impasse Rajani Generic Name: drospirenone, ethinyl estradiol, levomefolate calcium Dosage Form: tablets Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings User Reviews Drug Images Support Group Q & A Pricing & Coupons 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 for Rajani Oral Contraceptive Rajani is indicated for use by women to prevent pregnancy. Premenstrual Dysphoric Disorder (PMDD) Rajani 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 Rajani 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. Rajani has not been evaluated for the treatment of premenstrual syndrome (PMS). Acne Rajani 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. Rajani should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. Folate Supplementation Rajani is indicated in women who choose to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product. Slideshow Depression, Risk of Suicide, and Treatment Options Rajani Dosage and Administration How to Take Rajani 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, Rajani must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered. How to Start Rajani Instruct the patient to begin taking Rajani 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 Rajani use, instruct the patient to take one white Rajani tablet daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one white Rajani tablet daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Rajani 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. Rajani can be taken without regard to meals. If Rajani is first taken later than the first day of the menstrual cycle, Rajani 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 Rajani use, instruct the patient to take one white Rajani tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white Rajani tablet daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Rajani 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. Rajani can be taken without regard to meals. Rajani 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 Rajani on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her white tablets on the next day after ingestion of the last light orange folate tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Rajani is started later than the day following administration of the last light orange tablet, the patient should use another method of contraception until she has taken a white Rajani tablet daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, Rajani 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, Rajani should be started when the next application would have been due. When switching from an injection, Rajani should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Rajani should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last white tablet. If spotting or breakthrough bleeding occurs while taking Rajani, instruct the patient to continue taking Rajani 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 Rajani 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 Rajani if pregnancy is confirmed. The risk of pregnancy increases with each active white 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 light orange tablets, she should still be protected against pregnancy provided she begins taking a new cycle of white tablets on the proper day. For postpartum women who do not breastfeed or after a second trimester abortion, start Rajani no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Rajani 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 Rajani 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 to 4 hours after tablet-taking, this can be regarded as a missed tablet. Folate Supplementation The U.S. Preventive Services Task Force recommends that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily. 1 Consider other folate supplementation that a woman may be taking before prescribing Rajani. Ensure that folate supplementation is maintained if a woman discontinues Rajani due to pregnancy. Dosage Forms and Strengths Rajani (drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets) is available in blister packs. Each blister pack (28 film-coated tablets) contains in the following order: 24 white tablets each containing 3 mg drospirenone (DRSP), 0.02 mg ethinyl estradiol (EE) as betadex clathrate and 0.451 mg levomefolate calcium 4 light orange tablets each containing 0.451 mg levomefolate calcium Contraindications Do not prescribe Rajani 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)] Warnings and Precautions Thromboembolic Disorders and Other Vascular Problems Stop Rajani 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 Rajani 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 a All COCs available in the US during the conduct of the study b HR: 0.9 (0.5-1.6) EURAS (Dinger 2007) Initiators, including new users a All COCs available in Europe during the conduct of the study c Levonorgestrel/EE HR: 0.9 (0.6-1.4) HR: 1.0 (0.6-1.8) "FDA-funded study (2011) New users a Other COCs available during the course of the study d 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 d HR: 1.7 (1.4-2.1) Levonorgestrel/0.03 mg EE HR: 1.5 (1.2-1.8) a) New users - no use of combination hormonal contraception for at least the prior 6 months b) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate c) Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone d) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel 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 less than 1 indicates a lower risk of VTE for DRSP, greater than 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] 2 , EURAS (European Active Surveillance Study) [Dinger 2007] 3 , LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011] 4 , Danish [Lidegaard 2009] 5 , Danish re-analysis [ Lidegaard 2011] 6 , MEGA study [van Hylckama Vlieg 2009] 7 , German Case-Control study [Dinger 2010] 8 , PharMetrics [Jick 2011] 9 , GPRD study [Parkin 2011] 10 ) Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period (see Figure 2). The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 2: Likelihood of Developing a VTE If feasible, stop Rajani at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Rajani 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 (greater than 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 Rajani 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 Rajani contains 3 mg of the progestin DRSP, which has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Rajani 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 Rajani 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 Rajani 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 (greater than 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 Rajani 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 Rajani. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Headache If a woman taking Rajani develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Rajani 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. Data for Rajani show the average number of episodes of bleeding per reference period (90 days) was 3.2 in Cycles 4 to 6. The average number of bleeding and/or spotting days with Rajani was 15.1 days. The intensity of bleeding for Rajani based on the ratio of spotting-only days versus total bleeding and/or spotting days was 5.2/15.1 days. Based on patient diaries from two contraceptive clinical trials of *YAZ, 8 to 25% of women experienced unscheduled bleeding per 28-day cycle. A total of 12 subjects out of 1,056 (1.1%) discontinued *YAZ due to menstrual disorders including intermenstrual bleeding, menorrhagia, and metrorrhagia. Women who use Rajani may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from*YAZ 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. Discontinue Rajani if pregnancy is confirmed and initiate a prenatal vitamin containing folate supplementation. 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 Rajani 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 antimineralocorticoid activity. Folates may mask vitamin B12 deficiency. 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. Adverse Reactions 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 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Contraception, Acne and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of *YAZ (3 mg DRSP/0.02 mg EE), in the adequate and well-controlled studies for contraception (N=1,056), for moderate acne vulgaris (N=536) and folate supplementation (N=379). 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 *YAZ. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of *YAZ 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 *YAZ, evaluated the safety and efficacy during up to 6 cycles. For folate supplementation, the primary efficacy study using Rajani was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18 to 40 who were treated with Rajani or *YAZ for up to 24 weeks. The adverse reactions seen across the 3 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (greater than or equal to 2% of users) were: headache/migraine (5.9%), menstrual irregularities (including vaginal hemorrhage [primarily spotting], metrorrhagia and menorrhagia) (4.1%), nausea/vomiting (3.5%), and breast pain/tenderness (3.2%). 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 OC, Acne and Folate Supplementation 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 *YAZ during up to 3 cycles among 285 women aged 18 to 42, diagnosed with PMDD and who took at least one dose of *YAZ. Common adverse reactions (greater than or equal to 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 (greater than or equal to 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%) . Folate Clinical Trial Of 285 women, 4.6% who used Rajani or *YAZ discontinued from the clinical trials due to an adverse reaction; no reaction leading to discontinuation occurred in greater than or equal to 1% of women. 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 Folate Supplementation Clinical Trial: cervix carcinoma stage 0 PMDD Clinical Trials : cervical dysplasia Postmarketing Experience The following adverse reactions have been identified during post approval use of *YAZ. 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 Drug Interactions Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 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 drug instance
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