Norelgestromin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara E.Dagsali
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Black Box Warning
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WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and
CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m Norelgestromin and ethinyl estradiol transdermal system is contraindicated in women over 35 years old who smoke. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. Norelgestromin and ethinyl estradiol transdermal system is contraindicated for use in women with a BMI ≥ 30 kg/m . Women with a BMI ≥ 30 kg/m who use norelgestromin and ethinyl estradiol transdermal system may have a higher risk of venous thromboembolic events compared with women with a lower BMI.See full prescribing information for complete Boxed Warning.
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Overview
Norelgestromin is a hormonal contreceptive that is FDA approved for the prevention of Norelgestromin and ethinyl estradiol transdermal system is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m for whom a combined hormonal contraceptive is appropriate.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include 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 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 3,330 sexually active women (3,322 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..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
To achieve maximum contraceptive effectiveness, norelgestromin and ethinyl estradiol transdermal systems 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. 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 transdermal patch in any way. If the norelgestromin and ethinyl estradiol transdermal 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.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of norelgestromin and ethinyl estradiol 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.
Off-Label Use and Dosage (Pediatric)
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
- 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
- Body Mass Index ≥ 30 kg/m
- Liver tumors, benign or malignant, or liver disease
- Undiagnosed abnormal uterine bleeding
- Pregnancy, because there is no reason to use hormonal contraceptives during pregnancy
- Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive
- Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations
Warnings
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WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and
CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m Norelgestromin and ethinyl estradiol transdermal system is contraindicated in women over 35 years old who smoke. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. Norelgestromin and ethinyl estradiol transdermal system is contraindicated for use in women with a BMI ≥ 30 kg/m . Women with a BMI ≥ 30 kg/m who use norelgestromin and ethinyl estradiol transdermal system may have a higher risk of venous thromboembolic events compared with women with a lower BMI.See full prescribing information for complete Boxed Warning.
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5.1 Thromboembolic 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 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 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 compared to women with a lower BMI. While the risk of VTE associated with the use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the post-partum period. The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after a break of 4 weeks or longer. 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 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. Figure 1: Likelihood of Developing a VTE Within One Year Among Pregnant and Non-Pregnant Women
- CHC = combination hormonal contraception
- Pregnancy data based on actual duration of pregnancy in the reference studies.
Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. 5.2 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 norelgestromin and ethinyl estradiol transdermal system compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (C ) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system. 5.3 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 [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 max of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in longterm (>8 years) CHC users. However, the risk of liver cancers in CHC users is less than one case per million users. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (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 prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Norelgestromin and ethinyl estradiol can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 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. 5.6 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. 5.7 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 transdermal system there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on hormonal contraceptives. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives. 5.8 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). 5.9 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. Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy) Treatment Cycle Pooled data from 3 studies N=3,319 n % Cycle 1 2,994 18.2 Cycle 2 2,743 11.9 Cycle 3 2,699 11.6 Cycle 4 2,541 10.1 Cycle 5 2,532 9.2 Cycle 6 2,494 8.3 Cycle 7 698 8.3 Cycle 8 692 8.7 Cycle 9 654 8.6 Cycle 10 621 8.7 Cycle 11 631 8.9 Cycle 12 617 6.3 Cycle 13 611 8.0 Percentage of subjects with breakthrough bleeding/spotting events. 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. 5.10 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 transdermal system use if pregnancy is confirmed. Administration of CHCs should not be used as a test for pregnancy. 5.11 Depression Carefully observe women with a history of depression and discontinue norelgestromin and ethinyl estradiol if depression recurs to a serious degree. 5.12 Malignant Neoplasms Breast Cancer Norelgestromin and ethinyl estradiol is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use. Cervical Cancer 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. 5.13 Effect on Binding Globulins The estrogen component of CHCs may raise the serum concentrations of thyroxinebinding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.14 Monitoring A woman who is taking hormonal contraceptive should have routine visits with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.15 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.16 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
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 3,330 sexually active women (3,322 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.
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 , malaise Hepatobiliary disorders: Cholecystitis Investigations: Blood pressure increased, lipid disorders 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.
Postmarketing 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 to 1.12. Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs. 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 to 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 to 10 years of COC use.
Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol by System Organ Class:
- 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
- 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, suppresed 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
Drug Interactions
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/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 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. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer norelgestromin and ethinyl estradiol with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations. 7.4 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 metaanalyses 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):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norelgestromin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Norelgestromin during labor and delivery.
Nursing Mothers
The effects of norelgestromin and ethinyl estradiol 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 norelgestromin and ethinyl estradiol 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
Norelgestromin and ethinyl estradiol 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 with respect to specific gender populations.
Race
There is no FDA guidance on the use of Norelgestromin with respect to specific racial populations.
Renal Impairment
No studies with norelgestromin and ethinyl estradiol have been conducted in women with renal impairment.
Hepatic Impairment
No studies with norelgestromin and ethinyl estradiol 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 in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Norelgestromin in patients who are immunocompromised.
Administration and Monitoring
Administration
There are multiple options for starting the norelgestromin and ethinyl estradiol transdermal system, and the woman should choose the option that is most appropriate
Monitoring
A woman who is taking hormonal contraceptive should have routine visits with her healthcare provider for a blood pressure check and for other indicated healthcare.
IV Compatibility
There is limited information regarding the compatibility of Norelgestromin and IV administrations.
Overdosage
Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in women. In case of suspected overdose, all norelgestromin and ethinyl estradiol transdermal patches should be removed and symptomatic treatment given.
Pharmacology
There is limited information regarding Norelgestromin Pharmacology in the drug label.
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 transdermal system. 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
There is limited information regarding Norelgestromin Structure in the drug label.
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 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 norelgestromin and ethinyl estradiol transdermal system, 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, C 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 transdermal system 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 C and AUC for NGMN and EE following a single buttock application of norelgestromin and ethinyl estradiol transdermal system are summarized. In multiple dose studies, AUC for NGMN and EE was found to increase over time. In a three-cycle study, these PK parameters reached steady-state conditions during Cycle 3. 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 norelgestromin and ethinyl estradiol transdermal system 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 C 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 norelgestromin and ethinyl estradiol transdermal system 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 are delivered 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. 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 norelgestromin and ethinyl estradiol transdermal patch (containing NGMN 3.15 mg / EE 0.289 mg) during Cycle 2 in 32 healthy female volunteers.
Nonclinical Toxicology
13.1 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 18 to 45) completed 22,155 cycles of norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system 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 transdermal system use were among women with a baseline body weight ≥ 198 lbs., 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 transdermal system may be less effective in these women. Patch Adhesion In the clinical trials with norelgestromin and ethinyl estradiol transdermal system, 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%).
How Supplied
Norelgestromin and ethinyl estradiol transdermal system is available in one strength of 150 mcg/day NGMN, USP and 35 mcg/day EE, USP. Norelgestromin and ethinyl estradiol transdermal system is a 12.5 cm system with rounded corners with tan backing printed with “Norelgestromin and Ethinyl Estradiol 150/35 mcg per day” in brown ink, protected with a removable translucent oversized dimple slit-release liner. Each patch contains 3.15 mg of norelgestromin, USP and 0.289 mg of ethinyl estradiol, USP. Each transdermal system is packaged in a protective pouch. Norelgestromin and ethinyl estradiol transdermal system is available in folding cartons of 1 cycle each (NDC 69238-1521-3); each cycle contains 3 systems.
Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). 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.
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Patient Counseling Information
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.
- The use of CHCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of CHCs. The risk of VTE in women using CHCs is 3 to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after a break of 4
weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after use is discontinued.
- 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 norelgestromin and ethinyl estradiol, 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 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 transdermal 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. Backup 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 interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
NORELGESTROMIN AND ETHINLY ESTRADIOL- norelgestromin and ethinly estradiol patch
Look-Alike Drug Names
There is limited information regarding Norelgestromin Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.