Chain Drug Review, July 8, 2019

Carcinoma of Breasts and Cervix 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 Effect on Binding Globulins The estrogen component of CHCs may raise the serum concentrations of thyroxine binding globulin sex hormone binding globulin and cortisol binding globulin The dose of replacement thyroid hormone or cortisol therapy may need to be increased Monitoring A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare Hereditary Angioedema In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema Chloasma Chloasma may occasionally occur especially in women with a history of chloasma gravidarum Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using Xulane ADVERSE REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives including Xulane are discussed elsewhere in the labeling Serious cardiovascular events and stroke see Boxed Warning and Warnings and Precautions Vascular events including venous and arterial thromboembolic events see Warnings and Precautions Liver disease see Warnings and Precautions Adverse reactions commonly reported by users of combination hormonal contraceptives are Irregular uterine bleeding Nausea Breast tenderness Headache Clinical Trials Experience Because clinical trials are conducted under widely varying conditions adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice The data described below reflect exposure to norelgestromin and ethinyl estradiol 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 25 of norelgestromin and ethinyl estradiol transdermal system treated subjects in these trials are shown in Table 3 Table 3 Adverse Drug Reactions Reported by 25 of Norelgestromin and Ethinyl Estradiol Transdermal System treated Subjects in Three Phase 3 Clinical Trials System Organ Class Adverse reaction Norelgestromin and Ethinyl Estradiol Transdermal System n 3322 Reproductive system and breast disorders Breast symptoms 224 Dysmenorrhea 78 Vaginal bleeding and menstrual disorders 64 Gastrointestinal disorders Nausea 166 Abdominal pain 81 Vomiting 51 Diarrhea 42 Nervous system disorders Headache 210 Dizziness 33 Migraine 27 General disorders and administration site conditions Application site disorder 171 Fatigue 26 Psychiatric disorders Mood affect and anxiety disorders 63 Skin and subcutaneous tissue disorders Acne 29 Pruritus 25 Infections and infestations Vaginal yeast infection 39 Investigations Weight increased 27 MedDRA version 100 Represents a bundle of similar terms Additional adverse drug reactions that occurred in 25 of norelgestromin and ethinyl estradiol transd ermal system treated subjects in the above clinical trials datasets are Gastrointestinal disorders Abdominal distension General disorders and administration site conditions Fluid retention1 malaise Hepatobiliary disorders Cholecystitis Investigations Blood pressure increased lipid disorders1 Musculoskeletal and connective tissue disorders Muscle spasms Psychiatric disorders Insomnia libido decreased libido increased Reproductive system and breast disorders Galactorrhea genital discharge premenstrual syndrome uterine spasm vaginal discharge vulvovaginal dryness Respiratory thoracic and mediastinal disorders Pulmonary embolism Skin and subcutaneous tissue disorders Chloasma dermatitis contact erythema skin irritation 1 Represents a bundle of similar terms Postmarketing Experience The following adverse reactions Table 4 have been identified during postapproval use of norelgestromin and ethinyl estradiol transdermal system Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Table 4 Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol Transdermal System by System Organ Class System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction Endocrine disorders Hyperglycemia insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction edema Hepatobiliary disorders Blood cholesterol abnormal cholelithiasis cholestasis hepatic lesion jaundice cholestatic low density lipoprotein increased Immune system disorders Allergic reaction urticaria Investigations Blood glucose abnormal blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign malignant and unspecified Incl cysts and polyps Breast cancer cervix carcinoma hepatic adenoma hepatic neoplasm Nervous system disorders Dysgeusia migraine with aura Psychiatric disorders Anger emotional disorder frustration irritability Reproductive system and breast disorders Breast mass cervical dysplasia fibroadenoma of breast menstrual disorder suppressed lactation uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia eczema erythema multiforme erythema nodosum photosensitivity reaction pruritus generalized rash seborrheic dermatitis skin reaction Vascular disorders Arterial thrombosis cerebrovascular accident deep vein thrombosis hemorrhage intracranial hypertension hypertensive crisis pulmonary embolism thrombosis MedDRA version 100 Represents a bundle of similar terms DRUG INTERACTIONS Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations Effects of Other Drugs on Combined Hormonal Contraceptives Substances Decreasing the Plasma Concentrations of CHCs and Potentially Diminishing the Efficacy of CHCs Drugs or herbal products that induce certain enzymes including cytochrome P450 3A4 CYP3A4 may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin barbiturates carbamazepine bosentan felbamate griseofulvin oxcarbazepine rifampicin topiramate rifabutin rufinamide aprepitant and products containing St Johns wort Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and or contraceptive failure Counsel women to use an alternative method of contraception or a back up method when enzyme inducers are used with CHCs and to continue back up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability Substances Increasing the Plasma Concentrations of CHCs Co administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 20 to 25 Ascorbic acid and acetaminophen may increase plasma EE concentrations possibly by inhibition of conjugation CYP3A4 inhibitors such as itraconazole voriconazole fluconazole grapefruit juice or ketoconazole may increase plasma hormone concentrations Human Immunodeficiency Virus HIV Hepatitis C Virus HCV Protease Inhibitors and Non Nucleoside Reverse Transcriptase Inhibitors Significant changes increase or decrease in the plasma concentrations of estrogen and or progestin have been noted in some cases of co administration with HIV protease inhibitors decrease e g nelfinavir ritonavir darunavir ritonavir fos amprenavir ritonavir lopinavir ritnoavir and tipranavir ritonavir or increase e g indinavir and atazanavir ritonavir HCV protease inhibitors or with non nucleoside reverse transcriptase inhibitors decrease e g nevirapine or increase e g etravirine 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 see Warnings and Precautions 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 see Warnings and Precautions 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 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 Nursing Mothers 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 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 Geriatric Use Xulane has not been studied in postmenopausal women and is not indicated in this population Hepatic Impairment 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 Renal Impairment No studies with Xulane have been conducted in women with renal impairment Women with Weight 198 lbs 90 kg Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs 90 kg or more OVERDOSAGE 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 NONCLINICAL TOXICOLOGY Carcinogenesis Mutagenesis and Impairment of Fertility 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 PATIENT COUNSELING INFORMATION See FDA approved patient labeling Patient Information and Instructions for Use General Counsel patients about the following information Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use and that women who are over 35 years old and smoke should not use combined hormonal contraceptives 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 10000 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 Xulane does not protect against HIV infection AIDS and other sexually transmitted infections The Warnings and Precautions associated with combined hormonal contraceptives Xulane is not to be used during pregnancy if pregnancy occurs during use of Xulane 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 Xulane 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 Xulane patch becomes partially or completely detached and remains detached insufficient drug delivery occurs A patch should not be re applied if it is no longer sticky becomes stuck to itself or another surface has other material stuck to it or has become loose or fallen off before If a patch cannot be re applied a new patch should be applied immediately Supplemental adhesives or wraps should not be used A woman may not be protected from pregnancy if a patch is partially or completely detached for 24 hours or if the woman is not sure how long the patch has been detached She should start a new cycle immediately by applying a new patch Back up contraception such as a condom and spermicide or diaphragm and spermicide must be used for the first week of the new cycle The brands listed are trademarks of their respective owners Manufactured for Mylan Pharmaceuticals Morgantown WV 26505 U S A Revised 4 2017 NEETS R14 XUL 2019 0003