicides) as a back-up for those 7 days.   3. Call your healthcare provider if you miss your period, because you might be pregnant.

If you miss any of the 4 white pills in Week 4:

  Throw away the pills you missed.   Keep taking one pill each day until the pack is empty.   You do not need a back-up method.

Finally, if you are still not sure what to do about the pills you have missed:

  Use a back-up method (such as condoms and spermicides) anytime you have sex.   Contact your healthcare provider and continue taking one active light pink pill each day until otherwise directed.

WHO SHOULD NOT TAKE Gianvi?

 Your healthcare provider will not give you Gianvi if you:

• Ever had blood clots in your legs (deep vein thrombosis), lungs (pulmonary embolism), or eyes (retinal thrombosis)

• Ever had a stroke

• Ever had a heart attack

• Have certain heart valve problems or heart rhythm abnormalities that can cause blood clots to form in the heart

• Have an inherited problem with your blood that makes it clot more than normal

• Have high blood pressure that medicine can’t control

• Have diabetes with kidney, eye, nerve, or blood vessel damage

• Ever had certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision

• Ever had breast cancer or any cancer that is sensitive to female hormones

• Have liver disease, including liver tumors

• Have kidney disease

• Have adrenal disease

Also, do not take birth control pills if you:

• Smoke and are over 35 years old

• Are or suspect you are pregnant

Birth control pills may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy (also called cholestasis of pregnancy).

Tell your healthcare provider if you have ever had any of the above conditions (your healthcare provider can recommend another method of birth control).

What Else Should I Know about Taking Gianvi?

Birth control pills do not   protect you against any sexually transmitted disease, including HIV, the virus that causes AIDS.

Do not skip any pills, even if you do not have sex often.

If you miss a period, you could be pregnant. However, some women miss periods or have light periods on birth control pills, even when they are not pregnant. Contact your healthcare provider for advice if you:

• Think you are pregnant • Miss one period and have not taken your birth control pills every day • Miss two periods in a row

Birth control pills should not be taken during pregnancy. However, birth control pills taken by accident during pregnancy are not known to cause birth defects.

You should stop Gianvi at least four weeks before you have major surgery and not restart it until at least two weeks after the surgery due to an increased risk of blood clots.

If you are breastfeeding, consider another birth control method until you are ready to stop breastfeeding. Birth control pills that contain estrogen, like Gianvi, may decrease the amount of milk you make. A small amount of the pill's hormones pass into breast milk.

If you have vomiting or diarrhea, your birth control pills may not work as well. Use another birth control method, like condoms and a spermicide, until you check with your healthcare provider.

If you are scheduled for any laboratory tests, tell your doctor you are taking birth-control pills. Certain blood tests may be affected by birth-control pills.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Gianvi may affect the way other medicines work, and other medicines may affect how well Gianvi works. Know the medicines you take.

Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

What are the Most Serious Risks of Taking Birth Control Pills?

Like pregnancy, birth control pills increase the risk of serious blood clots (see following graph), especially in women who have other risk factors, such as smoking, obesity, or age greater than 35. This increased risk is highest when you first start taking birth control pills and when you restart the same or different birth control pills after not using them for a month or more. Women who use birth control pills with drospirenone (like Gianvi) may have a higher risk of getting a blood clot. Some studies reported that the risk of blood clots was higher for women who use birth control pills that contain drospirenone than for women who use birth control pills that do not contain drospirenone.

Talk with your healthcare provider about your risk of getting a blood clot before deciding which birth control pill is right for you.

It is possible to die or be permanently disabled from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious clots are blood clots in the:

• Legs (deep vein thrombosis or DVT) • Lungs (pulmonary embolus or PE) • Eyes (loss of eyesight) • Heart (heart attack) • Brain (stroke)

To put the risk of developing a blood clot into perspective: If 10,000 women who are not pregnant and do not use birth control pills are followed for one year, between 1 and 5 of these women will develop a blood clot. The figure below shows the likelihood of developing a serious blood clot for women who are not pregnant and do not use birth control pills, for women who use birth control pills, for pregnant women, and for women in the first 12 weeks after delivering a baby.

Likelihood of Developing a Serious Blood Clot

A few women who take birth control pills may get:

• High blood pressure • Gallbladder problems • Rare cancerous or noncancerous liver tumors

All of these events are uncommon in healthy women.

Call your healthcare provider right away if you have:

• Persistent leg pain • Sudden shortness of breath • Sudden blindness, partial or complete • Severe pain in your chest • Sudden, severe headache unlike your usual headaches • Weakness or numbness in an arm or leg, or trouble speaking • Yellowing of the skin or eyeballs

What are the Common Side Effects of Birth Control Pills?

The most common side effects of birth control pills are:

• Spotting or bleeding between menstrual periods • Nausea • Breast tenderness • Headache

These side effects are usually mild and usually disappear with time.

Less common side effects are:

• Acne • Less sexual desire • Bloating or fluid retention • Blotchy darkening of the skin, especially on the face • High blood sugar, especially in women who already have diabetes • High fat (cholesterol; triglyceride) levels in the blood • Depression, especially if you have had depression in the past. Call your healthcare provider immediately if you have any thoughts of harming yourself. • Problems tolerating contact lenses • Weight changes

This is not a complete list of possible side effects. Talk to your healthcare provider if you develop any side effects that concern you. You may report side effects to the FDA at 1-800-FDA-1088.

No serious problems have been reported from a birth control pill overdose, even when accidentally taken by children.

Do Birth Control Pills Cause Cancer?

Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones.

Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.

What Should I Know about My Period when Taking Gianvi?

Irregular vaginal bleeding or spotting may occur while you are taking Gianvi. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding, which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle, is unusually heavy, or lasts for more than a few days, call your healthcare provider.

Some women may not have a menstrual period but this should not be cause for alarm as long has you have taken the pills according to direction.

What if I Miss My Scheduled Period when Taking Gianvi?

It is not uncommon to miss your period. However, if you miss two periods in a row or miss one period when you have not taken your birth control pills according to directions, call your healthcare provider. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider checks you to find out if you are pregnant. Stop taking Gianvi if you are pregnant.

What If I Want to Become Pregnant?

You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.

General Advice about Gianvi

Your healthcare provider prescribed Gianvi for you. Please do not share Gianvi with anyone else. Keep Gianvi out of the reach of children.

If you have concerns or questions, ask your healthcare provider. You may also ask your healthcare provider for a more detailed label written for medical professionals.

Revised: June 2015

Manufactured For:

Bayer HealthCare Pharmaceuticals Inc.

Whippany, NJ 07981

Manufactured in Germany

Distributed by:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

© 2012 Bayer HealthCare Pharmaceuticals Inc. All Rights Reserved.

NDC 0093-5423-62

3 Units

28 DAY REGIMEN

Gianvi®

(drospirenone and ethinyl estradiol tablets)

3 mg /0.02 mg

Rx only

THIS PRODUCT (LIKE ALL ORAL CONTRACEPTIVES) IS INTENDED TO PREVENT PREGNANCY. IT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES

Gianvi  drospirenone and ethinyl estradiol kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0093-5423

Packaging # Item Code Package Description 1 NDC:0093-5423-62 3 BLISTER PACK in 1 PACKAGE 1 NDC:0093-5423-28 1 KIT in 1 BLISTER PACK 2 NDC:0093-5423-58 3 BLISTER PACK in 1 PACKAGE 2 NDC:0093-5423-28 1 KIT in 1 BLISTER PACK

Quantity of Parts Part # Package Quantity Total Product Quantity Part 1 24  Part 2 4

Part 1 of 2 Gianvi  drospirenone and ethinyl estradiol 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 0.02 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   FERRIC OXIDE RED   HYPROMELLOSES   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   TALC   TITANIUM DIOXIDE

Product Characteristics Color PINK Score no score Shape ROUND Size 6mm Flavor Imprint Code Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021676 03/30/2011

Part 2 of 2 INERT  inert tablet, film coated

Product Information Route of Administration ORAL DEA Schedule

Inactive Ingredients Ingredient Name Strength HYPROMELLOSES   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   TALC   TITANIUM DIOXIDE   CELLULOSE, MICROCRYSTALLINE

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021676 03/30/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021676 03/30/2011

Labeler - Teva Pharmaceuticals USA Inc (001627975)

Registrant - Bayer HealthCare Pharmaceuticals Inc. (005436809)

Establishment
Name	Address	ID/FEI	Operations
Bayer Weimar GmbH und Co. KG		331485631	MANUFACTURE(0093-5423)

Establishment
Name	Address	ID/FEI	Operations
Bayer Pharma AG		315015982	PACK(0093-5423)

Revised: 11/2016   Teva Pharmaceuticals USA Inc

Applies to drospirenone / ethinyl estradiol: oral tablet

Along with its needed effects, drospirenone / ethinyl estradiol may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking drospirenone / ethinyl estradiol:

More common

• Breast pain or tenderness
• headache, severe and throbbing
• heavy non-menstrual vaginal bleeding
• irregular menstrual periods
• nausea
• normal menstrual bleeding occurring earlier, possibly lasting longer than expected

Less common

• Longer or heavier menstrual periods
• unusual tiredness or weakness
• vomiting

Incidence not known

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• difficulty with breathing
• dizziness
• fever
• headache
• itching
• loss of appetite
• pain in the chest, groin, or legs, especially the calves
• rash
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• sudden, unexplained shortness of breath
• unpleasant breath odor
• unusual tiredness or weakness
• vision changes
• vomiting of blood
• yellow eyes or skin

Some side effects of drospirenone / ethinyl estradiol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Crying
• decreased interest in sexual intercourse
• delusions of persecution, mistrust, suspiciousness, and/or combativeness
• false or unusual sense of well-being
• inability to have or keep an erection
• irritability
• loss in sexual ability, desire, drive, or performance
• mental depression
• quick to react or overreact emotionally
• rapidly changing moods
• weight gain