Estrogen

Ethinyl Estradiol and Norelgestromin

Approved 14 Sept 2023TransdermalFilm, extended release

The FDA lists this product in 2 strengths and forms.

Indications

Norelgestromin and ethinyl estradiol transdermal system is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m 2 for whom a combined hormonal contraceptive is appropriate. Limitations of Use: Norelgestromin and ethinyl estradiol transdermal system may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more. Norelgestromin and ethinyl estradiol transdermal system is contraindicated for use in women with BMI ≥ 30 kg/m2 [ see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14 ) ].

Norelgestromin and ethinyl estradiol transdermal system is an estrogen/progestin combination hormonal contraceptive (CHC), indicated for the prevention of pregnancy in women with a BMI < 30 kg/m 2 for whom combined hormonal contraceptive is appropriate. ( 1 ) Limitations of Use: Norelgestromin and ethinyl estradiol transdermal system may be less effective in preventing pregnancy in women at or above 198 lbs (90 kg). ( 1 , 4 , 14 )

Contraindications

Norelgestromin and ethinyl estradiol transdermal system is contraindicated in females who are known to have or develop the following conditions: ● At high risk of arterial or venous thromboembolic events. Examples include women who: ○ Smoke, if over age 35 [see Boxed Warning, and Warnings and Precautions ( 5.1 )] ○ Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] ○ Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] ○ Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] ○ Have coronary artery disease [see Warnings and Precautions ( 5.1 )] ○ Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )] ○ Have uncontrolled hypertension [see Warnings and Precautions ( 5.5 )] ○ Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.7 )] ○ Have headaches with focal neurological symptoms or have migraine headaches with aura ■ Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.8 )] ● Body Mass Index ≥ 30 kg/m 2 [ see Warnings and Precautions ( 5.1 ) ] ● Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] ● Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )] ● Pregnancy, because there is no reason to use hormonal contraceptives during pregnancy [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 )] ● Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.12 )] ● Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations [see Warnings and Precautions ( 5.4 )] At high risk of arterial or venous thromboembolic events ( 4 ) BMI ≥ 30 kg/m 2 ( 4 ) Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

Warnings and precautions

Vascular risks : Stop norelgestromin and ethinyl estradiol transdermal system if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all women, particularly those over 35 years. ( 5.1 ) Liver disease : Discontinue norelgestromin and ethinyl estradiol transdermal system if jaundice occurs.

( 5.3 ) High blood pressure : Do not prescribe norelgestromin and ethinyl estradiol transdermal system for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking norelgestromin and ethinyl estradiol transdermal system. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.

( 5.7 ) Headache : Evaluate significant change in headaches and discontinue norelgestromin and ethinyl estradiol transdermal system if indicated. ( 5.8 ) Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.9 )

5.1Thromboembolic Disorders and Other Vascular Conditions

Stop norelgestromin and ethinyl estradiol transdermal system if an arterial or venous thromboembolic event (VTE) occurs. Stop norelgestromin and ethinyl estradiol transdermal system 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 transdermal system 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 transdermal system during prolonged immobilization and resume treatment based on clinical judgment. Start norelgestromin and ethinyl estradiol transdermal system 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.

Before starting norelgestromin and ethinyl estradiol transdermal system, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy [see Contraindications ( 4 )]. Arterial Events The use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke.

The risk is greater among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. Norelgestromin and ethinyl estradiol transdermal system is contraindicated in women over 35 years of age who smoke [see Contraindications ( 4 )]. Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events The use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs. The risk of VTE may be greater with norelgestromin and ethinyl estradiol transdermal system in women with a BMI ≥ 30 kg/m 2 compared to women with a lower BMI [see Contraindications ( 4 )].

While the increased risk of VTE associated with use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). 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.

This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued. Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs with a range of doses and routes of administration, for pregnant women, and for women in the postpartum period.

To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 1 Likelihood of Developing a VTE Within One Year Among Pregnant and Non-Pregnant Women

5.2Ethinyl 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 norelgestromin and ethinyl estradiol transdermal system compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (C max ) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system [see Clinical Pharmacology ( 12.3 )].

5.3Liver Disease Impaired Liver Function Do

not use norelgestromin and ethinyl estradiol transdermal system in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications ( 4 )]. Discontinue norelgestromin and ethinyl estradiol transdermal system 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 transdermal system is contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )] . 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.

5.4Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as CHCs. Discontinue norelgestromin and ethinyl estradiol transdermal system prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] .

Norelgestromin and ethinyl estradiol transdermal system can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.5High Blood Pressure Norelgestromin

and ethinyl estradiol transdermal system is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For women with well-controlled hypertension, monitor blood pressure and stop norelgestromin and ethinyl estradiol transdermal system 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.

5.6Gallbladder Disease

Studies suggest a small inc

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Interactions

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 (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 when enzyme inducers are used with CHCs.

( 7.1 )

7.1 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 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. 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 [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, 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]).

7.2Effects 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 [see Warnings and Precautions ( 5.13 )].

7.3Concomitant Use with HCV Combination

Therapy – Liver Enzyme Elevation Do not co-administer norelgestromin and ethinyl estradiol transdermal system with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.4 )].

7.4Interference 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.

Adverse reactions

The following serious adverse reactions with the use of combination hormonal contraceptives, including norelgestromin and ethinyl estradiol transdermal system, are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vascular events, including venous and arterial thromboembolic events [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.3 )] Adverse reactions commonly reported by users of combination hormonal contraceptives are: Irregular uterine bleeding Nausea Breast tenderness Headache The most frequent adverse reactions reported during clinical trials (≥ 5%) were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 transdermal system 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 transdermal system 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 transdermal system-treated subjects in these trials are shown in Table 3. Table 3: Adverse Drug Reactions Reported by ≥ 2.5% of Norelgestromin and Ethinyl Estradiol Transdermal System-treated Subjects in Three Phase 3 Clinical Trials System/Organ Class * Adverse reaction Norelgestromin and Ethinyl Estradiol Transdermal System (n = 3322) Reproductive system and breast disorders Breast symptoms † 22.4% Dysmenorrhea 7.8% Vaginal bleeding and menstrual disorders † 6.4% Gastrointestinal disorders Nausea 16.6% Abdominal pain † 8.1% Vomiting 5.1% Diarrhea 4.2% Nervous system disorders Headache 21.0% Dizziness 3.3% Migraine 2.7% General disorders and administration site conditions Application site disorder † 17.1% Fatigue 2.6% Psychiatric disorders Mood, affect and anxiety disorders † 6.3% Skin and subcutaneous tissue disorders Acne 2.9% Pruritus 2.5% Infections and infestations Vaginal yeast infection † 3.9% Investigations Weight increased 2.7% * MedDRA version 10.0 † Represents a bundle of similar terms Additional adverse drug reactions that occurred in < 2.5% of norelgestromin and ethinyl estradiol transdermal system-treated subjects in the above clinical trials datasets are: Gastrointestinal disorders : Abdominal distension General disorders and administration site conditions : Fluid retention 1 , malaise Hepatobiliary disorders : Cholecystitis Investigations : Blood pressure increased, lipid disorders 1 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, dermatitis contact, erythema, skin irritation 1 Represents a bundle of similar terms

6.2Postmarketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use.

The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use. Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use RR = relative risk; OR = odds ration; HR = hazard ration. "ever COC" are females with current or past COC use; "never COC use" are fmales that never used COCs.

The following adverse reactions (Table 4) have been identified during postapproval use of norelgestromin and ethinyl estradiol transdermal system. 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. Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol Transdermal System by System Organ Class* System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction † Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction † , edema † Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction † , urticaria Investigations Blood glucose abnormal, blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Breast cancer † , cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder † , suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash † , seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis † , cerebrovascular accident † , deep vein thrombosis † , hemorrhage intracranial † , hypertension, hypertensive crisis, pulmonary embolism † , thrombosis † *MedDRA version 10.0 † Represents a bundle of similar terms figure-2

Ethinyl Estradiol and Norelgestromin

Indications

Contraindications

Two medicines in one question?

Warnings and precautions

5.1Thromboembolic Disorders and Other Vascular Conditions

5.2Ethinyl Estradiol Exposure

5.3Liver Disease Impaired Liver Function Do

5.4Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.5High Blood Pressure Norelgestromin

5.6Gallbladder Disease

Interactions

7.2Effects of Combined Hormonal Contraceptives on Other Drugs

7.3Concomitant Use with HCV Combination

7.4Interference with Laboratory Tests

Pregnancy and breastfeeding

8.1Pregnancy

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines