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:
  • -Smoke, if over age 35
  • -Have deep vein thrombosis or pulmonary embolism, now or in the past
  • -Have inherited or acquired hypercoagulopathies
  • -Have cerebrovascular disease
  • -Have coronary artery disease
  • -Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
  • -Have uncontrolled hypertension
  • -Have diabetes mellitus with vascular disease
  • -Have headaches with focal neurological symptoms or have migraine headaches with aura
  • •Women over age 35 with any migraine headaches
• Liver tumors, benign or malignant, or liver disease
• Undiagnosed abnormal uterine bleeding
• Pregnancy, because there is no reason to use hormonal contraceptives during pregnancy
• Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past
• Do not prescribe Xulane to women using Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations

WARNINGS AND PRECAUTIONS

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.

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. The interpretations of relative risk estimates from these studies 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.

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.

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.

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.

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 norelgestromin and ethinyl estradiol transdermal system patch is different from the PK profile for oral contraceptives in that it has a higher C_ss and a lower C_max. 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 C_max 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.

Liver Disease

Do not use Xulane in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver. 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 excluded.

Xulane is contraindicated in women with benign and malignant liver tumors. 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, were significantly more frequent in women using ethinyl estradiol-containing medications. Discontinue Xulane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. 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. 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.

Gallbladder Disease

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 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 contraceptives.

Headache

If a woman taking Xulane develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue Xulane if indicated. 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).

Bleeding Irregularities

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 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

Discontinue Xulane use if pregnancy is confirmed. Administration of CHCs should not be used as a test for pregnancy.

Depression

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. 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.

Monitoring

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.

Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma

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.

Adverse Reactions

The following serious adverse reactions with the use of combination hormonal contraceptives, including Xulane, are discussed elsewhere in the Important Safety Information:

• Serious cardiovascular events and stroke
• Vascular events, including venous and arterial thromboembolic events
• Liver disease

Adverse reactions commonly reported by users of combination hormonal contraceptives are:

• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

The most common adverse reactions (≥ 5%) reported during clinical trials of norelgestromin and ethinyl estradiol transdermal system were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability.

Additional adverse drug reactions that occurred in < 2.5% of norelgestromin and ethinyl estradiol transdermal system-treated subjects in the clinical trials are:

• Abdominal distension
• Fluid retention¹, malaise
• Cholecystitis
• Blood pressure increased, lipid disorders¹
• Muscle spasms
• Insomnia, libido decreased, libido increased
• Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness
• Pulmonary embolism
• Chloasma, dermatitis contact, erythema, skin irritation

¹Represents a bundle of similar terms

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Coadministration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 20% to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of coadministration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

CHCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of CHCs.

Do not co-administer Xulane with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Use In Specific Populations

Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

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.

No studies with Xulane have been conducted in women with renal impairment.

Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.

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