Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including ORTHO EVRA®, should not be used by women who are over 35 years of age and 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. Area under the time-concentration curve (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 30-35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives).

ORTHO EVRA® and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives (CHCs). As with any CHC, the clinician should be alert to the earliest manifestations of thromboembolic disorders (e.g., venous thromboembolism (VTE), including pulmonary embolism; cerebrovascular disorders; and retinal thrombosis). Should any of these occur or be suspected, ORTHO EVRA® should be discontinued immediately.

Five epidemiologic studies^{107-111,113-116} are described below. These are 4 case control studies, that compared VTE rates among women using ORTHO EVRA® to rates among women using an OC comparator, and an FDA-funded cohort study that estimated and compared VTE rates among women using various hormonal contraceptives, including ORTHO EVRA®. All five studies were retrospective studies from U.S. electronic healthcare databases and included women aged 15-44 (10-55 in the FDA-funded study) who used ORTHO EVRA® or oral contraceptives containing 20-35 mcg of ethinyl estradiol (EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the prodrug for norelgestromin, the progestin in ORTHO EVRA®.

Some of the data from the epidemiologic studies suggest an increased risk of VTE with use of ORTHO EVRA®compared to use of some combined oral contraceptives (see Table 5). The studies used slightly different designs and reported relative risk estimates ranging from 1.2 to 2.2. None of the studies have adjusted for body mass index, smoking, and family history of VTE, which are potential confounders. The interpretations of these relative risk estimates range from no increase in risk to an approximate doubling of risk. One of the studies found a statistically significant increased risk of VTE for current users of ORTHO EVRA®.

The five 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; this study included patient chart review to confirm the VTE occurrence.
• 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, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review.
• BCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review.
• BCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review.
• FDA-funded study with two groups of comparators [1) LNG-containing oral contraceptives, and 2) oral contraceptives that contain LNG, norethindrone or norgestimate], based on Kaiser Permanente and Medicaid databases. This study used all cases of VTE (idiopathic and non-idiopathic) and included patient chart review to confirm the VTE occurrence.

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. Risk ratios from the original and various extensions of the i3 Ingenix and BCDSP NGM studies are provided in the footnotes to Table 5. The results of these studies are presented in Figure 5.

Table 5: Estimates (Risk Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA® Compared to Combined Oral Contraceptive Users

Epidemiologic StudyA	Comparator Product	Risk Ratios (95% CI)
i3 Ingenix NGM Study in Ingenix Research Datamart107,113,114,115	NGM/35 mcg EEB	2.2C (1.2-4.0)D
BCDSPE NGM Study in Pharmetrics database108,109,111	NGM/35 mcg EE	1.2 (0.9-1.8)F
BCDSPE LNG Study in Pharmetrics database110	LNGG/30 mcg EE	2.0 (0.9-4.1)H
BCDSPE LNG Study in Marketscan database110	LNG/30 mcg EE	1.3 (0.8-2.0)I
FDA-funded Study in Kaiser Permanente and Medicaid databasesJ, K, 116	“All progestinsL”/20-35 mcg EE	1.4 (0.9-2.0)
	LNG/ 30 mcg EE	1.2 (0.8-1.9)
A“New users” – i.e., women with no prior exposure to the drug studied during a pre-specified time period – are considered to be the most informative population to study in pharmacoepidemiologic safety studies. All estimates took account of new-user status. The method and time period used to identify “new users” varied from study to study. BNGM = norgestimate; EE = ethinyl estradiol CIncrease in risk of VTE is statistically significant DPooled risk ratio from references 107 and 113 covering the initial 33-month study plus 24-month extension. [Initial 33 months of data: Risk Ratio (95% CI) = 2.5C (1.1-5.5); Separate estimate from the 24 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.4 (0.5-3.7)]. These risk ratios are based on idiopathic cases (those in women without other known risk factors for VTE). If all VTE cases are considered, the pooled risk ratio and 95% CI are 2.0 (1.2-3.3). EBCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases. FPooled risk ratio from references 108, 109 and 111 covering the initial 36-month study, plus 17-month and 14-month extensions. [Initial 36 months of data: Risk 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: Risk 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: Risk Ratio (95% CI) = 2.4C(1.2-5.0)] GLNG = levonorgestrel H48 months of data. I69 months of data. J84 months of data in FDA-funded study KResults for “All users,” i.e., initiation and continuing use of study combination hormonal contraception: “All progestins”/20-35 mcg EE, Risk Ratio (95% CI) = 1.6 (1.2-2.1) and LNG/30 mcg EE, Risk Ratio (95% CI) = 1.3 (1.0-1.8). LIncludes the following progestins: LNG, norethindrone, norgestimate.

Figure 5: VTE Risk of ORTHO EVRA® Relative to Combined Oral Contraceptives

^aAll estimates took account of new-user status. The method and time period used to identify “new users” varied from study to study.
^bIncludes the following progestins: levonorgestrel (LNG), norethindrone, norgestimate (NGM). BCDSP = Boston Collaborative Drug Surveillance Program EE = ethinyl estradiol

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.

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 label, the retrospective epidemiologic studies reported are of two types: case control or 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. 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 non-users or users of comparator drug products. For further information, the reader is referred to a text on epidemiological methods.

Thromboembolic Disorders and Other Vascular Problems

Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of combination hormonal contraceptives (CHCs) is well established. Although the absolute VTE rates are increased for users of CHCs compared to non-users, the rates associated with pregnancy are even greater, especially during the post-partum period (see Figure 6).

The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years.

The risk of VTE is highest during the first year of use of combination hormonal contraception. The risk of thromboembolic disease due to combination hormonal contraceptives gradually disappears after use is discontinued.

Figure 6 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the post-partum period.

To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE.

Figure 6: Likelihood of Developing a VTE

*CHC=combination hormonal contraception

**Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY.

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 risk factors, such as smoking, obesity or family history of VTE, is twice that of women without such risk factors.^9,26

If feasible, discontinue hormonal contraceptives 1) at least four weeks prior to and for two weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism and 2) during and following prolonged immobilization.

Because 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.

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 7.)

Figure 7: 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

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

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.

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.

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
No fertility control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives, non-smoker†	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

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.

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.

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.

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.

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.

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.

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 disease⁷⁰ 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 contraceptives⁶⁸ and this increase is more likely in older hormonal contraceptive users⁶⁹ and with extended duration of use.⁶¹ Data from the Royal College of General Practitioners¹² and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.

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.

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).

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

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53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357.

54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361.

55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.

56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981: 140:521-524.

57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73-79.

58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.

59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439.

60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.

61. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974.

62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278.

63. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805.

64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341.

67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985;38:857-864.

68. Royal College of General Practitioners' Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.

69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503.

70. Laragh AJ. Oral contraceptive induced hypertension-nine years later. Am J Obstet Gynecol 1976; 126:141-147.

71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.)

97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90.

107. Cole JA, Norman H, Doherty M, Walker AM. Venous Thromboembolism, Myocardial Infarction, and Stroke Among Transdermal Contraceptive System Users. Obstetrics & Gynecology 2007; 109(2):339-346.

108. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 73 (2006): 223-228.

109. Jick S, Kaye JA, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 μg of EE. Contraception 2007;76:4-7.

110. Jick S, Hagberg K, Hernandez R, Kaye J. Postmarketing study of ORTHO EVRA® and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception 81 (2010):16-21.

111. Jick S, Hagberg K, Kaye J. ORTHO EVRA®and venous thromboembolism: an update. Letter to the Editor. Contraception 81 (2010):452-453.

113. Dore D, Norman H, Loughlin J, Seeger D. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 81 (2010):408-413.

114. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users [published erratum appears in Obstet Gynecol 2008:111:1449].

115. Dore D, Norman H, Seeger, J. Eligibility criteria in venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Letter to the Editor. Obstetrics & Gynecology 2009; 114(1):175.

116. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011.

Women should be counseled that ORTHO EVRA®does not protect against HIV infection (AIDS) and other sexually transmitted infections.

Body Weight ≥198 lbs. (90 kg)

Results of clinical trials suggest that ORTHO EVRA®may be less effective in women with body weight ≥198 lbs. (90 kg) than in women with lower body weights.

Physical Examination and Follow-Up

It is good medical practice for women using ORTHO EVRA® , as for all women, to have annual medical evaluation and physical examinations. The physical examination, however, may be deferred until after initiation of hormonal contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy or other pathology. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use ORTHO EVRA®. Some progestins may elevate LDL levels and may render the control of hyperlipidemias more difficult.

Liver Function

If jaundice develops in any woman using ORTHO EVRA® , the medication should be discontinued. The hormones in ORTHO EVRA®may be poorly metabolized in patients with impaired liver function.

Fluid Retention

Steroid hormones like those in ORTHO EVRA®may cause some degree of fluid retention. ORTHO EVRA® should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

Emotional Disorders

Women who become significantly depressed while using combination hormonal contraceptives such as ORTHO EVRA®should stop the medication and use another method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and ORTHO EVRA® discontinued if significant depression occurs.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Carcinogenesis

No carcinogenicity studies were conducted with norelgestromin. However, bridging PK studies were conducted using doses of norgestimate (NGM)/EE which were used previously in the 2-year rat carcinogenicity study and 10-year monkey toxicity study to support the approval of ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® under NDAs 19-653 and 19-697, respectively. The PK studies demonstrated that rats and monkeys were exposed to 16 and 8 times the human exposure, respectively, with the proposed ORTHO EVRA® transdermal contraceptive system.

Norelgestromin was tested in in vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in vivo test (rat micronucleus assay) and found to have no genotoxic potential.

See WARNINGS.

Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.

Norelgestromin was tested for its reproductive toxicity in a rabbit developmental toxicity study by the SC route of administration. Doses of 0, 1, 2, 4 and 6 mg/kg body weight, which gave systemic exposure of approximately 25 to 125 times the human exposure with ORTHO EVRA® , were administered daily on gestation days 7-19. Malformations reported were paw hyperflexion at 4 and 6 mg/kg and paw hyperextension and cleft palate at 6 mg/kg.

Nursing Mothers

The effects of ORTHO EVRA®in nursing mothers have not been evaluated and are unknown. Small amounts of combination hormonal contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination hormonal contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. Long-term follow-up of infants whose mothers used combination hormonal contraceptives while breastfeeding has shown no deleterious effects. However, the nursing mother should be advised not to use ORTHO EVRA®but to use other forms of contraception until she has completely weaned her child.

Pediatric Use

Safety and efficacy of ORTHO EVRA®have been established in women of reproductive age. Safety and efficacy are expected to be the same for post-pubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

Sexually Transmitted Diseases

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Patch Adhesion

Experience with more than 70,000 ORTHO EVRA®patches worn for contraception for 6-13 cycles showed that 4.7% of patches were replaced because they either fell off (1.8%) or were partly detached (2.9%). Similarly, in a small study of patch wear under conditions of physical exertion and variable temperature and humidity, less than 2% of patches were replaced for complete or partial detachment.

If the ORTHO EVRA® patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. A patch should not be re-applied if it is no longer sticky, if it has become stuck to itself or another surface, if it has other material stuck to it, or if it has become loose or fallen off before. If a patch cannot be re-applied, a new patch should be applied immediately. Supplemental adhesives or wraps should not be used to hold the ORTHO EVRA®patch in place.

If a patch is partially or completely detached for more than one day (24 hours or more) OR if the woman is not sure how long the patch has been detached, she may not be protected from pregnancy. She should stop the current contraceptive cycle and start a new cycle immediately by applying a new patch. Back-up contraception, such as a condom or diaphragm and spermicide, must be used for the first week of the new cycle.

Information for the Patient

See Patient Labeling.

Last reviewed on RxList: 10/10/2012
This monograph has been modified to include the generic and brand name in many instances.