Pharmacokinetic overview

The systemic delivery rate of norelgestromin (NGMN) and ethinyl estradiol (EE) transdermal system is approximately 150 mcg of NGMN and 35 mcg of EE per day based on a comparative analysis with intravenous (IV) data. Following a single application of (NGMN) and ethinyl estradiol (EE) transdermal system, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the three clinical studies have demonstrated that steady state is reached within 2 weeks of application.1

Transdermal and Combined Oral Contraceptive (COC) PK profiles

The figures below present mean PK profiles for NGMN and EE, respectively, following once-daily administration of an oral contraceptive (containing NGM 250 mcg /EE 35 mcg) compared to the 7-day norelgestromin and ethinyl estradiol transdermal system (containing NGMN 4.86 mg /EE 0.53 mg) during Cycle 2 in 32 healthy female volunteers.

PKprofilemap2

Mean serum concentration - time profiles of NGMN of Xulane versus a COC1*

PKprofilemap

Mean serum concentration - time profiles of EE of Xulane versus a COC1*

*Following once-daily administration of an oral contraceptive for two cycles or application of NGM for two cycles to the buttock in healthy female volunteers.
[Oral contraceptive: Cycle 2, Days 15 to 21, Xulane: Cycle 2, Week 3]

Pkprofiledata

Mean (%CV) NGMN and EE steady state PK parameters of Xulane and a COC1*

*Mean (%CV) NGMN and EE steady state pharmacokinetic parameters following application of norelgestromin and ethinyl estradiol transdermal system and once-daily administration of an oral contraceptive (containing NGM 250 mcg /EE 35 mcg) in healthy female volunteers
**Cycle 2, Week 3
Cycle 2, Day 21
NGM is rapidly metabolized to NGMN following oral administration
§Average weekly exposure, calculated as AUC24 x 7
Cavg

In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with norelgestromin and ethinyl estradiol transdermal system for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive. Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for norelgestromin and ethinyl estradiol transdermal system, and the Cmax was about 35% higher for the oral contraceptive, respectively.

Inter-subject variability (%CV) for PK parameters following delivery from NGMN and EE transdermal system was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.

Ethinyl Estradiol Exposure

Higher estrogen exposure may increase the risk of adverse reactions, including venous thromboembolism (VTE). The Area Under the Curve (AUC) for ethinyl estradiol (EE) is approximately 60% higher in women using XULANE compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system [see Clinical Pharmacology (12.3)].

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XULANE® (norelgestromin and ethinyl estradiol transdermal system) 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol

INDICATION AND USAGE

Xulane is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m2 for whom a transdermal delivery system is an appropriate method of contraception.

Limitations of Use:

Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs. (90 kg) or more. Xulane is contraindicated for use in women with BMI ≥ 30 kg/m2 [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Studies (14)].

IMPORTANT SAFETY INFORMATION

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m2

  • Cigarette Smoking and Serious Cardiovascular Events
    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, CHCs, including Xulane, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].
  • Contraindicated in Women with a BMI ≥ 30 kg/m2
    Xulane is contraindicated in women with a BMI ≥ 30 kg/m2. The risk of VTE may be greater with Xulane in women with a BMI > 30 kg/m2 compared to women with a lower BMI. [see Contraindications (4) and Warnings and Precautions (5.1)].

CONTRAINDICATIONS

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

  • A high risk of arterial or venous thrombotic diseases including women who: * smoke, if over age 35 * have now or have had deep vein thrombosis or pulmonary embolism * have inherited or acquired hypercoagulopathies * have cerebrovascular disease * have coronary artery disease * have thrombogenic valvular or thrombogenic rhythm diseases of the heart including 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;
  • Body Mass Index ≥ 30 kg/m2
  • Liver tumors or liver disease;
  • Undiagnosed abnormal uterine bleeding;
  • Pregnancy;
  • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past;
  • Use Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir.

WARNINGS AND PRECAUTIONS

Thromboembolic Disorders and Other Vascular Conditions

  • Do not use Xulane in women at high risk for arterial or venous thromboembolism diseases.
  • Combination hormonal contraceptives (CHCs) increase the risk of thromboembolic disorders including venous thromboembolism (VTE). Known risk factors for VTE include smoking, obesity and family history of VTE. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of 4 weeks or longer
  • Use of CHCs also increases the risk of arterial thromboses (e.g., stroke and myocardial infarction). The risk is greatest among hypertensive women who are > 35 years old and smoke. Use CHCs with caution in women with cardiovascular disease risk factors.
  • Stop Xulane if: * an arterial or VTE occurs; * there is unexplained loss of vision, proptosis, diplopia, papilledema, or retina vascular lesions; * at least 4 weeks before and through 2 weeks after major surgery or surgeries known to have an elevated risk of VTE.  
  • Start Xulane no earlier than 4 weeks after delivery in women who are not breastfeeding.

Ethinyl Estradiol Exposure

  • Higher estrogen exposure may increase the risk of adverse reactions, including VTE.
  • The Area Under the Curve (AUC) for ethinyl estradiol (EE) is approximately 60% higher in women using XULANE compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system. See Section 12.3 of the PI.

Liver Disease

  • Do not use Xulane in women with liver disease or tumors.
  • Discontinue Xulane if jaundice or acute or chronic disturbances of liver function develop.
  • Hepatic adenomas are associated with CHC use. Rupture of hepatic adenomas may cause death.

Risk of liver enzyme elevations with concomitant hepatitis C treatment

  • Discontinue Xulane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

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.

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.

Carbohydrate and Lipid Metabolic Effects

  • Carefully monitor prediabetic and diabetic women on Xulane. CHCs may decrease glucose tolerance in a dose-related fashion.  
  • Consider alternative contraception for women with uncontrolled dyslipidemia.
  • Women with (or family history of) hypertriglyceridemia may be at increased risk of pancreatitis.

Headache

  • Do not use Xulane in women who have headaches with focal neurological symptoms or migraine headaches with aura or in women over age 35 with any migraine headaches.
  • If a patient 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 migraines.

Bleeding Irregularities

  • Women may experience unscheduled bleeding and spotting on Xulane. Rule out malignancy, other pathology or pregnancy.
  • In the event of amenorrhea, consider the possibility of pregnancy.

Other Warnings and Precautions

  • Discontinue Xulane use if pregnancy is confirmed.
  • Carefully observe women with a history of depression and discontinue Xulane if depression recurs to a serious degree.
  • Xulane is contraindicated in women who currently have or have had breast cancer or other estrogen- or progestin-sensitive cancer. There is substantial evidence that CHCs do not increase the incidence of breast cancer.
  • Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.
  • 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.

ADVERSE REACTIONS

  • 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.

Patients should be counseled that Xulane does not protect against HIV infection (AIDS) and other sexually transmitted infections.

DRUG INTERACTIONS

  • Drugs or herbal products that induce certain enzymes (for example CYP3A4) may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception.
  • 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.

USE IN SPECIAL POPULATIONS

  • The effects of Xulane in nursing mothers have not been evaluated and are unknown. Advise women to use other forms of contraception while nursing.
  • Xulane has not been studied in postmenopausal women or in women before menarche and should not be used in these populations.

This is not all of the information you should read prior to prescribing Xulane.  Click here for Full Prescribing Information, including Boxed WARNING.

Reference:

  1. Xulane Prescribing Information. April 2020. Mylan Pharmaceuticals Inc. Morgantown, WV.

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IMPORTANT SAFETY INFORMATION

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m2

  • Cigarette Smoking and Serious Cardiovascular Events
    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, CHCs, including Xulane, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].
  • Contraindicated in Women with a BMI ≥ 30 kg/m2
    Xulane is contraindicated in women with a BMI ≥ 30 kg/m2. The risk of VTE may be greater with Xulane in women with a BMI > 30 kg/m2 compared to women with a lower BMI. [see Contraindications (4) and Warnings and Precautions (5.1)].

XULANE® (norelgestromin and ethinyl estradiol transdermal system) 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol

INDICATION AND USAGE

Xulane is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m2 for whom a transdermal delivery system is an appropriate method of contraception.

Limitations of Use:

Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs. (90 kg) or more. Xulane is contraindicated for use in women with BMI ≥ 30 kg/m2 [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Studies (14)].

IMPORTANT SAFETY INFORMATION

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m2

  • Cigarette Smoking and Serious Cardiovascular Events
    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, CHCs, including Xulane, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].
  • Contraindicated in Women with a BMI ≥ 30 kg/m2
    Xulane is contraindicated in women with a BMI ≥ 30 kg/m2. The risk of VTE may be greater with Xulane in women with a BMI > 30 kg/m2 compared to women with a lower BMI. [see Contraindications (4) and Warnings and Precautions (5.1)].

CONTRAINDICATIONS

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

  • A high risk of arterial or venous thrombotic diseases including women who: * smoke, if over age 35 * have now or have had deep vein thrombosis or pulmonary embolism * have inherited or acquired hypercoagulopathies * have cerebrovascular disease * have coronary artery disease * have thrombogenic valvular or thrombogenic rhythm diseases of the heart including 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;
  • Body Mass Index ≥ 30 kg/m2
  • Liver tumors or liver disease;
  • Undiagnosed abnormal uterine bleeding;
  • Pregnancy;
  • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past;
  • Use Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir.

WARNINGS AND PRECAUTIONS

Thromboembolic Disorders and Other Vascular Conditions

  • Do not use Xulane in women at high risk for arterial or venous thromboembolism diseases.
  • Combination hormonal contraceptives (CHCs) increase the risk of thromboembolic disorders including venous thromboembolism (VTE). Known risk factors for VTE include smoking, obesity and family history of VTE. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of 4 weeks or longer
  • Use of CHCs also increases the risk of arterial thromboses (e.g., stroke and myocardial infarction). The risk is greatest among hypertensive women who are > 35 years old and smoke. Use CHCs with caution in women with cardiovascular disease risk factors.
  • Stop Xulane if: * an arterial or VTE occurs; * there is unexplained loss of vision, proptosis, diplopia, papilledema, or retina vascular lesions; * at least 4 weeks before and through 2 weeks after major surgery or surgeries known to have an elevated risk of VTE.  
  • Start Xulane no earlier than 4 weeks after delivery in women who are not breastfeeding.

Ethinyl Estradiol Exposure

  • Higher estrogen exposure may increase the risk of adverse reactions, including VTE.
  • The Area Under the Curve (AUC) for ethinyl estradiol (EE) is approximately 60% higher in women using XULANE compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system. See Section 12.3 of the PI.

Liver Disease

  • Do not use Xulane in women with liver disease or tumors.
  • Discontinue Xulane if jaundice or acute or chronic disturbances of liver function develop.
  • Hepatic adenomas are associated with CHC use. Rupture of hepatic adenomas may cause death.

Risk of liver enzyme elevations with concomitant hepatitis C treatment

  • Discontinue Xulane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

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.

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.

Carbohydrate and Lipid Metabolic Effects

  • Carefully monitor prediabetic and diabetic women on Xulane. CHCs may decrease glucose tolerance in a dose-related fashion.  
  • Consider alternative contraception for women with uncontrolled dyslipidemia.
  • Women with (or family history of) hypertriglyceridemia may be at increased risk of pancreatitis.

Headache

  • Do not use Xulane in women who have headaches with focal neurological symptoms or migraine headaches with aura or in women over age 35 with any migraine headaches.
  • If a patient 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 migraines.

Bleeding Irregularities

  • Women may experience unscheduled bleeding and spotting on Xulane. Rule out malignancy, other pathology or pregnancy.
  • In the event of amenorrhea, consider the possibility of pregnancy.

Other Warnings and Precautions

  • Discontinue Xulane use if pregnancy is confirmed.
  • Carefully observe women with a history of depression and discontinue Xulane if depression recurs to a serious degree.
  • Xulane is contraindicated in women who currently have or have had breast cancer or other estrogen- or progestin-sensitive cancer. There is substantial evidence that CHCs do not increase the incidence of breast cancer.
  • Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.
  • 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.

ADVERSE REACTIONS

  • 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.

Patients should be counseled that Xulane does not protect against HIV infection (AIDS) and other sexually transmitted infections.

DRUG INTERACTIONS

  • Drugs or herbal products that induce certain enzymes (for example CYP3A4) may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception.
  • 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.

USE IN SPECIAL POPULATIONS

  • The effects of Xulane in nursing mothers have not been evaluated and are unknown. Advise women to use other forms of contraception while nursing.
  • Xulane has not been studied in postmenopausal women or in women before menarche and should not be used in these populations.

This is not all of the information you should read prior to prescribing Xulane.  Click here for Full Prescribing Information, including Boxed WARNING.