Included as part of the PRECAUTIONS section.
Thromboembolic Disorders And Other Vascular Problems
Stop Xulane if an arterial or deep venous thrombotic
event (VTE) occurs.
Stop Xulane if there is unexplained loss of vision,
proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for
retinal vein thrombosis immediately.
If feasible, stop Xulane 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 Xulane during prolonged immobilization
and resume treatment based on clinical judgment.
Start Xulane 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
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 norelgestromin and ethinyl estradiol
transdermal system are described below. These are 4 case control studies, that compared
VTE rates among women using norelgestromin and ethinyl estradiol transdermal
system 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 norelgestromin and ethinyl estradiol transdermal
system. All five studies were retrospective studies from U.S. electronic
healthcare databases and included women aged 15 to 44 (10 to 55 in the
FDA-funded study) who used norelgestromin and ethinyl estradiol transdermal
system or oral contraceptives containing 20 mcg to 35 mcg of ethinyl estradiol
(EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the
prodrug for NGMN, the progestin in Xulane.
Some of the data from the epidemiologic studies suggest
an increased risk of VTE with use of norelgestromin and ethinyl estradiol
transdermal system 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
norelgestromin and ethinyl estradiol transdermal system.
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 nonidiopathic) 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 Norelgestromin and Ethinyl Estradiol
Trans dermal System Compared to Combined Oral Contraceptive Users
||Risk Ratios (95% CI)
|i3 Ingenix NGM Study in Ingenix Research Datamart1,6,7,8
||NGM/35 mcg EE†
||2.2‡ (1.2 - 4.0)§
|BCDSP¶ NGM Study in Pharmetrics database2,3,5
||NGM/35 mcg EE
||1.2 (0.9 - 1.8)#
|BCDSP¶ LNG Study in Pharmetrics database4
||LNG^/30 mcg EE
||2.0 (0.9 - 4.1)β
|BCDSP¶ LNG Study in Marketscan database4
||LNG/30 mcg EE
||1.3 (0.8 - 2.1)à
|FDA-funded Study in Kaiser
Permanente and Medicaid databasesè,ð,9
|“All progestinsØ”/20 - 35 mcg EE
LNG/30 mcg EE
|1.4 (0.9 - 2.0)
1.2 (0.8 - 1.9)
|*“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.
†NGM = norgestimate; EE = ethinyl estradiol
‡Increase in risk of VTE is statistically significant
§ Pooled 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.
¶BCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on
#Pooled 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)]
ÞLNG = levonorgestrel
β4 8 months of data.
à69 months of data.
è84 months of data in FDA-funded study
ð Results 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).
Ø Includes the following progestins: LNG, norethindrone, norgestimate.
Figure 1: VTE Risk of Norelgestromin and Ethinyl
Estradiol Trans dermal System Relative to Combined Oral Contraceptives
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 postpartum 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 CHCs and when restarting hormonal contraception after a break of 4 weeks or
longer. The risk of thromboembolic disease due to CHCs gradually disappears
after CHC 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 postpartum 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 VTE
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 norelgestromin and ethinyl
estradiol transdermal system 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 norelgestromin and ethinyl
estradiol transdermal system compared with women using an oral contraceptive
containing EE 35 mcg. In contrast, the Cmax for EE is approximately 25% lower
in women using norelgestromin and ethinyl estradiol transdermal system.
Inter-subject variability results in increased exposure to EE in some women
using either norelgestromin and ethinyl estradiol transdermal system or oral
contraceptives. However, inter-subject variability in women using
norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl
estradiol transdermal system compared with women using oral contraceptives
containing 30 mcg to 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 Xulane in women with liver disease, such as
acute viral hepatitis or severe (decompensated) cirrhosis of liver [see
CONTRAINDICATIONS]. Discontinue Xulane 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
Xulane 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.
Risk Of Liver Enzyme Elevations With Concomitant
Hepatitis C Treatment
During clinical trials with the Hepatitis C combination
drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without
dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN),
including some cases greater than 20 times the ULN, were significantly more
frequent in women using ethinyl estradiol-containing medications, such as CHCs.
Discontinue Xulane prior to starting therapy with the combination drug regimen
ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see
CONTRAINDICATIONS]. Xulane can be restarted approximately 2 weeks following
completion of treatment with the Hepatitis C combination drug regimen.
High Blood Pressure
Xulane 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
Xulane 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
Carbohydrate And Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who take
Xulane. CHCs may decrease glucose tolerance in a dose-related fashion. In a
6-cycle clinical trial with norelgestromin and ethinyl estradiol transdermal
system there were no clinically significant changes in fasting blood glucose
from baseline to end of treatment.
Consider alternative contraception for women with
uncontrolled dyslipidemia. A small proportion of women will have adverse lipid
changes while on hormonal contraceptives.
Women with hypertriglyceridemia, or a family history
thereof, may be at an increased risk of pancreatitis when using hormonal
If a woman taking Xulane develops new headaches that are
recurrent, persistent or severe, evaluate the cause and discontinue Xulane if
Consider discontinuation of Xulane 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 norelgestromin and ethinyl estradiol transdermal
system. 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 norelgestromin and ethinyl estradiol
transdermal system 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 norelgestromin and
ethinyl estradiol transdermal system at least in part, due to bleeding or
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)
|T reatment Cycle
||Pooled data from 3 studies
N = 3319
|*Percentage of subjects with breakthrough
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
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
Xulane 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 Xulane if depression recurs to a serious degree.
Carcinoma Of Breasts And Cervix
Xulane is contraindicated in women who currently have or
have had breast cancer because breast cancer may be hormonally sensitive [see
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
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.
In women with hereditary angioedema, exogenous estrogens
may induce or exacerbate symptoms of angioedema.
Chloasma may occasionally occur, especially in women with
a history of chloasma gravidarum. Women with a tendency to chloasma should
avoid exposure to the sun or ultraviolet radiation while using Xulane.
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
- The use of CHCs increases the risk of VTE. However,
pregnancy increases the risk of VTE as much or more than the use of CHCs. The
risk of VTE in women using CHCs is 3 to 12 cases per 10,000 woman-years. The
risk of VTE is highest during the first year of use of CHCs and when restarting
hormonal contraception after a break of 4 weeks or longer. The risk of
thromboembolic disease due to CHCs gradually disappears after use is
- Xulane does not protect against HIV infection (AIDS) and
other sexually transmitted infections.
- The Warnings and Precautions associated with combined
- Xulane is not to be used during pregnancy; if pregnancy
occurs during use of Xulane, 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
- Use a back-up or alternative method of contraception when
enzyme inducers are used with Xulane.
- 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 Xulane 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
The brands listed are trademarks of their respective
Carcinogenesis, Mutagenesis, Impairment Of Fertility
See WARNINGS AND PRECAUTIONS and Use In Specific
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
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
The effects of Xulane 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 norelgestromin and ethinyl
estradiol transdermal system 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.
Xulane has not been studied in postmenopausal women and
is not indicated in this population.
No studies with Xulane 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
No studies with Xulane have been conducted in women with
Women With Weight ≥ 198 lbs (90 kg)
Xulane may be less effective in preventing pregnancy in
women who weigh 198 lbs (90 kg) or more.
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:
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;
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
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,