Xulane Drug Information

Xulane is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m 2 for whom a combined hormonal contraceptive is appropriate. Limitations of Use: Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs. (90 kg) or more. Xulane is contraindicated for use in women with BMI ≥ 30 kg/m 2.

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

How to Use Xulane The Xulane transdermal system uses a 28-day (4-week) cycle. A new patch is applied each week for 3 weeks (21 total days). Week 4 is patch-free.

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. Under no circumstances should there be more than a 7-day patch-free interval between dosing cycles.

How to Start Using Xulane There are multiple options for starting the Xulane patch, and the woman should choose the option that is most appropriate (see Table 1): Table 1: Instructions for Administration Use after Childbirth 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. Use after Abortion or Miscarriage 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.

How to Apply Xulane CHOOSING A PLACE ON THE BODY TO PUT THE PATCH • The patch may be placed on the upper outer arm, abdomen, buttock or back in a place where it won’t be rubbed by tight clothing. For example, it should not be placed under the waistband of clothing. • The patch should not be placed on the breasts, on cut or irritated skin, or on the same location as the previous patch. Before applying the patch: • The woman should make sure the skin is clean and dry. • She should not use lotions, creams, oils, powders, or make-up at the patch site.

It may cause the patch to fail to stick properly or to become loose. HOW TO APPLY THE PATCH • The woman should tear open the pouch at the top edge and one side edge. She should peel open the foil pouch.

She should gently remove the contents of the foil pouch and discard the additional pieces of film above and below the patch. • The woman should peel away half of the clear plastic. She should avoid touching the sticky surface with her fingers. • The woman should apply the sticky side of the patch on the skin she has cleaned and dried. She should then remove the other half of the clear plastic and attach the entire patch to her skin. • The woman should press firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. • She should run her fingers over the entire surface area to smooth out any “wrinkles” around the outer edges of the patch. • The woman should check her patch every day to make sure all edges are sticking correctly.

WHEN TO CHANGE THE Xulane PATCH • The patch works for 7 days (1 week). The woman should apply a new patch on the same day each week (her Patch Change Day) for 3 weeks in a row. She must make sure she has removed her old patch prior to applying the new patch. • During Week 4, she DOES NOT wear a patch.

She must make sure she removes her old patch. (Her period should begin during this week.) • Following Week 4, she repeats the cycle of three weekly applications followed by a patch-free week. WHAT IF THE PATCH BECOMES LOOSE OR FALLS OFF? The patch must stick securely to the skin to work properly.

If the 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: • The woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin.

She should run her fingers over the entire surface area to smooth out any “wrinkles” around the edges of the patch. • If her patch does not stick completely, she should remove it and apply a replacement patch. • She should not tape or wrap the patch to her skin or reapply a patch that is partially adhered to clothing. If the patch has been off or partially off: • For less than 1 Day, she should try to reapply it. If the patch does not adhere completely, she should apply a new patch immediately. (No backup contraception is needed and her Patch Change Day will stay the same). • For more than 1 Day or if she is not sure for how long, she may not be protected from pregnancy.

To reduce this risk, she should apply a new patch and start a new 4-week cycle. She will now have a new Patch Change Day and MUST USE NON-HORMONAL BACKUP CONTRACEPTION (such as a condom and spermicide or diaphragm and spermicide) for the first week of her new cycle. IF THE WOMAN FORGETS TO CHANGE HER PATCH • at the start of any patch cycle (Week 1/Day 1): SHE MAY NOT BE PROTECTED FROM PREGNANCY.

She should apply the first patch of her new cycle as soon as she remembers. There is now a new “Patch Change Day” and a new “Day 1.” The woman must use back-up contraception, such as a condom and spermicide or diaphragm and spermicide, for the first week of the new cycle. • in the middle of the patch cycle (Week 2/Day 8 or Week 3/Day 15), - for 1 or 2 days (up to 48 hours), she should apply a new patch immediately. The next patch should be applied on the usual “Patch Change Day.” No back-up contraception is needed. - for more than 2 days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNANCY.

She should stop the current contraceptive cycle and start a new 4-week cycle immediately by putting on a new patch. There is now a new “Patch Change Day” and a new “Day 1.” The woman must use back-up contraception for 1 week. • at the end of the patch cycle (Week 4/Day 22), - If the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual “Patch Change Day,” which is the day after Day 28.

No back-up contraception is needed. 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. Change Day Adjustment 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. Breakthrough Bleeding or Spotting 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. In Case of Skin Irritation If patch use results in uncomfortable irritation, the patch may be removed and a new patch may be applied to a different location until the next Change Day. Additional Instructions for Dosing Unscheduled bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives.

In case of breakthrough bleeding, as in all cases of irregular bleeding from the vagina, consider nonfunctional causes. In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina, take adequate diagnostic measures to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another method of contraception may solve the problem.

Use of Hormonal Contraceptives in the Event of a Missed Menstrual Period 1. If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of Xulane if pregnancy is confirmed. 2.

If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed. 3.

If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Choosing a place on the body for the patch How to apply the patch Figure 01 How to apply the patch Figure 02 How to apply the patch Figure 03 How to apply the patch Figure 04

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 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (norelgestromin and ethinyl estradiol transdermal system or an oral contraceptive comparator in 2 of the trials).

The women ranged in age from 18 to 45 years and were predominantly white (91%). The most common adverse reactions (≥ 5%) reported during clinical trials were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability.

Adverse drug reactions reported by ≥ 2.5% of norelgestromin and ethinyl estradiol transdermal system-treated subjects in these trials are shown in Table 3.

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

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

The following adverse reactions (Table 4) have been identified during postapproval use of norelgestromin and ethinyl estradiol transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol Transdermal System by Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use

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 or increase )/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease or increase ).

Effects of Combined Hormonal Contraceptives on Other Drugs

CHCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation.

This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of CHCs.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Xulane with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

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.

Pregnancy 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.

Pediatric Use 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 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: o Smoke, if over age 35 o Have deep vein thrombosis or pulmonary embolism, now or in the past o Have inherited or acquired hypercoagulopathies o Have cerebrovascular disease o Have coronary artery disease o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) o Have uncontrolled hypertension o Have diabetes mellitus with vascular disease o 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 2
• 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 alanine aminotransferase (ALT) elevations
• At high risk of arterial or venous thromboembolic events
• BMI ≥ 30 kg/m 2
• Breast cancer or other estrogen- or progestin-sensitive cancer
• Liver tumors or liver disease
• Undiagnosed abnormal uterine bleeding
• Pregnancy
• Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in women. In case of suspected overdose, all Xulane patches should be removed and symptomatic treatment given.