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What is Xulane?
Xulane is a birth control patch for women with a BMI less than 30 kg/m2 . It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called norelgestromin.
Hormones from Xulane get into the blood stream and are processed by the body differently than hormones from birth control pills. You will be exposed to about 60% more estrogen if you use Xulane than if you use a typical birth control pill containing 35 micrograms of estrogen. In general, increased estrogen may increase the risk of side effects.
What are the possible side effects of Xulane?
See "What is the most important information I should know about Xulane?"
Xulane may cause serious side effects, including:
It is possible to die or be permanently disabled from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious blood clots are blood clots in the:
To put the risk of developing a blood clot into perspective: If 10,000 women who are not pregnant and do not use hormonal birth control are followed for one year, between 1 and 5 of these women will develop a blood clot. The figure below shows the likelihood of developing a serious blood clot for women who are not pregnant and do not use hormonal birth control, for women who use hormonal birth control, for pregnant women, and for women in the first 12 weeks after delivering a baby.
Call your healthcare provider right away if you have:
Other serious risks include
The most common side effects of Xulane are:
Some women have spotting or light bleeding, breast tenderness, or feel sick to their stomach during norelgestromin and ethinyl estradiol transdermal system use. If these symptoms occur, do not stop using the Xulane patch. The problem will usually go away. If it does not go away, check with your healthcare provider.
Less common side effects are:
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the possible side effects of Xulane. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
WARNING
CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, AND PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOL
Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including Xulane, should not be used by women who are over 35 years of age and smoke.
The risk of venous thromboembolism (VTE) among women aged 15 to 44 who used the norelgestromin and ethinyl estradiol trans dermal system compared to women who used several different oral contraceptives was assessed in five U.S. epidemiologic studies using electronic healthcare claims data. The relative risk estimates ranged from 1.2 to 2.2; one of the studies found a statistically significant increased relative risk of VTE for current users of norelgestromin and ethinyl estradiol trans dermal system [see WARNINGS AND PRECAUTIONS].
The PK profile for the norelgestromin and ethinyl estradiol trans dermal system is different from the PK profile for oral contraceptives in that it has a higher steady state concentrations and a lower peak concentration. Area under the time-concentration curve (AUC) and average concentration at steady state (Css) for EE are approximately 60% higher in women using norelgestromin and ethinyl estradiol trans dermal system compared with women using an oral contraceptive containing 35 mcg of EE. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol trans dermal system. 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 trans dermal system compared with women using oral contraceptives containing 30 mcg to 35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including VTE [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Xulane is a transdermal system with a contact surface area of 14 cm². It contains 4.86 mg norelgestromin, USP (NGMN) and 0.53 mg ethinyl estradiol, USP (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 [AUC] and steady state concentration [Css]) of NGMN and EE during use of norelgestromin and ethinyl estradiol transdermal system are higher and the Cmax is lower than those produced by an oral contraceptive containing NGM 250 mcg / EE 35 mcg. [See BOXED WARNING and CLINICAL PHARMACOLOGY]
Xulane is a thin, matrix-type transdermal system consisting of three layers. The backing layer is composed of a peach flexible film consisting of a 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 polyisobutene adhesive, crospovidone, mineral oil, non-woven polyester fabric, oleyl alcohol and dipropylene glycol 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 polyester film with a fluoropolymer coating on the side that is in contact with the middle adhesive layer.
The outside of the backing layer is printed with “Xulane® (norelgestromin and ethinyl estradiol) 150/35 mcg per day” in brown ink.
Xulane transdermal systems are packaged with additional pieces of protective film above and below the system within each pouch. These pieces of protective film are removed and discarded at the time of use.
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, (17α)-
Chemical name for EE: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17β-diol, (17α)-
Xulane is indicated for the prevention of pregnancy in women who elect to use a transdermal patch as a method of contraception.
To achieve maximum contraceptive effectiveness, Xulane 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 Xulane transdermal system uses a 28-day (4-week) cycle. A new patch is applied each week for 3 Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or weeks (21 total days). Week 4 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 Xulane patch in any way. If the Xulane patch is cut, damaged or altered in size, contraceptive efficacy may be impaired.
On the day after Week 4 ends, a new 4-week cycle is started by applying a new patch. Under no circumstances should there be more than a 7-day patch-free interval between dosing cycles.
The woman has two options for starting the patch and she should choose the option that is right for her:
Start contraceptive therapy with Xulane 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 Xulane postpartum, and has not yet had a period, consider the possibility of ovulation and conception occurring prior to use of Xulane, and instruct her to use an additional method of contraception, such as a condom and spermicide or diaphragm and spermicide, for the first 7 days. [See WARNINGS AND PRECAUTIONS and Pregnancy]
After an abortion or miscarriage that occurs in the first trimester, Xulane may be started immediately. An additional method of contraception is not needed if Xulane is started immediately. If use of Xulane is not started within 5 days following a first trimester abortion, the woman should follow the instructions for a woman starting Xulane 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 Xulane no earlier than 4 weeks after a second trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
CHOOSING A PLACE ON THE BODY TO PUT THE PATCH
 |
Before applying the patch:
HOW TO APPLY THE PATCH
 |
 |
 |
 |
WHEN TO CHANGE THE XULANE PATCH
WHAT IF THE PATCH BECOMES LOOSE OR FALLS OFF?
The patch must stick securely to the skin to work properly. If the Xulane 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:
If the patch has been off or partially off:
IF THE WOMAN FORGETS TO CHANGE HER PATCH
Under no circumstances should there be more than a 7-day patch-free interval between cycles. If there are more than 7 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 7 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.
If the woman wishes to change her Patch Change Day, she should complete her current cycle, removing the third Xulane patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying a new Xulane patch on the desired day. In no case should there be more than 7 consecutive patch-free days.
In the event of unscheduled or breakthrough bleeding or spotting (bleeding that occurs on the days that Xulane is worn), treatment should be continued. If unscheduled bleeding persists longer than a few cycles, consider causes other than Xulane.
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 Xulane 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 Xulane if pregnancy is confirmed.
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.
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.
Xulane® (norelgestromin and ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day norelgestromin (NGMN) and 35 mcg/day ethinyl estradiol (EE).
Xulane® is a 14 cm² peach, transdermal system printed with “Xulane (norelgestromin and ethinyl estradiol) 150/35 mcg per day” in brown ink. Each system contains 4.86 mg norelgestromin, USP and 0.53 mg ethinyl estradiol, USP.
Xulane® (norelgestromin and ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day NGMN and 35 mcg/day EE.
Xulane® is a 14 cm² peach, transdermal system printed with “Xulane® (norelgestromin and ethinyl estradiol) 150/35 mcg per day” in brown ink. Each system contains 4.86 mg norelgestromin, USP and 0.53 mg ethinyl estradiol, USP.
Each transdermal system is packaged in a protective pouch.
Xulane® (norelgestromin and ethinyl estradiol transdermal system) is available in folding cartons of one cycle each (NDC 0378-3340-53); each cycle contains 3 systems.
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
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.
Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. Revised: Apr 2017
REFERENCES
10. Heit JA, Kobbervig CE, James AH, Petterson TM, Kent R. Bailey, KR; Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year populationbased study. Ann Intern Med. 2005; 143: 697-706.
The following serious adverse reactions with the use of combination hormonal contraceptives, including Xulane, are discussed elsewhere in the labeling:
Adverse reactions commonly reported by users of combination hormonal contraceptives are:
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 systemtreated subjects in these trials are shown in Table 3.
Table 3: Adverse Drug Reactions Reported by ≥
2.5% of Norelgestromin and Ethinyl Estradiol Trans dermal 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:
1Represents a bundle of similar terms
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 Trans dermal 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 |
|
Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. 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.
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.
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]).
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].
Do not co-administer Xulane with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS].
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Included as part of the PRECAUTIONS section.
Stop Xulane if an arterial or deep venous thrombotic event (VTE) occurs.
Stop Xulane if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
If feasible, stop Xulane at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of Xulane during prolonged immobilization and resume treatment based on clinical judgment.
Start Xulane no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of combination hormonal contraceptives (CHCs) increases the risk of VTE. Known risk factors for VTE include smoking, obesity and family history of VTE, in addition to other factors that contraindicate use of CHCs [see CONTRAINDICATIONS].
Five epidemiologic studies1-9 that assessed the risk of VTE associated with use of norelgestromin and ethinyl estradiol transdermal system are described below. These are 4 case control studies, that compared VTE rates among women using norelgestromin and ethinyl estradiol transdermal system 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 transdermal system. All five studies were retrospective studies from U.S. electronic healthcare databases and included women aged 15 to 44 (10 to 55 in the FDA-funded study) who used norelgestromin and ethinyl estradiol transdermal system or oral contraceptives containing 20 mcg to 35 mcg of ethinyl estradiol (EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the prodrug for NGMN, the progestin in Xulane.
Some of the data from the epidemiologic studies suggest an increased risk of VTE with use of norelgestromin and ethinyl estradiol transdermal system compared to use of some combined oral contraceptives (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 transdermal system.
The five studies are:
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.
Table 1: Estimates (Risk Ratios ) of Venous
Thromboembolism Risk in Current Users of Norelgestromin and Ethinyl Estradiol
Trans dermal System Compared to Combined Oral Contraceptive Users
| Epidemiologic Study* | Comparator Product | Risk Ratios (95% CI) |
| i3 Ingenix NGM Study in Ingenix Research Datamart1,6,7,8 | NGM/35 mcg EE† | 2.2‡ (1.2 - 4.0)§ |
| BCDSP¶ NGM Study in Pharmetrics database2,3,5 | NGM/35 mcg EE | 1.2 (0.9 - 1.8)# |
| BCDSP¶ LNG Study in Pharmetrics database4 | LNG^/30 mcg EE | 2.0 (0.9 - 4.1)β |
| BCDSP¶ LNG Study in Marketscan database4 | LNG/30 mcg EE | 1.3 (0.8 - 2.1)à |
| FDA-funded Study in Kaiser Permanente and Medicaid databasesè,ð,9 |
“All progestinsØ”/20 - 35 mcg EE LNG/30 mcg EE |
1.4 (0.9 - 2.0) 1.2 (0.8 - 1.9) |
| *“New users” – i.e., women with no prior exposure to the
drug studied during a pre-specified time period – are considered to be the most
informative population to study in pharmacoepidemiologic safety studies. All
estimates took account of new-user status. The method and time period used to
identify “new users” varied from study to study. †NGM = norgestimate; EE = ethinyl estradiol ‡Increase in risk of VTE is statistically significant § Pooled risk ratio from references 1 and 6 covering the initial 33-month study plus 24 -month extension. [Initial 33 months of data: Risk Ratio (95% CI) = 2.5C (1.1-5.5); Separate estimate from the 24 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.4 (0.5-3.7)]. These risk ratios are based on idiopathic cases (those in women without other known risk factors for VTE). If all VTE cases are considered, the pooled risk ratio and 95% CI are 2.0 (1.2-3.3)C. ¶BCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases. #Pooled risk ratio from references 2, 3 and 5 covering the initial 36-month study, plus 17-month and 14 –month extensions. [Initial 36 months of data: Risk Ratio (95% CI) = 0.9 (0.5-1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.1 (0.6-2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Risk Ratio (95% CI) = 2.4C (1.2- 5.0)] ÞLNG = levonorgestrel β4 8 months of data. à69 months of data. è84 months of data in FDA-funded study ð Results for “All users,” i.e., initiation and continuing use of study combination hormonal contraception: “All progestins”/20-35 mcg EE, Risk Ratio (95% CI) = 1.6 (1.2-2.1)C and LNG/30 mcg EE, Risk Ratio (95% CI) = 1.3 (1.0-1.8). Ø Includes the following progestins: LNG, norethindrone, norgestimate. |
||
Figure 1: VTE Risk of Norelgestromin and Ethinyl
Estradiol Trans dermal System Relative to Combined Oral Contraceptives
 |
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 postpartum 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 CHCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued.
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 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 2: Likelihood of Developing 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.
The PK profile for the norelgestromin and ethinyl estradiol transdermal system 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 transdermal system 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 transdermal system. Inter-subject variability results in increased exposure to EE in some women using either norelgestromin and ethinyl estradiol transdermal system or oral contraceptives. However, inter-subject variability in women using norelgestromin and ethinyl estradiol transdermal system is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using norelgestromin and ethinyl estradiol transdermal system compared with women using oral contraceptives containing 30 mcg to 35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. [See BOXED WARNING and CLINICAL PHARMACOLOGY]
Do not use Xulane in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS]. Discontinue Xulane if jaundice develops. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded.
Xulane is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. 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.
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 Xulane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS]. Xulane can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
Xulane is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For women with well-controlled hypertension, monitor blood pressure and stop Xulane if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.
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.
Carefully monitor prediabetic and diabetic women who take Xulane. CHCs may decrease glucose tolerance in a dose-related fashion. In a 6-cycle clinical trial with norelgestromin and ethinyl estradiol transdermal system there were no clinically significant changes in fasting blood glucose from baseline to end of treatment.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on hormonal contraceptives.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.
If a woman taking Xulane develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue Xulane if indicated.
Consider discontinuation of Xulane in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event).
Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using norelgestromin and ethinyl estradiol transdermal system. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or a change to another contraceptive product may resolve the bleeding.
In the 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 transdermal system in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies] 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 transdermal system 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)
| T reatment Cycle | Pooled data from 3 studies N = 3319 |
|
| n | %* | |
| Cycle 1 | 2994 | 18.2 |
| Cycle 2 | 2743 | 11.9 |
| Cycle 3 | 2699 | 11.6 |
| Cycle 4 | 2541 | 10.1 |
| Cycle 5 | 2532 | 9.2 |
| Cycle 6 | 2494 | 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. | ||
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.
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 Xulane use if pregnancy is confirmed.
Administration of CHCs should not be used as a test for pregnancy [see Use In Specific Populations].
Carefully observe women with a history of depression and discontinue Xulane if depression recurs to a serious degree.
Xulane is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS].
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.
The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using Xulane.
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
Counsel patients about the following information:
The brands listed are trademarks of their respective owners.
See WARNINGS AND PRECAUTIONS and Use In Specific Populations.
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.
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.
The effects of Xulane in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.
Safety and efficacy of norelgestromin and ethinyl estradiol transdermal system have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Xulane has not been studied in postmenopausal women and is not indicated in this population.
No studies with Xulane have been conducted in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
No studies with Xulane have been conducted in women with renal impairment.
Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.
REFERENCES
1. Cole JA, Norman H, Doherty M, Walker AM. Venous Thromboembolism, Myocardial Infarction, and Stroke among Transdermal Contraceptive System Users. Obstetrics & Gynecology 2007; 109(2):339-346.
2. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 2006; 73: 223-228.
3. Jick S, Kaye JA, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 μg of EE. Contraception 2007; 76: 4-7.
4. Jick S, Hagberg K, Hernandez R, Kaye J. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception 2010; 81: 16-21.
5. Jick S, Hagberg K, Kaye J. ORTHO EVRA® and venous thromboembolism: an update. Letter to the Editor. Contraception 2010; 81: 452-453.
6. Dore D, Norman H, Loughlin J, Seeger D. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010; 81: 408- 413.
7. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users [published erratum appears in Obstet Gynecol 2008; 111:1449].
8. Dore D, Norman H, Seeger, J. Eligibility criteria in venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Letter to the Editor. Obstetrics & Gynecology 2009; 114(1):175.
9. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney,S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011.
Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in females. In case of suspected overdose, all Xulane patches should be removed and symptomatic treatment given.
Do not prescribe Xulane to women who are known to have the following conditions:
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).
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.
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, 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 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 Css and AUC0-168 for NGMN and EE following a single buttock application of norelgestromin and ethinyl estradiol transdermal system are summarized in Table 5.
In multiple dose studies, AUC0-168 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.
Table 5: Mean (%CV*) PK Parameters of NGMN and EE
Following Three Consecutive Cycles of Norelgestromin and Ethinyl Estradiol
Trans dermal System Wear on the Buttock
| Analyte | Parameter | Cycle 1 Week 1 | Cycle 3 Week 1 | Cycle 3 Week 2 | Cycle 3 Week 3 |
| NGMN | Css (ng/mL) | 0.70 (39.4) | 0.70 (41.8) | 0.80 (28.7) | 0.70 (45.3) |
| AUC0-168 (ng•h/mL) | 107 (44.2) | 105 (43.2) | 132 (43.4) | 120 (43.9) | |
| t½ (h) | nc | nc | nc | 32.1 (40.3) | |
| EE | Css (pg/mL) | 46.4 (38.5) | 47.6 (36.4) | 59.0 (42.5) | 49.6 (54.4) |
| AUC0-168 (pg•h/mL) | 6796 (39.3) | 7160 (40.4) | 10054 (41.8) | 8840 (58.6) | |
| t½ (h) | nc | nc | nc | 21.0 (43.2) | |
| *%CV is % of Coefficient of variation = 100 (standard deviation/mean) | |||||
Figure 3: Mean Serum NGMN Concentrations (ng/mL) in
Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl
Estradiol Trans dermal System on the Buttock for Three Consecutive Cycles
(Vertical arrow indicates time of patch removal)
 |
Figure 4: Mean Serum EE Concentrations (pg/mL) in
Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl
Estradiol Trans dermal System on the Buttock for Three Consecutive Cycles
(Vertical arrow indicates time of patch removal.)
 |
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 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 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.
Since norelgestromin and ethinyl estradiol transdermal system 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.
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).
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.
The norelgestromin and ethinyl estradiol transdermal system delivers EE and NGMN over a 7-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 system (containing NGMN 4.86 mg / EE 0.53 mg) during Cycle 2 in 32 healthy female volunteers.
Figure 5: Mean Serum Concentration-Time Profiles of
NGMN Following Once-Daily Administration of an Oral Contraceptive for Two
Cycles or Application of Norelgestromin and Ethinyl Estradiol Trans dermal
System for Two Cycles to the Buttock in Healthy Female Volunteers . [Oral
contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Trans
dermal System: Cycle 2, Week 3]
 |
Figure 6: Mean Serum Concentration-Time Profiles of EE
Following Once-Daily Administration of an Oral Contraceptive for Two Cycles or
Application of Norelgestromin and Ethinyl Estradiol Trans dermal System for Two
Cycles to the Buttock in Healthy Female Volunteers . [Oral contraceptive: Cycle
2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Trans dermal System:
Cycle 2, Week 3]
 |
Table 6 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.
Table 6: Mean (%CV) NGMN and EE Steady State
Pharmacokinetic Parameters Following Application of Norelgestromin and Ethinyl
Estradiol Trans dermal System and Once-Daily Administration of an Oral
Contraceptive (containing NGM 250 mcg / EE 35 mcg) in Healthy Female Volunteers
| Parameter | Norelgestromin and Ethinyl Estradiol Transdermal System * | ORAL CONTRACEPTIVEt |
| NGMN‡ | ||
| Cmax (ng/mL) | 1.12 (33.6) | 2.16 (25.2) |
| AUC0-168 (ng•h/mL) | 145 (36.8) | 123 (30.2)§ |
| Css (ng/mL) | 0.888 (36.6) | 0.732 (30.2)¶ |
| EE | ||
| Cmax (pg/mL) | 97.4 (31.6) | 133 (27.7) |
| AUC0-168 (pg•h/mL) | 12,971 (33.1) | 8,281(26.9)§ |
| Css (pg/mL) | 80.0 (33.5) | 49.3 (26.9)¶ |
| *Cycle 2, Week 3 †Cycle 2, Day 21 ‡NGM is rapidly metabolized to NGMN following oral administration §Average weekly exposure, calculated as AUC24 x 7 ¶Cavg |
||
In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with norelgestromin and ethinyl estradiol transdermal system for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral
contraceptive. Under steady state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for 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 transdermal system was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.
In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for norelgestromin and ethinyl estradiol transdermal system users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for norelgestromin and ethinyl estradiol transdermal system and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.
Table 7: Mean Percent Change (%CV) in SHBG and CBG
Concentrations Following Once-Daily Adminis tration of an Oral Contraceptive
(containing NGM 250 mcg / EE 35 mcg) for One Cycle and Application of Norelges
tromin and Ethinyl Es tradiol Trans dermal Sys tem for One Cycle in Healthy
Female Volunteers
| Parameter | Norelgestromin and Ethinyl Estradiol Transdermal System (% change from Day 1 to Day 22) | ORAL CONTRACEPTIVE (% change from Day 1 to Day 22) |
| SHBG | 334 (39.3) | 200 (43.2) |
| CBG | 153 (40.2) | 157 (33.4) |
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 norelgestromin and ethinyl estradiol transdermal system did not significantly affect the PK of NGMN or EE.
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 norelgestromin and ethinyl estradiol transdermal system. 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 (10% to 25%) of the overall variability in the PK of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system 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.
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. (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 transdermal system may be less effective in these women.
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 one 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, refer to Dosage and Administration (2).
Xulane®
[zhoo' lane]
(norelgestromin and ethinyl estradiol trans dermal system) 150
mcg/day norelgestromin and 35 mcg/day ethinyl estradiol
What is the most important information I should know about Xulane?
Do not use Xulane if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control methods, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
Women 15 to 44 years of age who use Xulane may have an increased risk of blood clots compared to women who us e certain birth control pills.
You will be exposed to about 60% more estrogen if you use Xulane than if you us e a typical birth control pill containing 35 micrograms of estrogen. In general, increased estrogen may increase the risk of side effects, including blood clots.
Hormonal birth control methods help to lower the chances of becoming pregnant. They do not protect against HIV infection (AIDS) and other sexually transmitted infections.
What is Xulane?
Xulane is a birth control patch. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called norelgestromin.
Hormones from Xulane get into the blood stream and are processed by the body differently than hormones from birth control pills. You will be exposed to about 60% more estrogen if you use Xulane than if you use a typical birth control pill containing 35 micrograms of estrogen. In general, increased estrogen may increase the risk of side effects.
How well does Xulane work?
Your chance of getting pregnant depends on how well you follow the directions for using Xulane. The better you follow the directions, the less chance you have of getting pregnant.
In clinical studies, 1 to 2 out of 100 women got pregnant during the first year that they used norelgestromin and ethinyl estradiol transdermal system.
Xulane may not be as effective in women weighing more than 198 lbs. (90 kg). If you weigh more than 198 lbs. (90 kg), talk to your healthcare provider about which method of birth control is right for you.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
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Who Should Not Use Xulane?
Do not use Xulane if you:
Hormonal birth control methods may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy or related to previous use of hormonal birth control.
Tell your healthcare provider if you have ever had any of the above conditions. Your healthcare provider may recommend another method of birth control.
What should I tell my healthcare provider before using Xulane?
Before you use Xulane tell your healthcare provider:
Tell your healthcare provider about all medicines and herbal products that you take.
Some medicines and herbal products may make hormonal birth control less effective, including, but not limited to:
Use another birth control method (such as a condom and spermicide or diaphragm and spermicide) when you take medicines that may make the Xulane patch less effective.
Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if used together, including:
Hormonal birth control methods may interact with lamotrigine, an anti-seizure medicine used for epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust the dose of lamotrigine.
Women on thyroid replacement therapy may need increased doses of thyroid hormone.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I use Xulane?
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What are the possible side effects of Xulane?
See “What is the most important information I should know about Xulane?”
Xulane may cause serious side effects, including:
To put the risk of developing a blood clot into perspective: If 10,000 women who are not pregnant and do not use hormonal birth control are followed for one year, between 1 and 5 of these women will develop a blood clot. The figure below shows the likelihood of developing a serious blood clot for women who are not pregnant and do not use hormonal birth control, for women who use hormonal birth control, for pregnant women, and for women in the first 12 weeks after delivering a baby.
Likelihood of Developing a Serious Blood Clot (Venous Thromboembolism [VTE])
 |
Call your healthcare provider right away if you have:
Other serious risks include
The most common side effects of Xulane are:
Some women have spotting or light bleeding, breast tenderness, or feel sick to their stomach during norelgestromin and ethinyl estradiol transdermal system use. If these symptoms occur, do not stop using the Xulane patch. The problem will usually go away. If it doesn't go away, check with your healthcare provider.
Less common side effects are:
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the possible side effects of Xulane. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store and throw away used Xulane patches ?
Keep Xulane and all medicines out of the reach of children.
General information about the safe and effective use of Xulane
Medicines are sometimes prescribed for purposes other than those listed in Patient Information. Do not use Xulane for a condition for which it was not prescribed. Do not give Xulane to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Xulane. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Xulane that is written for health professionals.
For more information, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in Xulane?
Active ingredient: norelgestromin and ethinyl estradiol
Inactive ingredient: polyethylene, polyester, polyisobutene adhesive, crospovidone, mineral oil, nonwoven polyester fabric, oleyl alcohol, dipropylene glycol, and a polyester film with a fluoropolymer coating.
Do hormonal birth control methods cause cancer?
Hormonal birth control methods do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use hormonal birth control methods because some breast cancers are sensitive to hormones.
Women who use hormonal birth control methods may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.
What should I know about my period when using Xulane?
When you use Xulane you may have bleeding and spotting between periods, called unplanned bleeding. Unplanned bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Unplanned bleeding occurs most often during the first few months of Xulane use, but may also occur after you have been using the patch for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue using the patch on schedule. If the unplanned bleeding or spotting is heavy or lasts for more than a few days, you should discuss this with your healthcare provider.
What if I miss my scheduled period when using Xulane?
Some women miss periods on hormonal birth control, even when they are not pregnant. However, if you go 2 or more months in a row without a period, or you miss your period after a month where you did not use all of your patches correctly, or you have symptoms associated with pregnancy, such as morning sickness or unusual breast tenderness, call your healthcare provider because you may be pregnant. Stop taking Xulane if you are pregnant.
What if I want to become pregnant?
You may stop using Xulane whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop using the patch.
Instructions for Use
Xulane is for s kin us e only.
Do not cut, damage, or alter the Xulane patch in any way.
How to start using your Xulane patch:
Figure A
 |
Figure B is a picture of the Xulane patch.
Figure B
 |
Step 1. Choose a place on your body for your Xulane patch
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Step 2: Apply your Xulane patch
 |
 |
 |
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Step 3: Throwing away your Xulane patch
Important notes :
This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.
