DailyMed Label: GIANVI

DailyMed Label: GIANVI

2010

DailyMed Prescription

GIANVI

drospirenone and ethinyl estradiol

Physicians Total Care, Inc.

NDC: 54868-6162

NDC: 54868-6162

Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg provides an oral contraceptive regimen consisting of 24 active film-coated tablets each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol and 4 inert film-coated tablets. Other ingredients are anhydrous lactose, corn starch, crospovidone, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch and titanium dioxide. The inert tablets contain anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose. 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. Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound. The structural formulas are as follows: Drospirenone C 24 H 30 O 3 Molecular Weight: 366.5 Ethinyl Estradiol C 20 H 24 O 2 Molecular Weight: 296.4 Structural Formula EE Structural Formula

Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive. Oral contraceptives are highly effective. Table II lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization and contraceptive implants and IUDs, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Gianvi™ (drospirenone and ethinyl estradiol tablets) 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. Gianvi™ (drospirenone and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. TABLE II: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR: UNITED STATES.     % of Women Experiencing an Unintended Pregnancy Within the First Year of Use % of Women Continuing Use at One Year Method (1) Typical Use  (2) Perfect Use  (3) (4) Chance  85 85 40 Spermicides  26 6 63 Periodic abstinence 25 Calendar 9 Ovulation method 3 Sympto-thermal 2 Post-ovulation 1 Withdrawal 19 4 Cap With spermicidal cream or jelly. Parous women 40 26 42 Nulliparous women 20 9 56 Sponge Parous women 40 20 42 Nulliparous women 20 9 56 Diaphragm 20 6 56 Condom  Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 progestin only 0.5 combined 0.1 IUD Progesterone T 2 1.5 81 Copper T 380A 0.8 0.6 78 Lng 20 0.1 0.1 81 Depo Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.1 100 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.  Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.  Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D, Contraceptive Technology: Seventeenth Revised Edition . New York NY: Irvington Publishers, 1998. In the primary contraceptive efficacy study of drospirenone and ethinyl estradiol tablets (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 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 drospirenone and ethinyl estradiol tablets in women 35 years of age or younger during cycles in which no other form of contraception was used. In two multicenter, double blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received drospirenone and ethinyl estradiol tablets 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 III: TABLE III: EFFICACY RESULTS FOR ACNE TRIALS* * Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population Study 1 Study 2 Drospirenone and Ethinyl Estradiol Tablets N=228 Placebo N=230 Drospirenone and Ethinyl Estradiol Tablets N=218 Placebo 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%)

To achieve maximum contraceptive effectiveness, Gianvi tablets must be taken exactly as directed at intervals not exceeding 24 hours. Gianvi tablets consist of 24 pink active tablets of a monophasic combined hormonal preparation plus 4 inert white tablets. The dosage of Gianvi tablets is one pink tablet daily for 24 consecutive days followed by 4 white inert tablets per menstrual cycle. A patient should begin to take Gianvi tablets 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). During the first cycle of Gianvi tablet use, the patient should be instructed to take one pink Gianvi tablet daily, beginning on Day one (1) of her menstrual cycle. (The first day of menstruation is Day one.) She should take one pink Gianvi tablet daily for 24 consecutive days, followed by one white inert tablet daily on menstrual cycle days 25 through 28. It is recommended that Gianvi tablets be taken at the same time each day, preferably after the evening meal or at bedtime. Gianvi tablets can be taken without regard to meals. If Gianvi tablets are first taken later than the first day of the menstrual cycle, Gianvi tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. The possibility of ovulation and conception prior to initiation of medication should be considered. During the first cycle of Gianvi tablet use, the patient should be instructed to take one pink Gianvi tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink Gianvi tablet daily for 24 consecutive days, followed by one white inert tablet daily on menstrual cycle days 25 through 28. It is recommended that Gianvi tablets be taken at the same time each day, preferably after the evening meal or at bedtime. Gianvi tablets can be taken without regard to meals. Gianvi tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. 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 tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her 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 tablets 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 pink Gianvi tablet daily for seven consecutive days. When switching from another oral contraceptive, Gianvi tablets should be started on the same day that a new pack of the previous oral contraceptive would have been started. Withdrawal bleeding usually occurs within 3 days following the last pink tablet. If spotting or breakthrough bleeding occurs while taking Gianvi, the patient should be instructed to continue taking her Gianvi tablets as instructed and by the regimen described above. She should be instructed that this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient should be advised to consult her physician. Although the occurrence of pregnancy is low if Gianvi tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. 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), the possibility of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraceptives should be discontinued if pregnancy is confirmed. The risk of pregnancy increases with each active pink tablet missed. For additional patient instructions regarding missed pills, see the “WHAT TO DO IF YOU MISS PILLS” section in the DETAILED PATIENT LABELING, which follows. 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 pink tablets again on the proper day. In the nonlactating mother, Gianvi tablets may be initiated 4 to 6 weeks postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS concerning thromboembolic disease.) The timing and initiation of dosing with Gianvi tablets in women with acne should follow the guideline for use of Gianvi tablets as an oral contraceptive. The 28-day dosage regimen for Gianvi tablets for treating facial acne consists of one active tablet daily for 24 consecutive days followed by one inert tablet daily for 4 days. After 28 tablets are taken, a new course is started the next day.

Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in women who have the following: Renal insufficiency Hepatic dysfunction Adrenal insufficiency Thrombophlebitis or thromboembolic disorders A past history of deep-vein thrombophlebitis or thromboembolic disorders Cerebral-vascular or coronary-artery disease (current or history) Valvular heart disease with thrombogenic complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Known or suspected pregnancy Liver tumor (benign or malignant) or active liver disease Heavy smoking (≥ 15 cigarettes per day) and over age 35 Hypersensitivity to any component of this product

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS 1d.) In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis. If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. Rifampin: Metabolism of ethinyl estradiol and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin. Minocycline: Minocycline-related changes in estradiol, progesterone, FSH and LH plasma levels, breakthrough bleeding, or contraceptive failure cannot be ruled out. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of ethinyl estradiol and/or some progestins, which could result in a reduction of contraceptive effectiveness. Antibiotics: Pregnancy while taking combined hormonal contraceptives has been reported when the combined hormonal contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects of antibiotics (other than rifampin-see above) on plasma concentrations of synthetic steroids. See also separate discussion on minocycline (above). Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%,  respectively. St. John’s Wort: Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives and emergency contraceptive pills. This may also result in breakthrough bleeding. Other: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic estrogens, possibly by inhibition of conjugation. Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo . Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of 3 mg DRSP/day. There is a potential for an increase in serum potassium in women taking drospirenone and ethinyl estradiol tablets with other drugs (see BOLDED WARNING). Of note, occasional or chronic use of NSAID medication was not restricted in any of the clinical trials with 3 mg DRSP/0.03 mg EE tablets. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium C max and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Combined oral contraceptives containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives. Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. Other binding proteins may be elevated in serum. Sex-hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. Triglycerides may be increased. Glucose tolerance may be decreased. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day drospirenone alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of drospirenone and ethinyl estradiol, 0.1 to 2 times the exposure (AUC of drospirenone) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day drospirenone and ethinyl estradiol, 0.8 to 10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone. Drospirenone was not mutagenic in a number of in vitro (Ames, Chinese Hamster Lung gene mutation and chromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA. (See WARNINGS). Estrogens and progestins should not be used during pregnancy. Fourteen pregnancies that occurred during exposure with 3 mg DRSP/0.03 mg EE tablets in utero (none with more than a single cycle of exposure) have been identified. One infant was born with esophageal atresia. A causal association with the 3 mg DRSP/0.03 mg EE tablet is unknown. Twelve pregnancies that occurred with drospirenone and ethinyl estradiol tablets exposure in utero (none with more than a single cycle of exposure) have been identified. There were no known cases of congenital anomalies. A teratology study in pregnant rats given drospirenone orally at doses of 5, 15 and 45 mg/kg/day, 6 to 50 times the human exposure based on AUC of drospirenone, resulted in an increased number of fetuses with delayed ossification of bones of the feet in the two higher doses. A similar study in rabbits dosed orally with 1, 30 and 100 mg/kg/day drospirenone, 2 to 27 times the human exposure, resulted in an increase in fetal loss and retardation of fetal development (delayed ossification of small bones, multiple fusions of ribs) at the high dose only. When drospirenone was administered with ethinyl estradiol (100:1) during late pregnancy (the period of genital development) at doses of 5, 15 and 45 mg/kg, there was a dose dependent increase in feminization of male rat fetuses. In a study in 36 cynomolgous monkeys, no teratogenic or feminization effects were observed with orally administered drospirenone and ethinyl estradiol (100:1) at doses up to 10 mg/kg/day drospirenone, 30 times the human exposure. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. After oral administration of 3 mg DRSP/0.03 mg EE tablets about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg drospirenone in an infant. Safety and efficacy of drospirenone and ethinyl estradiol tablets has been established in women of reproductive age. Safety and efficacy are expected to be the same for post-pubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. See “Patient Labeling” printed below.

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS).

Rifampin: Metabolism of ethinyl estradiol and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin. Minocycline: Minocycline-related changes in estradiol, progesterone, FSH and LH plasma levels, breakthrough bleeding, or contraceptive failure cannot be ruled out. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of ethinyl estradiol and/or some progestins, which could result in a reduction of contraceptive effectiveness. Antibiotics: Pregnancy while taking combined hormonal contraceptives has been reported when the combined hormonal contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects of antibiotics (other than rifampin-see above) on plasma concentrations of synthetic steroids. See also separate discussion on minocycline (above). Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%,  respectively. St. John’s Wort: Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives and emergency contraceptive pills. This may also result in breakthrough bleeding. Other: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic estrogens, possibly by inhibition of conjugation. Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo . Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of 3 mg DRSP/day. There is a potential for an increase in serum potassium in women taking drospirenone and ethinyl estradiol tablets with other drugs (see BOLDED WARNING). Of note, occasional or chronic use of NSAID medication was not restricted in any of the clinical trials with 3 mg DRSP/0.03 mg EE tablets. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium C max and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Combined oral contraceptives containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg – 28-Day Regimen are available in 1 blister pack  ( NDC 54868-6162-0 ). Each blister card contains 24 active pink, round, unscored, film-coated tablets, debossed with stylized b on one side and 257 on the other side, each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol, and 4 inert white, round, unscored tablets debossed with stylized b on one side and 208 on the other side. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation). Drospirenone is a spironolactone analogue with antimineralocorticoid activity . Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity. Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of ethinyl estradiol and drospirenone increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of drospirenone on acne is not known. The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism.  The absolute bioavailability of drospirenone and ethinyl estradiol tablets,  which is a combination tablet of drospirenone and ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1 to 2 hours after administration of drospirenone and ethinyl estradiol tablets. The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol tablets, steady-state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum C max and AUC (0-24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol tablets  (see Table I). For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol tablets  serum C max and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table I). TABLE I: TABLE OF PHARMACOKINETIC PARAMETERS OF DROSPIRENONE AND ETHINYL ESTRADIOL TABLETS (Drospirenone 3 mg and Ethinyl Estradiol 0.02 mg) Drospirenone Cycle / Day No. of Subjects C max   geometric mean (geometric coefficient of variation)   (ng/mL) T max median (range) (h) AUC (0-24h) (ng • h/mL) t 1/2 (h) 1/1 23 38.4 (25) 1.5 (1 to 2) 268 (19) NA 1/21 23 70.3 (15) 1.5 (1 to 2) 763 (17) 30.8 (22) Ethinyl Estradiol Cycle / Day No. of Subjects C max (pg/mL) T max (h) AUC (0-24h) (pg • h/mL) t 1/2 (h) 1/1 23 32.8 (45) 1.5 (1 to 2) 108 (52) NA 1/21 23 45.1 (35) 1.5 (1 to 2) 220 (57) NA NA = Not available The rate of absorption of DRSP and EE following single administration of a formulation similar to drospirenone and ethinyl estradiol tablets was slower under fed (high fat meal) conditions with the serum C max being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions. DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels).  EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4). EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20% of the metabolites were excreted as glucuronides and sulfates. For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation. No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 20 to 35) when drospirenone and ethinyl estradiol tablets were administered daily for 21 days. Other ethnic groups have not been studied. Drospirenone and ethinyl estradiol tablets are contraindicated in patients with hepatic dysfunction (see CONTRAINDICATIONS and BOLDED WARNING).  The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Drospirenone and ethinyl estradiol tablets have not been studied in women with severe hepatic impairment. Drospirenone and ethinyl estradiol tablets are contraindicated in patients with renal insufficiency (see CONTRAINDICATIONS and BOLDED WARNING). The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 to 65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50 to 80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30 to 50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Gianvi™ (drospirenone and ethinyl estradiol tablets) containing the following: 24 pink - “active” tablets 4 white – “inert” tablets 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 tablets) is different from other birth control pills because it contains the progestin drospirenone. Drospirenone may increase potassium. Therefore, you should not take drospirenone and ethinyl estradiol tablets 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 drospirenone and ethinyl estradiol tablets is right for you, and during the first month that you take drospirenone and ethinyl estradiol tablets, you should have a blood test to check your potassium level. NSAIDs (ibuprofen [Motrin*, Advil*], naprosyn [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™ (drospirenone and ethinyl estradiol tablets) is an oral contraceptive, also known as a “birth control pill” or “the pill.” Oral contraceptives are taken to prevent pregnancy, and, when taken correctly without missing any pills, have a failure rate of approximately 1% per year (1 pregnancy per 100 women per year of use). The typical failure rate in pill users is approximately 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. Forgetting to take pills considerably increases the chances of pregnancy. Gianvi™ (drospirenone and ethinyl estradiol tablets) may also be taken to treat moderate acne in women who are able to and wish to use the pill for birth control. Any woman who needs contraception (birth control) and chooses to use an oral contraceptive should understand the benefits and risks of using the pill. This leaflet will give you much of the information you will need to help you decide if you should use the pill for contraception and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups while you are on the pill. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you: smoke have high blood pressure, diabetes, high cholesterol, or are obese have or have had clotting disorders, heart attack, stroke, angina pectoris (severe chest pains), cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), blockage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. Women with migraine headaches also may be at increased risk of stroke when taking the pill. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. 4. Cancer of the breast. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of getting breast cancer begin to go back down. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use the pill. However, this finding may be related to factors other than the use of the pill. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants, some antibiotics and some herbal products such as St. John’s Wort, may decrease oral contraceptive effectiveness. Taking the pill may provide some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is appropriate to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information booklet gives you further information, which you should read and discuss with your healthcare provider. This product (like all oral contraceptives) is intended to prevent pregnancy. Oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENTS HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. 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. GIANVI™ TABLETS 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, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 TO 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 or 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 tablets at about the same time every day. Gianvi tablets can be taken without regard to meals. 2. LOOK AT YOUR PILL PACK: – IT HAS 28 PILLS: The Gianvi tablets -pill pack has 24 pink “active” pills (with hormones) to be taken for 24 days, followed by 4 white “reminder” pills (without hormones) to be taken for four days. 3. ALSO FIND: 1) Where on the pack to start taking pills, 2) In what order to take the pills (follow the arrows) 3) The week numbers are shown on the blister card picture below 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicides) to use as a back-up in case you miss pills. 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 pink “active” pill of the first 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. SUNDAY START: 1. Take the first pink “active” pill of the first 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 condoms or spermicides) as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). WHEN YOU SWITCH FROM A DIFFERENT BIRTH CONTROL PILL When switching from another birth control pill, Gianvi tablets should be started on the same day that a new pack of the previous birth control pills would have been started. 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 “reminder” pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 pink “active” pill in Week 1 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 pink “active” 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 condoms or spermicides) as a back-up for those 7 days. If you MISS 2 pink “active” 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 condoms or 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 pink “active” 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 or spermicides) 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 ANY of the 4 white “reminder” 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 of birth control. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD (such as condoms or spermicides) anytime you have sex. KEEP TAKING ONE ACTIVE PINK PILL EACH DAY until you can contact your healthcare provider. For additional information see “Detailed Patient Labeling” blister card

NDC 54868-6162-0 Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg Contents : One dispenser of 28 tablets, 24 pink tablets and 4 white inert tablets. Each pink tablet (24) contains 3 mg drospirenone and 0.02 mg ethinyl estradiol. Each white tablet (4) contains inert ingredients. 28 DAY REGIMEN 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. TEVA SHAPING WOMEN'S HEALTH ® Gianvi (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg Pouch