WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Vascular risks: Stop OCELLA 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 OCELLA 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 OCELLA if jaundice occurs. (5.4) • High blood pressure: Do not prescribe OCELLA for women with uncontrolled hypertension or hypertension with vascular disease. (5.5) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking OCELLA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7) • Headache: Evaluate significant change in headaches and discontinue OCELLA if indicated. (5.8) • Uterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.9) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop OCELLA if an arterial or venous thrombotic (VTE) event occurs. Based on presently available information on OCELLA, 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 OCELLA 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 3 mg of DRSP and 0.03 mg of EE) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 1. Table 1 Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Yasmin Compared to Users of Oral Contraceptives that Contain Other Progestins Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product (all are low-dose COCs; with ≤ 0.04 mg of EE) Hazard Ratio (HR) (95% CI) i3 Ingenix (Seeger 2007) Initiators, including new users”New users” – no use of combination hormonal contraception for at least the prior 6 months All COCs available in the US during the conduct of the studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate HR: 0.9 (0.5-1.6) EURAS (Dinger 2007) Initiators, including new users All COCs available in Europe during the conduct of the studyIncludes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone HR: 0.9 (0.6-1.4) Levonorgestrel/EE HR: 1.0 (0.6-1.8) “FDA-funded study” (2011) New users Other COCs available during the course of the studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel HR: 1.8 (1.3-2.4) Levonorgestrel/0.03 mg EE HR: 1.6 (1.1-2.2) All users (i.e., initiation and continuing use of study combination hormonal contraception) Other COCs available during the course of the study HR: 1.7 (1.4-2.1) Levonorgestrel/0.03 mg EE HR: 1.5 (1.2-1.8) In addition to these “regulatory studies,” other studies of various designs have been conducted. Overall, there are two prospective cohort studies (see Table 1): the US post-approval safety study Ingenix [Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study) [Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 1), and two from Denmark [Lidegaard 2009, Lidegaard 2011]. There are two case-control studies: the Dutch MEGA study analysis [van HylckamaVlieg 2009] and the German case-control study [Dinger 2010]. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011] and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1. Figure 1 VTE Risk with Yasmin Relative to LNG-Containing COCs (adjusted risk#) Risk ratios displayed on logarithmic scale; risk ratio 1 indicates an increased risk of VTE for DRSP. *Comparator “Other COCs”, including LNG- containing COCs † LASS is an extension of the EURAS study #Some adjustment factors are indicated by superscript letters: a) Current heavy smoking, b) hypertension, c) obesity, d) family history, e) age, f) BMI, g) duration of use, h) VTE history, i) period of inclusion, j) calendar year, k) education, l) length of use, m) parity, n) chronic disease, o) concomitant medication, p) smoking, q) duration of exposure, r) site (References: Ingenix [Seeger 2007]1, EURAS (European Active Surveillance Study) [Dinger 2007]2, LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011]3, Danish [Lidegaard 2009]4, Danish re-analysis [Lidegaard 2011]5, MEGA study [van HylckamaVlieg 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 OCELLA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start OCELLA 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 OCELLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [See Adverse Reactions ( 6 ).] fig 1 Figure 2 5.2 Hyperkalemia OCELLA 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. OCELLA 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 OCELLA 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 OCELLA 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 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop OCELLA 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. 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.7 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking OCELLA. 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. 5.8 Headache If a woman taking OCELLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue OCELLA 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. 5.9 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 from ten contraceptive efficacy clinical trials (N=2,467) show that the percent of women who took OCELLA and experienced unscheduled bleeding decreased over time from 12% at cycle 2 to 6% (cycle 13). A total of 24 subjects out of 2,837 in the OCELLA trials (<1%) discontinued due to bleeding complaints. These are described as metrorrhagia, vaginal hemorrhage, menorrhagia, abnormal withdrawal bleeding, and menometrorrhagia. The average duration of scheduled bleeding episodes in the majority of subjects (86%-88%) was 4-7 days. Women who use OCELLA may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from contraceptive efficacy trials, during cycles 2–13, 1-11% of women per cycle experienced 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. 5.10 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 when COCs are taken inadvertently during early pregnancy, particularly in so far as cardiac anomalies and limb-reduction defects are concerned. 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)]. 5.11 Depression Women with a history of depression should be carefully observed and OCELLA discontinued if depression recurs to a serious degree. 5.12 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. 5.13 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. 5.14 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.