Norelgestromin and ethinyl estradiol transdermal system

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# Black Box Warning

# Overview
Norelgestromin and ethinyl estradiol transdermal system is a hormonal contraceptive that is FDA approved for the prophylaxis of pregnancy prevention. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- Norelgestromin and ethinyl estradiol  is indicated for the prevention of pregnancy in women who elect to use a transdermal patch as a method of contraception.
Limitation of Use:
- Norelgestromin and ethinyl estradiol  may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.

# Dosing
- To achieve maximum contraceptive effectiveness, norelgestromin and ethinyl estradiol  must be used exactly as directed.
- Complete instructions to facilitate patient counseling on proper system usage may be found in the FDA-Approved Patient Labeling.
How to Use ORTHO EVRA
- The norelgestromin and ethinyl estradiol  transdermal system uses a 28-day (four-week) cycle. A new patch is applied each week for three weeks (21 total days). Week Four is patch-free. Withdrawal bleeding is expected during this time.
- Every new patch should be applied on the same day of the week. This day is known as the "Patch Change Day." For example, if the first patch is applied on a Monday, all subsequent patches should be applied on a Monday. Only one patch should be worn at a time.
- Do not cut, damage or alter the norelgestromin and ethinyl estradiol  patch in any way. If the norelgestromin and ethinyl estradiol  patch is cut, damaged or altered in size, contraceptive efficacy may be impaired.
- On the day after Week Four ends, a new four-week cycle is started by applying a new patch. Under no circumstances should there be more than a seven-day patch-free interval between dosing cycles.

## How to Start Using ORTHO EVRA
The woman has two options for starting the patch and she should choose the option that is right for her:
- First Day StartThe woman should apply her first patch during the first 24 hours of her menstrual period.
- Sunday StartThe woman should apply her first patch on the first Sunday after her menstrual period begins. With this option, a non-hormonal backup method of birth control, such as a condom and spermicide or diaphragm and spermicide, is needed for the first 7 days of the first cycle only. If her period starts on a Sunday, the first patch should be applied that day, and no backup contraception is needed.
- When Switching From the Pill or Vaginal Contraceptive Ring to the PatchIf the woman is switching from the pill or vaginal contraceptive ring to norelgestromin and ethinyl estradiol , she should complete her current pill cycle or vaginal ring cycle and apply the first norelgestromin and ethinyl estradiol  patch on the day she would normally start her next pill or insert her next vaginal ring. If she does not get her period within a week after taking the last active pill or removing the last vaginal ring, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start norelgestromin and ethinyl estradiol  for contraception. If the patch is applied more than a week after taking the last active pill or removal of the last vaginal ring, she should use a non-hormonal contraceptive concurrently for the first 7 days of patch use.
Use after Childbirth
- Start contraceptive therapy with norelgestromin and ethinyl estradiol  in women who elect not to breastfeed no sooner than 4 weeks after childbirth due to increased risk of thromboembolism. If a woman begins using norelgestromin and ethinyl estradiol  postpartum, and has not yet had a period, consider the possibility of ovulation and conception occurring prior to use of norelgestromin and ethinyl estradiol , and instruct her to use an additional method of contraception, such as a condom and spermicide or diaphragm and spermicide, for the first seven days.
Use after Abortion or Miscarriage
- After an abortion or miscarriage that occurs in the first trimester, norelgestromin and ethinyl estradiol  may be started immediately. An additional method of contraception is not needed if norelgestromin and ethinyl estradiol  is started immediately. If use of norelgestromin and ethinyl estradiol  is not started within 5 days following a first trimester abortion, the woman should follow the instructions for a woman starting norelgestromin and ethinyl estradiol  for the first time. In the meantime she should be advised to use a non-hormonal contraceptive method. Ovulation may occur within 10 days of an abortion or miscarriage.
- Start norelgestromin and ethinyl estradiol  no earlier than 4 weeks after a second trimester abortion or miscarriage, due to the increased risk of thromboembolic disease.

# DOSAGE FORMS AND STRENGTHS
- Transdermal system: 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Norelgestromin and ethinyl estradiol transdermal system in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Norelgestromin and ethinyl estradiol transdermal system in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Norelgestromin and ethinyl estradiol transdermal system in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Norelgestromin and ethinyl estradiol transdermal system in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Norelgestromin and ethinyl estradiol transdermal system in pediatric patients.

# Contraindications
Do not prescribe norelgestromin and ethinyl estradiol  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

# Warnings
Thromboembolic Disorders and Other Vascular Problems
- Stop norelgestromin and ethinyl estradiol  if an arterial or deep venous thrombotic event (VTE) occurs.
- Stop norelgestromin and ethinyl estradiol  if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
- If feasible, stop norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol  during prolonged immobilization and resume treatment based on clinical judgment.
- Start norelgestromin and ethinyl estradiol  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.
- Five epidemiologic studies19 that assessed the risk of VTE associated with use of norelgestromin and ethinyl estradiol  are described below. These are 4 case control studies, that compared VTE rates among women using norelgestromin and ethinyl estradiol  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 . All five studies were retrospective studies from U.S. electronic healthcare databases and included women aged 1544 (1055 in the FDA-funded study) who used norelgestromin and ethinyl estradiol  or oral contraceptives containing 2035 mcg of ethinyl estradiol (EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the prodrug for NGMN, the progestin in norelgestromin and ethinyl estradiol .
- Some of the data from the epidemiologic studies suggest an increased risk of VTE with use of norelgestromin and ethinyl estradiol  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 .
- 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 , 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.
All estimates took account of new-user status. The method and time period used to identify "new users" varied from study to study.
Includes 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.
- 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.
- 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  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 norelgestromin and ethinyl estradiol  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 . Inter-subject variability results in increased exposure to EE in some women using either norelgestromin and ethinyl estradiol  or oral contraceptives. However, inter-subject variability in women using norelgestromin and ethinyl estradiol  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  compared with women using oral contraceptives containing 3035 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism.
Liver Disease
Impaired Liver Function
- Do not use norelgestromin and ethinyl estradiol  in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver. Discontinue norelgestromin and ethinyl estradiol  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.
Liver Tumors
- Norelgestromin and ethinyl estradiol  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.
High Blood Pressure
- Norelgestromin and ethinyl estradiol  is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease. For women with well-controlled hypertension, monitor blood pressure and stop norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol . CHCs may decrease glucose tolerance in a dose-related fashion. In a 6-cycle clinical trial with norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol  develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue norelgestromin and ethinyl estradiol  if indicated.
- Consider discontinuation of norelgestromin and ethinyl estradiol  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 Bleeding and Spotting
- Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using norelgestromin and ethinyl estradiol . 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  in preventing pregnancy assessed scheduled and unscheduled bleeding 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  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.
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 norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol  if depression recurs to a serious degree.
Carcinoma of Breasts and Cervix
- Norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol .

# Adverse Reactions

## Clinical Trials Experience
- The following serious adverse reactions with the use of combination hormonal contraceptives, including norelgestromin and ethinyl estradiol , are discussed elsewhere in the labeling:
- 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
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The data described below reflect exposure to norelgestromin and ethinyl estradiol  in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (norelgestromin and ethinyl estradiol  or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%).
- The most common adverse reactions ( 5%) reported during clinical trials 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.
- Adverse drug reactions reported by  2.5% of norelgestromin and ethinyl estradiol -treated subjects in these trials are shown in Table 3.
- Additional adverse drug reactions that occurred in < 2.5% of norelgestromin and ethinyl estradiol -treated subjects in the above clinical trials datasets are:
- Gastrointestinal disorders: Abdominal distension
- General disorders and administration site conditions: Fluid retention, malaise
- Hepatobiliary disorders: Cholecystitis
- Investigations: Blood pressure increased, lipid disorders1
- Musculoskeletal and connective tissue disorders: Muscle spasms
- Psychiatric disorders: Insomnia, libido decreased, libido increased
- Reproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome uterine spasm, vaginal discharge, vulvovaginal dryness
- Respiratory, thoracic and mediastinal disorders: Pulmonary embolism
- Skin and subcutaneous tissue disorders: Chloasma, contact dermatitis , erythema, skin irritation

## Postmarketing Experience
- The following adverse reactions (Table 4) have been identified during postapproval use of norelgestromin and ethinyl estradiol . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

# Drug Interactions
- Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Hormonal Contraceptives
- Substances decreasing the plasma concentrations of CHCs and potentially diminishing the efficacy of CHCs:
- 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. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. 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.
- Substances increasing the plasma concentrations of CHCs:
- Co-administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 2025%. 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.
- Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:
- Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease  or increase )/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease  or increase ).
Effects of Combined Hormonal Contraceptives on Other Drugs
- 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
Interference with Laboratory Tests
- 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

### Pregnancy
Pregnancy Category (FDA):
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norelgestromin and ethinyl estradiol transdermal system in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Norelgestromin and ethinyl estradiol transdermal system during labor and delivery.

### Nursing Mothers
- 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.

### Pediatric Use
- 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.

### Geriatic Use
- ORTHO EVRA has not been studied in postmenopausal women and is not indicated in this population.

### Gender
There is no FDA guidance on the use of Norelgestromin and ethinyl estradiol transdermal system with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Norelgestromin and ethinyl estradiol transdermal system with respect to specific racial populations.

### Renal Impairment
- No studies with ORTHO EVRA have been conducted in women with renal impairment.

### Hepatic Impairment
- 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Norelgestromin and ethinyl estradiol transdermal system in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Norelgestromin and ethinyl estradiol transdermal system in patients who are immunocompromised.

# Administration and Monitoring

### Administration

# How to Apply ORTHO EVRA
CHOOSING A PLACE ON THE BODY TO PUT THE PATCH
- The patch may be placed on the upper outer arm, abdomen, buttock or back in a place where it won't be rubbed by tight clothing. For example, it should not be placed under the waistband of clothing.
- The patch should not be placed on the breasts, on cut or irritated skin, or on the same location as the previous patch.
Before applying the patch:
- The woman should make sure the skin is clean and dry.
- She should not use lotions, creams, oils, powders, or make-up at the patch site. It may cause the patch to fail to stick properly or to become loose.
HOW TO APPLY THE PATCH
- The woman should check her patch every day to make sure all edges are sticking correctly.
WHEN TO CHANGE THE ORTHO EVRA PATCH
- The patch works for seven days (one week). The woman should apply a new patch on the same day each week (her Patch Change Day) for 3 weeks in a row. She must make sure she has removed her old patch prior to applying the new patch.
- During Week 4, she DOES NOT wear a patch. She must make sure she removes her old patch. (Her period should begin during this week.)
- Following Week 4, she repeats the cycle of three weekly applications followed by a patch-free week.
WHAT IF THE PATCH BECOMES LOOSE OR FALLS OFF?
- The patch must stick securely to the skin to work properly. If the norelgestromin and ethinyl estradiol  patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. The woman should not try to reapply a patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it.
If a patch edge lifts up:
- The woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. She should run her fingers over the entire surface area to smooth out any "wrinkles" around the edges of the patch.
- If her patch does not stick completely, she should remove it and apply a replacement patch.
- She should not tape or wrap the patch to her skin or reapply a patch that is partially adhered to clothing.
If the patch has been off or partially off:
- For less than 1 Day, she should try to reapply it. If the patch does not adhere completely, she should apply a new patch immediately. (No backup contraception is needed and her Patch Change Day will stay the same).
- For more than 1 Day or if she is not sure for how long, she may not be protected from pregnancy. To reduce this risk, she should apply a new patch and start a new 4-week cycle. She will now have a new Patch Change Day and MUST USE NON-HORMONAL BACKUP CONTRACEPTION (such as a condom and spermicide or diaphragm and spermicide) for the first week of her new cycle.
IF THE WOMAN FORGETS TO CHANGE HER PATCH
- At the start of any patch cycle (Week One/Day 1): SHE MAY NOT BE PROTECTED FROM PREGNANCY. She should apply the first patch of her new cycle as soon as she remembers. There is now a new "Patch Change Day" and a new "Day 1." The woman must use back-up contraception, such as a condom and spermicide or diaphragm and spermicide, for the first week of the new cycle.
- In the middle of the patch cycle (Week Two/Day 8 or Week Three/Day 15),
- For one or two days (up to 48 hours), she should apply a new patch immediately. The next patch should be applied on the usual "Patch Change Day." No back-up contraception is needed.
- For more than two days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNANCY. She should stop the current contraceptive cycle and start a new four-week cycle immediately by putting on a new patch. There is now a new "Patch Change Day" and a new "Day 1." The woman must use back-up contraception for one week.
- At the end of the patch cycle (Week Four/Day 22),
- If the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual "Patch Change Day," which is the day after Day 28. No back-up contraception is needed.
Under no circumstances should there be more than a seven-day patch-free interval between cycles. If there are more than seven patch-free days, THE WOMAN MAY NOT BE PROTECTED FROM PREGNANCY and back-up contraception, such as a condom and spermicide or diaphragm and spermicide, must be used for seven days. As with combined oral contraceptives, the risk of ovulation increases with each day beyond the recommended drug-free period. If she has had intercourse during such an extended patch-free interval, consider the possibility of pregnancy.
Change Day Adjustment
- If the woman wishes to change her Patch Change Day, she should complete her current cycle, removing the third norelgestromin and ethinyl estradiol  patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying a new norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol  is worn), treatment should be continued. If unscheduled bleeding persists longer than a few cycles, consider causes other than norelgestromin and ethinyl estradiol .
- 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 norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol  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
- 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 norelgestromin and ethinyl estradiol  if pregnancy is confirmed.
- 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 norelgestromin and ethinyl estradiol  use if pregnancy is confirmed.
If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue norelgestromin and ethinyl estradiol  use if pregnancy is confirmed.

### Monitoring
There is limited information regarding Monitoring of Norelgestromin and ethinyl estradiol transdermal system in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Norelgestromin and ethinyl estradiol transdermal system in the drug label.

# Overdosage
- Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in females. In case of suspected overdose, all norelgestromin and ethinyl estradiol  patches should be removed and symptomatic treatment given.

# Pharmacology

## Mechanism of Action
- NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of norelgestromin and ethinyl estradiol . NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products.
- Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

## Structure
- Norelgestromin and ethinyl estradiol  is a transdermal system with a contact surface area of 20 cm2. It contains 6 mg NGMN and 0.75 mg EE, and its delivery rate is approximately 150 mcg of NGMN and 35 mcg of EE per day. Systemic exposures (as measured by area under the curve  and steady state concentration ) of NGMN and EE during use of norelgestromin and ethinyl estradiol  are higher and the Cmax is lower than those produced by an oral contraceptive containing NGM 250 mcg / EE 35 mcg.
- Norelgestromin and ethinyl estradiol  is a thin, matrix-type transdermal system consisting of three layers. The backing layer is composed of a beige flexible film consisting of a low-density pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and lauryl lactate as inactive components. The active components in this layer are the hormones, NGMN and EE. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer.
- The outside of the backing layer is heat-stamped "norelgestromin and ethinyl estradiol ".
- The structural formulas of the components are:
- Molecular weight, NGMN: 327.47
- Molecular weight, EE: 296.41
- Chemical name for NGMN: 18, 19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,3-oxime,(17)
- Chemical name for EE: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17-diol,(17)

## Pharmacodynamics
- One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.

## Pharmacokinetics
Absorption
- The systemic delivery rate of NGMN and EE from norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol , both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady state is reached within 2 weeks of application. In one of the clinical studies, Css concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE.
- Absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol  to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.
- The mean (%CV) PK parameters Css and AUC0168 for NGMN and EE following a single buttock application of norelgestromin and ethinyl estradiol  are summarized in Table 5.
- In multiple dose studies, AUC0168 for NGMN and EE was found to increase over time (Table 5). In a three-cycle study, these PK parameters reached steady state conditions during Cycle 3 (Figures 3 and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days.
- The absorption of NGMN and EE following application of ORTHO EVRA was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN, there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.
- Results from a study of consecutive ORTHO EVRA wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations.
Metabolism
- Since norelgestromin and ethinyl estradiol  is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Distribution
- NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see TABLE 5).
Elimination
- Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways.
Transdermal versus Oral Contraceptives
- The norelgestromin and ethinyl estradiol  transdermal patch delivers EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis. Figures 5 and 6 present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg / EE 35 mcg) compared to the 7-day transdermal norelgestromin and ethinyl estradiol  patch (containing NGMN 6 mg / EE 0.75 mg) during Cycle 2 in 32 healthy female volunteers.
- In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with ORTHO EVRA for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from norelgestromin and ethinyl estradiol  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.
- In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin  and Corticosteroid Binding Globulin ) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for norelgestromin and ethinyl estradiol  users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for ORTHO EVRA and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.
Drug Interactions
- In a PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for 3 days prior to and 7 days during wear of ORTHO EVRA did not significantly affect the PK of NGMN or EE.
Use in Specific Populations
Effects of Age, Body Weight, Body Surface Area and Race
- The effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of ORTHO EVRA. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only a small fraction (1025%) of the overall variability in the PK of NGMN and EE following application of ORTHO EVRA may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
- 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.

# Clinical Studies
- In 3 large clinical trials lasting 12 months, in North America, Europe and South Africa, 3,330 women (ages 1845) completed 22,155 cycles of ORTHO EVRA use, the pregnancy rate in women aged 18 to 35 years was 1.07 (95% confidence interval 0.60, 1.76) per 100 woman-years of ORTHO EVRA use. The racial distribution was 91% Caucasian, 4.9% Black, 1.6% Asian, and 2.4% Other.
- With respect to weight, 5 of the 15 pregnancies reported with norelgestromin and ethinyl estradiol  use were among women with a baseline body weight  198 lbs. (90 kg), which constituted < 3% of the study population. The greater proportion of pregnancies among women at or above 198 lbs. was statistically significant and suggests that norelgestromin and ethinyl estradiol  may be less effective in these women.
Patch Adhesion
- In the clinical trials with norelgestromin and ethinyl estradiol , approximately 2% of the cumulative number of patches completely detached and 3% partially detached. The proportion of subjects with at least 1 patch that completely detached ranged from 2% to 6%, with a reduction from Cycle 1 (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches.

# How Supplied
- ORTHO EVRA (norelgestromin/ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day NGMN and 35 mcg/day EE.
- Norelgestromin and ethinyl estradiol  is a 20 cm2 beige, transdermal system heat stamped with norelgestromin and ethinyl estradiol . Each system contains 6 mg NGMN and 0.75 mg EE.
- Each transdermal system is packaged in a protective pouch.
- Norelgestromin and ethinyl estradiol  is available in folding cartons of 1 cycle each (NDC 50458-192-15); each cycle contains 3 systems.
- Norelgestromin and ethinyl estradiol  is available for clinic usage in folding cartons of 1 cycle each (NDC 50458-192-24); each cycle contains 3 systems.
- Norelgestromin and ethinyl estradiol  is also available in folding cartons containing a single system (NDC 50458-192-01), intended for use as a replacement in the event that a patch is inadvertently lost or destroyed.

## Storage
- Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F).
- Store patches in their protective pouches. Apply immediately upon removal from the protective pouch.
- Do not store in the refrigerator or freezer.
- Used patches still contain some active hormones. The sticky sides of the patch should be folded together and the folded patch placed in a sturdy container, preferably with a child-resistant cap, and the container thrown in the trash. Used patches should not be flushed down the toilet.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
General
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.
- Norelgestromin and ethinyl estradiol  does not protect against HIV infection (AIDS) and other sexually transmitted infections.
- The Warnings and Precautions associated with combined hormonal contraceptives.
- Norelgestromin and ethinyl estradiol  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 norelgestromin and ethinyl estradiol .
- 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 norelgestromin and ethinyl estradiol  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.

# Precautions with Alcohol
- Alcohol-Norelgestromin and ethinyl estradiol transdermal system interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ORTHO EVRA 

# Look-Alike Drug Names
There is limited information regarding Norelgestromin and ethinyl estradiol transdermal system Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price