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Thromboembolic Disorders and Other Vascular Problems
Stop ORTHO EVRA if an arterial or deep venous thrombotic event (VTE) occurs.
If feasible, stop ORTHO EVRA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of ORTHO EVRA during prolonged immobilization and resume treatment based on clinical judgment.
Start ORTHO EVRA no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of combination hormonal contraceptives (CHCs) increases the risk of VTE. Known risk factors for VTE include smoking, obesity and family history of VTE, in addition to other factors that contraindicate use of CHCs [see CONTRAINDICATIONS].
Five epidemiologic studies1-9 that assessed the risk of VTE associated with use of ORTHO EVRA 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 NGMN, 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 1). 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 Table 1. The results of these studies are presented in Figure 1.
Table 1: Estimates (Risk Ratios) of Venous
Thromboembolism Risk in Current Users of ORTHO EVRA Compared to Combined Oral
|Epidemiologic StudyA||Comparator Product||Risk Ratios (95% CI)|
|i3 Ingenix NGM Study in Ingenix Research Datamart1,6,7,8||NGM/35 mcg EEB||2.2C (1.2-4.0)D|
|BCDSPE NGM Study in Pharmetrics database2,3,5||NGM/35 mcg EE||1.2 (0.9-1.8)F|
|BCDSPE LNG Study in Pharmetrics database4||LNGG/30 mcg EE||2.0 (0.9-4.1)H|
|BCDSPE LNG Study in Marketscan database4||LNG/30 mcg EE||1.3 (0.8-2.1)I|
|FDA-funded Study in Kaiser Permanente and Medicaid databasesJ, K, 9||“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 1 and 6 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)C.
EBCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases.
FPooled risk ratio from references 2, 3 and 5 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)C and LNG/30 mcg EE, Risk Ratio (95% CI) = 1.3 (1.0-1.8).
LIncludes the following progestins: LNG, norethindrone, norgestimate.
Figure 1: 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
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 2).
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 2 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 2: Likelihood of Developing a V TE
**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.
Use of CHCs also increases the risk of arterial thromboses such as, cerebrovascular events (thrombotic and hemorrhagic strokes) and myocardial infarctions, especially in women with other risk factors for these events. In general, the risk is greatest among older ( > 35 years of age), hypertensive women who also smoke. Use CHCs with caution in women with cardiovascular disease risk factors.
PK Profile of Ethinyl Estradiol
The PK profile for the ORTHO EVRA patch is different from the PK profile for oral contraceptives in that it has a higher Css and a lower Cmax. AUC and average Css for EE are approximately 60% higher in women using ORTHO EVRA compared with women using an oral contraceptive containing EE 35 mcg. In contrast, the Cmax for EE is 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 PK 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 BOXED WARNING and CLINICAL PHARMACOLOGY.]
Impaired Liver Function
Do not use ORTHO EVRA in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS]. Discontinue ORTHO EVRA if jaundice develops. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded.
ORTHO EVRA is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC 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) CHC users. However, the risk of liver cancers in CHC users is less than one case per million users.
High Blood Pressure
ORTHO EVRA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For women with well-controlled hypertension, monitor blood pressure and stop ORTHO EVRA if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.
Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.
Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who take ORTHO EVRA. CHCs may decrease glucose tolerance in a dose-related fashion. 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.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.
If a woman taking ORTHO EVRA develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue ORTHO EVRA if indicated.
Consider discontinuation of ORTHO EVRA in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event).
Unscheduled Bleeding and Spotting
Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using ORTHO EVRA. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or a change to another contraceptive product may resolve the bleeding.
In the clinical trials, most women started their scheduled (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 scheduled and unscheduled bleeding and/or spotting). Three clinical studies of the efficacy of ORTHO EVRA in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies] in 3,330 women who completed 22,155 cycles of exposure. A total of 36 (1.1%) of the women discontinued ORTHO EVRA at least in part, due to bleeding or spotting.
Table 2 summarizes the proportion of subjects who experienced unscheduled (breakthrough) bleeding/spotting by treatment cycle.
Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy)
|Treatment Cycle||Pooled data from 3 studies
|aPercentage of subjects with breakthrough bleeding/spotting events.|
Amenorrhea and Oligomenorrhea
In the event of amenorrhea, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one patch or started the patch 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.
Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent.
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. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue ORTHO EVRA use if pregnancy is confirmed.
Administration of CHCs should not be used as a test for pregnancy [see Use In Specific Populations].
Carefully observe women with a history of depression and discontinue ORTHO EVRA if depression recurs to a serious degree.
Carcinoma of Breasts and Cervix
There is substantial evidence that CHCs do not increase the incidence of breast cancer. Although some past studies have suggested that CHCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
Effect on Binding Globulins
The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.
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 using ORTHO EVRA.
1. 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.
2. 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 2006; 73: 223-228.
3. 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.
4. 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 2010; 81: 16-21.
5. Jick S, Hagberg K, Kaye J. ORTHO EVRA®and venous thromboembolism: an update. Letter to the Editor. Contraception 2010; 81: 452-453.
6. Dore D, Norman H, Loughlin J, Seeger D. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010; 81: 408-413.
7. 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].
8. 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.
9. 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.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
Counsel patients about the following information:
- Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use, and that women who are over 35 years old and smoke should not use combined hormonal contraceptives.
- ORTHO EVRA does not protect against HIV infection (AIDS) and other sexually transmitted infections.
- The WARNINGS AND PRECAUTIONS associated with combined hormonal contraceptives.
- ORTHO EVRA is not to be used during pregnancy; if pregnancy occurs during use of ORTHO EVRA, instruct the patient to stop further use.
- Apply a single patch the same day every week (Weeks 1 through 3). Instruct patients what to do in the event a patch is missed. See “WHAT IF I FORGET TO CHANGE MY PATCH?” section in FDA-Approved Patient Labeling.
- Use a back-up or alternative method of contraception when enzyme inducers are used with ORTHO EVRA.
- Combined hormonal contraceptives may reduce breast milk production; this is less likely to occur if breastfeeding is well established.
- Women who start combined hormonal contraceptives postpartum, and who have not yet had a period, should use an additional method of contraception until they have used a patch for 7 consecutive days.
- Amenorrhea may occur. Consider pregnancy in the event of amenorrhea. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles, amenorrhea in one cycle if the woman has not adhered to the dosing schedule, or if associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.
- 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, becomes stuck to itself or another surface, has other material stuck to it, or 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.
- A woman may not be protected from pregnancy if a patch is partially or completely detached for ≥ 24 hours (or if the woman is not sure how long the patch has been detached). She should start a new cycle immediately by applying a new patch. Back-up contraception, such as a condom and spermicide or diaphragm and spermicide, must be used for the first week of the new cycle.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
See WARNINGS AND PRECAUTIONS and Use in Specific Populations.
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.
Use In Specific Populations
There is little or no increased risk of birth defects in women who inadvertently use hormonal contraceptives during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose hormonal contraceptives prior to conception or during early pregnancy.
The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
The effects of ORTHO EVRA in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.
Safety and efficacy of ORTHO EVRA have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
ORTHO EVRA has not been studied in postmenopausal women and is not indicated in this population.
No studies with ORTHO EVRA have been conducted in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
No studies with ORTHO EVRA have been conducted in women with renal impairment.
Women with Weight > 198 lbs (90 kg)
ORTHO EVRA may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/12/2013
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