This information is not for clinical use. These highlights do not include all the information needed to use Nikki safely and effectively. Before taking Nikki please consult with your doctor. See full prescribing information for Nikki.
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. Women over 35 years old who smoke should not use Nikki (4). Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. (4) WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [see CONTRAINDICATIONS (4) ].
Indications And Usage
Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg is an estrogen/progestin COC, indicated for use by women to: Prevent pregnancy. (1.1) Treat symptoms of premenstrual dysphoric disorder (PMDD) for women who choose to use an oral contraceptive for contraception. (1.2) Treat moderate acne for women at least 14 years old only if the patient desires an oral contraceptive for birth control. (1.3) 1.1 Oral Contraceptive Nikki™ (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg is indicated for use by women to prevent pregnancy. 1.2 Premenstrual Dysphoric Disorder (PMDD) Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg is also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive as their method of contraception. The effectiveness of Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg for PMDD when used for more than three menstrual cycles has not been evaluated. The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders. Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg has not been evaluated for the treatment of premenstrual syndrome (PMS). 1.3 Acne Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg 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. Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
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Dosage Forms And Strengths
Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg consists of 28 film-coated, round, biconvex tablets in the following order (3): 24 pink tablets, each containing 3 mg drospirenone (DRSP) and 0.02 mg ethinyl estradiol (EE) 4 white to off-white inert tablets Nikki (drospirenone and ethinyl estradiol tablets USP), 3 mg/0.02 mg are available in wallet packs. Each wallet pack (28 round, biconvex film-coated tablets) contains in the following order: 24 pink tablets each containing 3 mg drospirenone (DRSP) and 0.02 mg ethinyl estradiol (EE) 4 white to off-white inert tablets
Renal impairment (4) Adrenal insufficiency (4) A high risk of arterial or venous thrombotic diseases (4) Undiagnosed abnormal uterine bleeding (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Pregnancy (4) Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir (4) Do not prescribe Nikki 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: о Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ] о Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS (5.1) ] о Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS (5.1) ] о Have coronary artery disease [see WARNINGS AND PRECAUTIONS (5.1) ] о 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) ] о Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1) ] о Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.5) ] о Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS (5.7) ] о Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see WARNINGS AND PRECAUTIONS (5.8) ] Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS (5.9) ] Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see WARNINGS AND PRECAUTIONS (5.3) ] Liver tumors, benign or malignant, or liver disease [see WARNINGS AND PRECAUTIONS (5.4) and USE IN SPECIFIC POPULATIONS (8.7) ] Pregnancy, because there is no reason to use COCs during pregnancy [see WARNINGS AND PRECAUTIONS (5.10) and USE IN SPECIFIC POPULATIONS (8.1) ] Use of Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations [see WARNINGS AND PRECAUTIONS (5.5) and DRUG INTERACTIONS (7.3) ].
Warning and Cautions
Vascular risks : Stop Nikki if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1) COCs containing DRSP may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing levonorgestrel or some other progestins. Before initiating Nikki in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. (5.1) Hyperkalemia : DRSP has anti-mineralocorticoid activity. Do not use in patients predisposed to hyperkalemia. Check serum potassium concentration during the first treatment cycle in women on long-term treatment with medications that may increase serum potassium concentration. (5.2, 7.1, 7.2) Liver disease : Discontinue Nikki if jaundice occurs. (5.4) High blood pressure : Do not prescribe Nikki for women with uncontrolled hypertension or hypertension with vascular disease. (5.5) Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Nikki. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7) Headache : Evaluate significant change in headaches and discontinue Nikki if indicated. (5.8) Uterine bleeding : Evaluate irregular bleeding or amenorrhea. (5.9) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Nikki 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 Nikki in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see CONTRAINDICATIONS (4) ]. A number of studies have compared the risk of VTE for users of Yasmin (which contains 0.03 mg of EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 1. Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Yasmin Compared to Users of Oral Contraceptives that Contain Other Progestins Epidemiologic Study ( Author , Year of Publication ) Population Studied Comparator Product ( all are low - dose COCs ; with ≤ 0 . 04 mg of EE ) Hazard Ratio ( HR ) ( 95 % CI ) i3 Ingenix (Seeger 2007) Initiators, including new users“New users” - no use of combination hormonal contraception for at least the prior 6 months All COCs available in the US during the conduct of the studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate HR: 0.9 (0.5 to 1.6) EURAS (Dinger 2007) All COCs available in Europe during the conduct of the studyIncludes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone HR: 0.9 (0.6 to 1.4) Initiators, including new users Levonorgestrel/EE HR: 1.0 (0.6 to 1.8) “FDA-funded study” (2011) New users Other COCs available during the course of the studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel HR: 1.8 (1.3 to 2.4) Levonorgestrel/0.03 mg EE HR: 1.6 (1.1 to 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 to 2.1) Levonorgestrel/0.03 mg EE HR: 1.5 (1.2 to 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 reanalysis [ 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 Nikki at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Nikki 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 Nikki if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [see ADVERSE REACTIONS (6) ] 5.2 Hyperkalemia Nikki 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. Nikki is contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDS. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see CLINICAL PHARMACOLOGY (12.3)]. 5.3 Carcinoma of the Breasts and Reproductive Organs Women who currently have or have had breast cancer should not use Nikki because breast cancer is a hormonally-sensitive tumor. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 5.4 Liver Disease Discontinue Nikki if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.5 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Nikki prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS (4)]. Nikki can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.6 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Nikki if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.7 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.8 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Nikki. COCs may decrease glucose intolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COC's. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.9 Headache If a woman taking Nikki develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Nikki if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.10 Bleeding Irregularities Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Based on patient diaries from two contraceptive clinical trials of Nikki, 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 Nikki may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from contraception trials for up to 13 cycles, 6 to 10% of women experienced cycles with no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 5.11 COC Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see USE IN SPECIFIC POPULATIONS (8.1) ] 5.12 Depression Women with a history of depression should be carefully observed and Nikki discontinued if depression recurs to a serious degree. 5.13 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see DRUG INTERACTIONS (7.2) ]. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. 5.14 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.15 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. Fig-1 Fig-2
The most frequent adverse reactions (> 2%) in contraception and acne clinical trials were: headache/migraine (6.7%), menstrual irregularities (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4.0%) and mood changes (2.2%). (6.1) The most frequent adverse reactions (≥ 2%) in PMDD clinical trials were: menstrual irregularities (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ] Vascular events [see WARNINGS AND PRECAUTIONS (5.1) ] Liver disease [see WARNINGS AND PRECAUTIONS (5.4) ] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Contraception and Acne Clinical Trials The data provided reflect the experience with the use of Nikki in the adequate and well-controlled studies for contraception (N=1,056) and for moderate acne vulgaris (N=536). For contraception, a Phase 3, multicenter, multinational, open-label study was conducted to evaluate safety and efficacy up to one year in 1,027 women aged 17 to 36 who took at least one dose of Nikki. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of Nikki on carbohydrate metabolism, lipids and hemostasis in 29 women aged 18 to 35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14 to 45 with moderate acne vulgaris who took at least one dose of Nikki, evaluated the safety and efficacy during up to 6 cycles. The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (> 2% of users) were: headache/migraine (6.7%), menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (mood swings, depression, depressed mood and affect lability) (2.2%). PMDD Clinical Trials Safety data from trials for the indication of PMDD are reported separately due to differences in study design and setting in the Contraception and Acne studies as compared to the PMDD clinical program. Two (one parallel and one crossover designed) multicenter, double-blind, randomized, placebo controlled trials for the secondary indication of treating the symptoms of PMDD evaluated safety and efficacy of Nikki during up to 3 cycles among 285 women aged 18 to 42, diagnosed with PMDD and who took at least one dose of Nikki. Common adverse reactions (≥ 2% of users) were: menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). Adverse Reactions (≥1%) Leading to Study Discontinuation Contraception Clinical Trials: Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1.0%). Acne Clinical Trials: Of 536 women, 5.4% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was menstrual irregularities (including menometrorrhagia, menorrhagia, metrorrhagia and vaginal hemorrhage) (2.2%). PMDD Clinical Trials: Of 285 women, 11.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were: nausea/vomiting (4.6%), menstrual irregularity (including vaginal hemorrhage, menorrhagia, menstrual disorder, menstruation irregular and metrorrhagia) (4.2%), fatigue (1.8%), breast tenderness (1.4%), depression (1.4%), headache (1.1%), and irritability (1.1%). Serious Adverse Reactions Contraception Clinical Trials: migraine and cervical dysplasia Acne Clinical Trials: none reported in the clinical trials PMDD Clinical Trials: cervical dysplasia 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Nikki. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are grouped into System Organ Classes, and ordered by frequency. Vascular Disorders Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, retinal thrombosis, myocardial infarction and stroke), hypertension (including hypertensive crisis) Hepatobiliary Disorders Gallbladder disease, liver function disturbances, liver tumors Immune System Disorders Hypersensitivity (including anaphylactic reaction) Metabolism and Nutrition Disorders Hyperkalemia, hypertriglyceridemia, changes in glucose tolerance or effect on peripheral insulin resistance (including diabetes mellitus) Skin and Subcutaneous Tissue Disorders Chloasma, angioedema, erythema nodosum, erythema multiforme. Gastrointestinal Disorders Inflammatory bowel disease Musculoskeletal and Connective Tissue Disorders Systemic lupus erythematosus
Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs (7.1) Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Diminishing the Efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John's wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing the Plasma Concentrations of COCs Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see WARNINGS AND PRECAUTIONS (5.2) and CLINICAL PHARMACOLOGY (12.3)]. Human immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. COCs Increasing the Plasma Concentrations of CYP450 Enzymes: In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations [see CLINICAL PHARMACOLOGY (12.3) ]. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Potential to Increase Serum Potassium Concentration There is a potential for an increase in serum potassium concentration in women taking Nikki with other drugs that may increase serum potassium concentration [see WARNING AND PRECAUTION (5.2) and CLINICAL PHARMACOLOGY (12.3) ]. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Nikki with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS (5.5)]. 7.4 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. [see WARNINGS AND PRECAUTIONS (5.12) and(7.2) .]
Use In Specific Populations
Nursing Mothers: Not recommended; can decrease milk production. (8.3) 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed may start COCs no earlier than four weeks postpartum. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. After oral administration of 3 mg DRSP/0.03 mg EE (Yasmin) tablets, about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 0.003 mg DRSP in an infant. 8.4 Pediatric Use Safety and efficacy of Nikki have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Nikki has not been studied in postmenopausal women and is not indicated in this population. 8.6 Patients with Renal Impairment Nikki is contraindicated in patients with renal impairment [see CONTRAINDICATIONS (4) and WARNING AND PRECAUTIONS (5.2) ]. In subjects with creatinine clearance (CLcr) of 50 to 79 mL/min, serum DRSP levels were comparable to those in a control group with CLcr ≥80 mL/min. In subjects with CLcr of 30 to 49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs [see CLINICAL PHARMACOLOGY (12.3) ]. 8.7 Patients with Hepatic Impairment Nikki is contraindicated in patients with hepatic disease [see CONTRAINDICATIONS (4) and WARNING AND PRECAUTIONS (5.4) ]. 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. Nikki has not been studied in women with severe hepatic impairment. 8.8 Race No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see CLINICAL PHARMACOLOGY (12.3) ].