XULANE (Page 2 of 11)

Change Day Adjustment

If the woman wishes to change her Patch Change Day, she should complete her current cycle, removing the third Xulane patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying a new Xulane patch on the desired day. In no case should there be more than 7 consecutive patch-free days.

Breakthrough Bleeding or Spotting

In the event of unscheduled or breakthrough bleeding or spotting (bleeding that occurs on the days that Xulane is worn), treatment should be continued. If unscheduled bleeding persists longer than a few cycles, consider causes other than Xulane.

If the woman does not have scheduled or withdrawal bleeding (bleeding that should occur during the patch-free week), she should resume treatment on the next scheduled Change Day. If Xulane has been used correctly, the absence of withdrawal bleeding is not necessarily an indication of pregnancy. Nevertheless, consider the possibility of pregnancy, especially if absence of withdrawal bleeding occurs in 2 consecutive cycles. Discontinue Xulane if pregnancy is confirmed.

In Case of Skin Irritation

If patch use results in uncomfortable irritation, the patch may be removed and a new patch may be applied to a different location until the next Change Day. Only one patch should be worn at a time.

Additional Instructions for Dosing

Unscheduled bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives. In case of breakthrough bleeding, as in all cases of irregular bleeding from the vagina, consider nonfunctional causes. In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina, take adequate diagnostic measures to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another method of contraception may solve the problem.

Use of Hormonal Contraceptives in the Event of a Missed Menstrual Period

1.
If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of Xulane if pregnancy is confirmed.
2.
If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed.
3.
If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed.

3 DOSAGE FORMS AND STRENGTHS

Xulane® (norelgestromin and ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day norelgestromin (NGMN) and 35 mcg/day ethinyl estradiol (EE).

Xulane® is a 14 cm² peach, transdermal system printed with “Xulane® (norelgestromin and ethinyl estradiol) 150/35 mcg per day” in brown ink. Each system contains 4.86 mg norelgestromin, USP and 0.53 mg ethinyl estradiol, USP.

4 CONTRAINDICATIONS

Do not prescribe Xulane to women who are known to have the following conditions:

A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
o
Smoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)]
o
Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
o
Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
o
Have cerebrovascular disease [see Warnings and Precautions (5.1)]
o
Have coronary artery disease [see Warnings and Precautions (5.1)]
o
Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
o
Have uncontrolled hypertension [see Warnings and Precautions (5.5)]
o
Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.7)]
o
Have headaches with focal neurological symptoms or have migraine headaches with aura
Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]
Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]
Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)]
Pregnancy, because there is no reason to use hormonal contraceptives during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.12)]
Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations [see Warnings and Precautions (5.4)]

5 WARNINGS AND PRECAUTIONS

5.1 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 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 (4)].

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 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 Norelgestromin and Ethinyl Estradiol Transdermal System Compared to Combined Oral Contraceptive Users
*
“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 idiopathic cases.
#
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)]
Þ
LNG = levonorgestrel
ß
48 months of data.
à
69 months of data.
è
84 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.

Epidemiologic Study *

Comparator Product

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 Þ/30 mcg EE

2.0 (0.9 – 4.1) ß

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 databases è, ð,9

“All progestins ø”/20 — 35 mcg EE

LNG/30 mcg EE

1.4 (0.9 – 2.0)

1.2 (0.8 – 1.9)

Figure 1: VTE Risk of Norelgestromin and Ethinyl Estradiol Transdermal System Relative to Combined Oral Contraceptives

Figure 1:  VTE Risk of Norelgestromin and Ethinyl Estradiol Transdermal System Relative to Combined Oral Contraceptives
(click image for full-size original)

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

Figure 2:  Likelihood of Developing a VTE
(click image for full-size original)

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.

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