FDA label 02c45039-f960-4d02-baed-91e23bbd7fe4

Cigarette smoking increases the risk of serious cardiovascular side effects from hormonal 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 hormonal contraceptives, including ORTHO EVRA ® , should be strongly advised not to smoke.

WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from hormonal 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 hormonal contraceptives, including ORTHO EVRA ® , should be strongly advised not to smoke. The pharmacokinetic (PK) profile for the ORTHO EVRA ® patch is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. AUC and average concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using ORTHO EVRA ® compared with women using an oral contraceptive containing EE 35 mcg. In contrast, peak concentrations for EE are approximately 25% lower in women using ORTHO EVRA ® . Inter-subject variability results in increased exposure to EE in some women using either ORTHO EVRA ® or oral contraceptives. However, inter-subject variability in women using ORTHO EVRA ® is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in pharmacokinetic profiles of EE in women using ORTHO EVRA ® compared with women using oral contraceptives containing 35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives ). Four epidemiologic, case-control studies 107–111,113–115 were conducted in the U.S. using electronic healthcare claims data to evaluate the risk of venous thromboembolism (VTE) among women aged 15–44 who used ORTHO EVRA ® compared to women who used oral contraceptives containing 30–35 mcg of ethinyl estradiol (EE) and either norgestimate (NGM) or levonorgestrel (LNG). NGM is the prodrug for norelgestromin, the progestin in ORTHO EVRA ® . These studies (see Table 5 ) used slightly different designs and reported odds ratios ranging from 1.2 to 2.2. The interpretations of these odds ratios range from no increase in risk to an approximate doubling of risk. Only one study (i3 Ingenix) included patient chart review to confirm the VTE occurrence. The four studies are: The i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including a 24 month extension, based on the Ingenix Research Datamart The Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database BCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database BCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database The i3 Ingenix and BCDSP NGM studies have provided data on additional cases identified in study extensions; however, each study extension was not powered to provide independent estimates of risk. The pooled estimates provide the most reliable estimates of VTE risk. Odds ratios from the original and various extensions of the i3 Ingenix and BCDSP NGM studies are provided in the footnotes to Table 5. Table 5: Estimates (Odds Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA ® Compared to Oral Contraceptive Users Epidemiologic Study Comparator Product Odds Ratio (95% C.I.) i3 Ingenix NGM Study in Ingenix Research Datamart 107,113,114,115 NGM/35 mcg EE NGM = norgestimate; EE = ethinyl estradiol 2.2 Increase in risk of VTE is statistically significant (1.2–4.0) Pooled odds ratio from references 107 and 113. [Initial 33 months of data: Odds Ratio (95% CI) = 2.5* (1.1–5.5); Separate estimate from 24 months of data on new cases not included in the previous estimate: Odds Ratio (95% CI) = 1.4 (0.5–3.7)] BCDSP BCDSP = Boston Collaborative Drug Surveillance Program NGM Study in Pharmetrics database 108,109,111 NGM/35 mcg EE 1.2 (0.9–1.8) Pooled odds ratio from references 108, 109 and 111. [Initial 36 months of data: Odds Ratio (95% CI) = 0.9 (0.5–1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Odds Ratio (95% CI) = 1.1 (0.6–2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Odds Ratio (95% CI) = 2.4* (1.2–5.0)] BCDSP LNG Study in Pharmetrics database 110 LNG LNG = levonorgestrel /30 mcg EE 2.0 (0.9–4.1) 48 months of data. BCDSP LNG Study in Marketscan database 110 LNG/30 mcg EE 1.3 (0.8–2.0) 69 months of data. In 3 large clinical trials (N= 3,330 with 1,704 women-years of exposure), one case of non-fatal pulmonary embolism occurred during ORTHO EVRA ® use, and one case of post-operative non-fatal pulmonary embolism was reported following ORTHO EVRA ® use. ORTHO EVRA ® and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives. As with any combination hormonal contraceptive, the clinician should be alert to the earliest manifestations of thromboembolic disorders (thrombophlebitis, VTE including pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, ORTHO EVRA ® should be discontinued immediately. Practitioners prescribing ORTHO EVRA ® should be familiar with the following information relating to risks: The use of combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. The information that follows in this section of the package insert is principally based on studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestins than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestin administered by any route remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and cohort studies. Case control studies provide an estimate of the relative risk or odds for developing a disease, namely, a ratio of the disease among oral contraceptive users to that among nonusers or users of a comparator drug product. The odds ratio does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of the incidence of a disease in an exposed population. The relative risk is the ratio of the incidence density in the exposed population relative to the incidence density in a comparator population. Cohort studies also provide a measure of attributable risk, which is the difference in the incidence of disease between hormonal contraceptive users and nonusers or comparator drug products. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of hormonal contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease 2,3,19–24 . Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization 25 . The risk of thromboembolic disease associated with hormonal contraceptives is not related to length of use and disappears after hormonal contraceptive use is stopped 2 . A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of hormonal contraceptives 9,26 . The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions 9,26 . If feasible, hormonal contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, hormonal contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed. b. Myocardial Infarction An increased risk of myocardial infarction has been attributed to hormonal contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current hormonal contraceptive users has been estimated to be two to six 4–10 compared to non-users. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases 11 . Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives. (See Figure 5 ) Figure 5: Circulatory Disease Mortality Rates Per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use Hormonal contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity 13 . In particular, some progestins are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism 14–18 . Hormonal contraceptives have been shown to increase blood pressure among some users (see Section 9 in WARNINGS ). Similar effects on risk factors have been associated with an increased risk of heart disease. Hormonal contraceptives, including ORTHO EVRA ® , must be used with caution in women with cardiovascular disease risk factors. Norgestimate and norelgestromin have minimal androgenic activity (see CLINICAL PHARMACOLOGY ). There is some evidence that the risk of myocardial infarction associated with hormonal contraceptives is lower when the progestin has minimal androgenic activity than when the activity is greater 97 . Figure 5 c. Cerebrovascular Diseases Hormonal contraceptives 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), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke 27–29 . In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension 30 . The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used hormonal contraceptives, 2.6 for smokers who did not use hormonal contraceptives, 7.6 for smokers who used hormonal contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension 30 . The attributable risk is also greater in older women 3 . d. Dose-Related Risk of Vascular Disease from Hormonal Contraceptives A positive association has been observed between the amount of estrogen and progestin in hormonal contraceptives and the risk of vascular disease 31–33 . A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents 14–16 . A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of a hormonal contraceptive depends on a balance achieved between doses of estrogen and progestin and the activity of the progestin used in the contraceptives. The activity and amount of both hormones should be considered in the choice of a hormonal contraceptive. e. Persistence of Risk of Vascular Disease There are two studies that have shown persistence of risk of vascular disease for ever-users of combination hormonal contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing combination hormonal contraceptives persists for at least 9 years for women 40–49 years who had used combination hormonal contraceptives for five or more years, but this increased risk was not demonstrated in other age groups 8 . In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of combination hormonal contraceptives, although excess risk was very small 34 . However, both studies were performed with combination hormonal contraceptive formulations containing 50 micrograms or higher of estrogens. 2. Estimates of Mortality from Combination Hormonal Contraceptive Use One study gathered data from a variety of sources that have estimated the mortality rate associated with different methods of contraception at different ages (Table 6). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of combination oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for combination oral contraceptive users is based on data gathered in the 1970's but not reported until 1983 35 . Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of combination hormonal contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with combination hormonal 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 and with the alternative surgical and medical procedures that may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose combination hormonal contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks 36, 37 . Although the data are mainly obtained with oral contraceptives, this is likely to apply to ORTHO EVRA ® as well. Women of all ages who use combination hormonal contraceptives, should use the lowest possible dose formulation that is effective and meets the individual patient needs. Table 6: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Non-Sterile Women, by Fertility Control Method According to Age Method of control and outcome 15–19 20–24 25–29 30–34 35–39 40–44 Adapted from H.W. Ory, ref. # 35. No fertility control methods Deaths are birth-related 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives, non-smoker Deaths are method-related 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives, smoker 2.2 3.4 6.6 13.5 51.1 117.2 IUD 0.8 0.8 1.0 1.0 1.4 1.4 Condom 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence 2.5 1.6 1.6 1.7 2.9 3.6 3. Carcinoma of the Reproductive Organs and Breasts Numerous epidemiological studies give conflicting reports on the relationship between breast cancer and COC use. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history. In addition, breast cancers diagnosed in current or ever oral contraceptive users may be less clinically advanced than in never-users. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormonally sensitive tumor. Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women 45–48 . However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. It is not known whether ORTHO EVRA ® is distinct from oral contraceptives with regard to the above statements. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with hormonal contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use, especially with hormonal contraceptives containing 50 micrograms or more of estrogen 49 . Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage 50,51 . Studies from Britain and the U.S. have shown an increased risk of developing hepatocellular carcinoma in long term (≥ 8 years) 52–54,96 oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. It is unknown whether ORTHO EVRA ® is distinct from oral contraceptives in this regard. 5. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of hormonal contraceptives. ORTHO EVRA ® should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. Hormonal Contraceptive 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 56,57 . Studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned 55,56,58,59 , when oral contraceptives are taken inadvertently during early pregnancy. Combination hormonal contraceptives such as ORTHO EVRA ® should not be used to induce withdrawal bleeding as a test for pregnancy. ORTHO EVRA ® should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule for the use of ORTHO EVRA ® the possibility of pregnancy should be considered at the time of the first missed period. Hormonal contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of hormonal contraceptives and estrogens 60,61 . More recent studies, however, have shown that the relative risk of developing gallbladder disease among hormonal contraceptive users may be minimal 62–64 . The recent findings of minimal risk may be related to the use of hormonal contraceptive formulations containing lower hormonal doses of estrogens and progestins. Combination hormonal contraceptives such as ORTHO EVRA ® may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Women with a history of combination hormonal contraceptive-related cholestasis are more likely to have the condition recur with subsequent combination hormonal contraceptive use. 8. Carbohydrate and Lipid Metabolic Effects Hormonal contraceptives have been shown to cause a decrease in glucose tolerance in some users 17 . However, in the non-diabetic woman, combination hormonal contraceptives appear to have no effect on fasting blood glucose 67 . Prediabetic and diabetic women in particular should be carefully monitored while taking combination hormonal contraceptives such as ORTHO EVRA ® . In clinical trials with oral contraceptives containing ethinyl estradiol and norgestimate there were no clinically significant changes in fasting blood glucose levels. There were no clinically significant changes in glucose levels over 24 cycles of use. Moreover, glucose tolerance tests showed no clinically significant changes from baseline to cycles 3, 12 and 24. In a 6-cycle clinical trial with ORTHO EVRA ® there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. A small proportion of women will have persistent hypertriglyceridemia while taking hormonal contraceptives. As discussed earlier (see WARNINGS 1a and 1d ), changes in serum triglycerides and lipoprotein levels have been reported in hormonal contraceptive users. 9. Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception 103 . Women with a history of hypertension or hypertension-related diseases, or renal disease 70 should be encouraged to use another method of contraception. If these women elect to use ORTHO EVRA ® , they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, ORTHO EVRA ® should be discontinued. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended. 112 For most women, elevated blood pressure will return to normal after stopping hormonal contraceptives, and there is no difference in the occurrence of hypertension between former and never users 68–71 . An increase in blood pressure has been reported in women taking hormonal contraceptives 68 and this increase is more likely in older hormonal contraceptive users 69 and with extended duration of use 61 . Data from the Royal College of General Practitioners 12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. 10. Headache The onset or exacerbation of migraine headache or the development of headache with a new pattern that is recurrent, persistent or severe requires discontinuation of ORTHO EVRA ® and evaluation of the cause. 11. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in women using ORTHO EVRA ® . Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy, other pathology, or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another contraceptive product may resolve the bleeding. In the event of amenorrhea, pregnancy should be ruled out before initiating use of ORTHO EVRA ® . Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent. Bleeding Patterns In the clinical trials most women started their withdrawal bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average 26% of women per cycle had 7 or more total days of bleeding and/or spotting (this includes both withdrawal flow and breakthrough bleeding and/or spotting). 12. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

<table width="80%" ID="table5"> <caption>Table 5: Estimates (Odds Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA^&#xAE; Compared to Oral Contraceptive Users</caption> <col width="35%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="35%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">Epidemiologic Study</th> <th styleCode="Rrule">Comparator Product</th> <th styleCode="Rrule">Odds Ratio (95% C.I.)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">i3 Ingenix NGM Study in Ingenix Research Datamart^{107,113,114,115} </td> <td styleCode="Rrule">NGM/35 mcg EE<footnote>NGM = norgestimate; EE = ethinyl estradiol</footnote> </td> <td styleCode="Rrule"> <content styleCode="bold">2.2<footnote>Increase in risk of VTE is statistically significant</footnote> (1.2&#x2013;4.0)<footnote>Pooled odds ratio from references 107 and 113. [Initial 33 months of data: Odds Ratio (95% CI) = 2.5* (1.1&#x2013;5.5); Separate estimate from 24 months of data on new cases not included in the previous estimate: Odds Ratio (95% CI) = 1.4 (0.5&#x2013;3.7)]</footnote> </content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">BCDSP<footnote>BCDSP = Boston Collaborative Drug Surveillance Program</footnote> NGM Study in Pharmetrics database^108,109,111 </td> <td styleCode="Rrule">NGM/35 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.2 (0.9&#x2013;1.8)<footnote>Pooled odds ratio from references 108, 109 and 111. [Initial 36 months of data: Odds Ratio (95% CI) = 0.9 (0.5&#x2013;1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Odds Ratio (95% CI) = 1.1 (0.6&#x2013;2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Odds Ratio (95% CI) = 2.4* (1.2&#x2013;5.0)]</footnote> </content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">BCDSP LNG Study in Pharmetrics database¹¹⁰ </td> <td styleCode="Rrule">LNG<footnote>LNG = levonorgestrel</footnote>/30 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">2.0 (0.9&#x2013;4.1)<footnote>48 months of data.</footnote> </content> </td> </tr> <tr> <td styleCode="Lrule Rrule">BCDSP LNG Study in Marketscan database¹¹⁰ </td> <td styleCode="Rrule">LNG/30 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.3 (0.8&#x2013;2.0)<footnote>69 months of data.</footnote> </content> </td> </tr> </tbody> </table>

<table width="90%" ID="id1ff3fad-60d4-4c0c-8ca3-672f50eef952"> <caption>Table 6: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Non-Sterile Women, by Fertility Control Method According to Age</caption> <col width="40%" align="left" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <col width="10%" align="center" valign="bottom"/> <thead> <tr> <th>Method of control and outcome</th> <th>15&#x2013;19</th> <th>20&#x2013;24</th> <th>25&#x2013;29</th> <th>30&#x2013;34</th> <th>35&#x2013;39</th> <th>40&#x2013;44</th> </tr> </thead> <tfoot> <tr> <td colspan="7" align="left">Adapted from H.W. Ory, ref. # 35.</td> </tr> </tfoot> <tbody> <tr> <td>No fertility control methods<footnote ID="t61">Deaths are birth-related</footnote> </td> <td>7.0</td> <td>7.4</td> <td>9.1</td> <td>14.8</td> <td>25.7</td> <td>28.2</td> </tr> <tr> <td>Oral contraceptives, non-smoker<footnote ID="t62">Deaths are method-related</footnote> </td> <td>0.3</td> <td>0.5</td> <td>0.9</td> <td>1.9</td> <td>13.8</td> <td>31.6</td> </tr> <tr> <td>Oral contraceptives, smoker<footnoteRef IDREF="t62"/> </td> <td>2.2</td> <td>3.4</td> <td>6.6</td> <td>13.5</td> <td>51.1</td> <td>117.2</td> </tr> <tr> <td>IUD<footnoteRef IDREF="t62"/> </td> <td>0.8</td> <td>0.8</td> <td>1.0</td> <td>1.0</td> <td>1.4</td> <td>1.4</td> </tr> <tr> <td>Condom<footnoteRef IDREF="t61"/> </td> <td>1.1</td> <td>1.6</td> <td>0.7</td> <td>0.2</td> <td>0.3</td> <td>0.4</td> </tr> <tr> <td>Diaphragm/spermicide<footnoteRef IDREF="t61"/> </td> <td>1.9</td> <td>1.2</td> <td>1.2</td> <td>1.3</td> <td>2.2</td> <td>2.8</td> </tr> <tr> <td>Periodic abstinence<footnoteRef IDREF="t61"/> </td> <td>2.5</td> <td>1.6</td> <td>1.6</td> <td>1.7</td> <td>2.9</td> <td>3.6</td> </tr> </tbody> </table>

ADVERSE REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives, including ORTHO EVRA ® , are discussed elsewhere in the labeling: Serious cardiovascular events and smoking (see WARNINGS ) Vascular events, including venous and arterial thromboembolic events (see WARNINGS ) Liver disease (see WARNINGS and PRECAUTIONS ) Adverse reactions commonly reported by users of combination hormonal contraceptives are: Irregular uterine bleeding Nausea Breast tenderness Headache 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. The data described below reflect exposure to ORTHO EVRA ® in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (ORTHO EVRA ® or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%). The most common adverse reactions reported during clinical trials were breast symptoms, headache, application site disorder, nausea, dysmenorrhea and abdominal pain. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability. Adverse drug reactions reported by ≥ 2.5% of ORTHO EVRA ® -treated subjects in these trials are shown in Table 7. Table 7. Adverse Drug Reactions Reported by ≥ 2.5% of ORTHO EVRA ® -treated Subjects in Three Phase 3 Clinical Trials System/Organ Class MedDRA version 10.0 Adverse reaction ORTHO EVRA ® (n=3322) Reproductive system and breast disorders Breast symptoms Represents a bundle of similar terms Dysmenorrhea Vaginal bleeding and menstrual disorders 22.4% 7.8% 6.4% Gastrointestinal disorders Nausea Abdominal pain Vomiting Diarrhea 16.6% 8.1% 5.1% 4.2% Nervous system disorders Headache Dizziness Migraine 21.0% 3.3% 2.7% General disorders and administration site conditions Application site disorder Fatigue 17.1% 2.6% Psychiatric disorders Mood, affect and anxiety disorders 6.3% Skin and subcutaneous tissue disorders Acne Pruritus 2.9% 2.5% Infections and infestations Vaginal yeast infection 3.9% Investigations Weight increased 2.7% Additional adverse drug reactions that occurred in < 2.5 % of ORTHO EVRA ® -treated subjects in the above clinical trials datasets are: Gastrointestinal disorders: Abdominal distension General disorders and administration site conditions: Fluid retention Represents a bundle of similar terms , malaise Hepatobiliary disorders: Cholecystitis Investigations: Blood pressure increased, lipid disorders Musculoskeletal and connective tissue disorders: Muscle spasms Psychiatric disorders: Insomnia, libido decreased, libido increased Reproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness Respiratory, thoracic and mediastinal disorders: Pulmonary embolism Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation Postmarketing Experience The following adverse reactions (Table 8) have been identified during postapproval use of ORTHO EVRA ® . 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. Table 8. Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ORTHO EVRA ® /EVRA ® by System Organ Class MedDRA version 10.0 System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction Represents a bundle of similar terms Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction , edema Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction , urticaria Investigations Blood glucose abnormal, blood glucose decreased Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Breast cancer , cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder , suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash , seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis , cerebrovascular accident , deep vein thrombosis , hemorrhage intracranial , hypertension, hypertensive crisis, pulmonary embolism , thrombosis

<table width="90%" ID="iaea5fc68-ca67-43b8-812e-5ffaf565c19e"> <caption>Table 7. Adverse Drug Reactions Reported by &#x2265; 2.5% of ORTHO EVRA^&#xAE;-treated Subjects in Three Phase 3 Clinical Trials</caption> <col width="75%" align="left" valign="bottom"/> <col width="25%" align="center" valign="bottom"/> <thead> <tr> <th styleCode="Lrule Rrule">System/Organ Class<footnote>MedDRA version 10.0</footnote> Adverse reaction</th> <th styleCode="Rrule">ORTHO EVRA^&#xAE; (n=3322)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Reproductive system and breast disorders</content> Breast symptoms<footnote ID="t71">Represents a bundle of similar terms</footnote> Dysmenorrhea Vaginal bleeding and menstrual disorders<footnoteRef IDREF="t71"/> </td> <td styleCode="Rrule"> 22.4% 7.8% 6.4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> Nausea Abdominal pain<footnoteRef IDREF="t71"/> Vomiting Diarrhea</td> <td styleCode="Rrule"> 16.6% 8.1% 5.1% 4.2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> Headache Dizziness Migraine</td> <td styleCode="Rrule"> 21.0% 3.3% 2.7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> Application site disorder<footnoteRef IDREF="t71"/> Fatigue</td> <td styleCode="Rrule"> 17.1% 2.6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Psychiatric disorders</content> Mood, affect and anxiety disorders<footnoteRef IDREF="t71"/> </td> <td styleCode="Rrule"> 6.3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> Acne Pruritus</td> <td styleCode="Rrule"> 2.9% 2.5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> Vaginal yeast infection<footnoteRef IDREF="t71"/> </td> <td styleCode="Rrule"> 3.9%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Investigations</content> Weight increased</td> <td styleCode="Rrule"> 2.7%</td> </tr> </tbody> </table>

<table width="90%" ID="i2af7bf6b-c810-4463-8c94-9b6e7eefd77f"> <caption>Table 8. Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ORTHO EVRA^&#xAE;/EVRA^&#xAE; by System Organ Class<footnote>MedDRA version 10.0</footnote> </caption> <col width="40%" align="left" valign="top"/> <col width="60%" align="left" valign="top"/> <thead> <tr> <th align="center">System Organ Class</th> <th align="center">Adverse Drug Reactions</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Cardiac disorders</content> </td> <td> Myocardial infarction<footnote ID="ft81">Represents a bundle of similar terms</footnote> </td> </tr> <tr> <td> <content styleCode="bold">Endocrine disorders</content> </td> <td> Hyperglycemia, insulin resistance</td> </tr> <tr> <td> <content styleCode="bold">Eye disorders</content> </td> <td> Contact lens intolerance or complication</td> </tr> <tr> <td> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td> Colitis</td> </tr> <tr> <td> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td> Application site reaction<footnoteRef IDREF="ft81"/>, edema<footnoteRef IDREF="ft81"/> </td> </tr> <tr> <td> <content styleCode="bold">Hepatobiliary disorders</content> </td> <td> Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased</td> </tr> <tr> <td> <content styleCode="bold">Immune system disorders</content> </td> <td> Allergic reaction<footnoteRef IDREF="ft81"/>, urticaria</td> </tr> <tr> <td> <content styleCode="bold">Investigations</content> </td> <td> Blood glucose abnormal, blood glucose decreased</td> </tr> <tr> <td> <content styleCode="bold">Neoplasms benign, malignant and unspecified (Incl cysts and polyps)</content> </td> <td> Breast cancer<footnoteRef IDREF="ft81"/>, cervix carcinoma, hepatic adenoma, hepatic neoplasm</td> </tr> <tr> <td> <content styleCode="bold">Nervous system disorders</content> </td> <td> Dysgeusia, migraine with aura</td> </tr> <tr> <td> <content styleCode="bold">Psychiatric disorders</content> </td> <td> Anger, emotional disorder, frustration, irritability</td> </tr> <tr> <td> <content styleCode="bold">Reproductive system and breast disorders</content> </td> <td> Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder<footnoteRef IDREF="ft81"/>, suppressed lactation, uterine leiomyoma</td> </tr> <tr> <td> <content styleCode="bold">Skin and subcutaneous tissues disorders</content> </td> <td> Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash<footnoteRef IDREF="ft81"/>, seborrheic dermatitis, skin reaction</td> </tr> <tr> <td> <content styleCode="bold">Vascular disorders</content> </td> <td> Arterial thrombosis<footnoteRef IDREF="ft81"/>, cerebrovascular accident<footnoteRef IDREF="ft81"/>, deep vein thrombosis<footnoteRef IDREF="ft81"/>, hemorrhage intracranial<footnoteRef IDREF="ft81"/>, hypertension, hypertensive crisis, pulmonary embolism<footnoteRef IDREF="ft81"/>, thrombosis<footnoteRef IDREF="ft81"/> </td> </tr> </tbody> </table>