Norelgestromin-Ethinyl Estradiol Patch (XULANE): An Unsafe Choice for Birth Control

Important Warnings About Norelgestromin-Ethinyl Estradiol*[1]

Food and Drug Administration (FDA)-Required Black-Box Warning

Cigarette smoking and serious cardiovascular risks: Cigarette smoking increases the risk of serious adverse cardiovascular events (for example, heart attack and stroke) from hormonal contraceptive use. This risk increases with age, particularly in women older than 35, and with the number of cigarettes smoked. Therefore, hormonal contraceptives, including norelgestromin-ethinyl estradiol, should not be used by women who are older than 35 and smoke.

Risk of venous thromboembolism: The risk of venous thromboembolism (VTE) — blood clots in the deep veins of the leg, groin or arm that can dislodge and travel in the blood, lodging in the lungs (known as pulmonary embolism) — among women aged 15 to 44 who used the norelgestromin-ethinyl estradiol patch was approximately 20% to 100% higher than the risk of VTE among women using several different oral contraceptives.

Higher estrogen exposure: Estrogen exposure on average is approximately 60% higher in women using norelgestromin-ethinyl estradiol than in women using combination oral contraceptives containing 35 micrograms of ethinyl estradiol. This increased estrogen exposure may increase the risk of adverse events, including VTE.

Some Additional Notable Safety Warnings

• Increases risk of serious cardiovascular adverse events, such as heart attack, stroke and venous blood clots
• Increases risk of breast cancer and other estrogen-sensitive cancers
• Increases risk of liver damage, particularly in women with liver disease such as viral hepatitis and liver cirrhosis
• Increases risk of benign liver tumors and liver cancer
• Can increase blood pressure, particularly in older women and with long-term use

*These warnings are paraphrased in part from the FDA-approved product labeling.

The norelgestromin-ethinyl estradiol patch was first approved by the Food and Drug Administration (FDA) in November 2001 under the brand name ORTHO EVRA for pregnancy prevention and is the only contraceptive product available as a skin patch.[2]

The patch, like many combination oral birth control pills, contains two hormones: a progestin and an estrogen. The progestin in this case was a then-new third-generation synthetic progestin, norelgestromin, whereas the estrogen was ethinyl estradiol, an older estrogen that previously had been a component of several oral contraceptives.

Since 2005, Public Citizen’s Health Research Group has designated the norelgestromin-ethinyl estradiol patch as Do Not Use because it is associated with an increased risk of venous thromboembolism (VTE) — dangerous blood clots in the deep veins of the leg, groin or arm that can dislodge and travel in the blood, lodging in the lungs (known as pulmonary embolism) — and death compared with older oral contraceptives.[3] In addition, there was no evidence that it was a more effective contraceptive than older oral contraceptives.

Public Citizen petitioned the FDA in 2008 to remove Ortho Evra from the market due to its unfavorable risk-benefit profile.[4] Despite preapproval and postapproval evidence of increased estrogen exposure causing an increased risk of dangerous blood clots compared with older oral contraceptives,[5] the FDA denied the petition in 2012.[6] In late 2014, Janssen Pharmaceuticals, the manufacturer of Ortho Evra, voluntarily discontinued marketing of the product.[7] However, earlier in 2014, the FDA had approved a generic version of the norelgestromin-ethinyl estradiol patch, which is sold by Mylan Pharmaceuticals under the brand name XULANE.[8]

No additional contraceptive benefits, higher discontinuation rates

During preapproval clinical trials, the pregnancy rate among women taking Ortho Evra was about 1% per year, which was similar to the rate among women using older, safer combination oral contraceptives.[9]

However, clinical trial evidence also showed that women using Ortho Evra were more likely to drop out of the trials and discontinue the drug — largely due to experiencing adverse effects, such as breast discomfort, more severe menstrual cramps, nausea and vomiting — than those using combination oral contraceptives.[10]

Moreover, during an FDA advisory committee meeting in 2011 to reassess the risk-benefit profile of Ortho Evra, the FDA concluded that for certain high-risk groups of women, the rate of pregnancy was higher among women using Ortho Evra than among those using oral contraceptives.[11]

Excess levels of estrogen

The norelgestromin-ethinyl estradiol patch is associated with a number of serious, potentially fatal, adverse effects that have led to a series of product labeling changes since Ortho Evra’s approval in 2001.

Importantly, evidence from one preapproval clinical trial indicated that Ortho Evra exposed women to twice the amount of estrogen on average compared with women using older oral contraceptives.[12] These data, however, were not mentioned in Ortho Evra’s initial product labeling and were only released to the public in 2005 as a result of litigation against Johnson and Johnson.[13]

Only after a postapproval clinical trial had demonstrated that exposure to estrogen from use of Ortho Evra was 60% higher than exposure from use of an oral contraceptive containing a standard 35-microgram (mcg) daily dose of estrogen[14] did the FDA finally require the manufacturer to disclose this crucial safety information in the drug’s product labeling in 2005.[15],[16]

Notably, by 1991 the FDA had requested the withdrawal from the market of all oral contraceptives containing daily estrogen doses of greater than 50 mcg because of the increased risk of dangerous blood clots without any increase in contraceptive effectiveness.[17] Ortho Evra delivered the equivalent, on average, of a 56-mcg daily dose of estrogen, and thus never should have been approved by the FDA in 2001.[18]

Increased cardiovascular risk, including fatal blood clots

Prior to approving Ortho Evra, the FDA recognized the potential increased risk of dangerous blood clots in women who used the drug during preapproval clinical trials, but the agency failed to ensure that the initial product labeling conveyed this risk.

In 2006, the FDA belatedly approved revisions to Ortho Evra’s product labeling that included findings from a postapproval observational study revealing a more than twofold increase in the risk of dangerous blood clots in women using the patch compared with those using standard oral contraceptives.[19],[20] Finally, in 2011, the FDA appropriately required that Ortho Evra’s product labeling include a black-box warning about the increased exposure to estrogen and the increased risk of VTE (see Text Box, above).[21],[22]

What You Can Do

If you are using the norelgestromin-ethinyl estradiol patch, talk to your doctor about switching to another birth control option. Do not stop using the patch suddenly.

Safer alternatives are combination birth control pills that contain low-dose estrogen (30-mcg or lower daily dose) and either levonorgestrel, norgestrel or norethindrone (there are multiple generic brands available for each of these combination products).
 

References

[1] Mylan Pharmaceuticals. Label: norelgestromin and ethinyl estradiol transdermal system (XULANE). April 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f7848550-086a-43d8-8ae5-047f4b9e4382. Accessed January 29, 2020.

[2] Food and Drug Administration. Approval Letter: Ortho-Evra (NDA #021-180). November 21, 2001. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/021-180_Ortho%20EVRA_Approv.pdf. Accessed January 29, 2020.

[3] Birth control patch ORTHO EVRA linked to dangerous blood clots. Worst Pills, Best Pills News. September 2005. /newsletters/view/413. Accessed January 29, 2020.

[4] Public Citizen. Petition to ban ethinyl estradiol/norelgestromin (Ortho-Evra). May 8, 2008. https://www.citizen.org/article/petition-to-ban-ethinyl-estradiol-norelgestromin-ortho-evra/. Accessed January 30, 2020.

[5] Ibid.

[6] Food and Drug Administration. Letter to Public Citizen denying petition to ban Ortho Evra. August 22, 2012. https://www.regulations.gov/document?D=FDA-2008-P-0296-0023. Accessed January 29, 2020.

[7] United States Securities and Exchange Commission. Form 10-K, Agile Therapeutics for year ending December 31, 2018. https://www.sec.gov/Archives/edgar/data/1261249/000104746919001136/a2237968z10-k.htm. Accessed January 29, 2020.

[8] Food and Drug Administration. Approval letter: Xulane (ANDA #200910). April 16, 2014. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200910Orig1s000.pdf. Accessed January 29, 2020. Accessed January 29, 2020.

[9] Ortho Evra – a contraceptive patch. Med Lett Drugs Ther. 2002;44(1122):8-9.

[10] Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2013;(4):CD003552.

[11] Food and Drug Administration. Background document for joint meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. December 9, 2011. https://wayback.archive-it.org/7993/20170405210925/https:/www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM282634.pdf. Accessed January 29, 2020.

[12] Johnson and Johnson Pharmaceutical Research Institute. “Clinical Study Report Protocol NRGEEP-PHI-017; Phase 1.” June 11, 1999. In Ortho-Evra Products Liability Litigation, MDL 1742, N.D. Ohio, Case No. 1:06-cv-40000,Ex.629.

[13] Ibid.

[14] van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72(3):168-174.

[15] Food and Drug Administration. Approval letter: Ortho-Evra (NDA #021-180/S-019). November 10, 2005. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021180s019ltr.pdf. Accessed January 30, 2020.

[16] Ortho-McNeil Pharmaceutical. Label: norelgestromin/ethinyl estradiol transdermal system (ORTHO EVRA). November 2005. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021180s019lbl.pdf. Accessed January 30, 2020.

[17] Institute of Medicine. Oral Contraceptives and Breast Cancer. 1991. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/1814/oral-contraceptives-and-breast-cancer. Accessed February 3, 2020. Pages 58 and 143.

[18] Public Citizen. Petition to ban ethinyl estradiol/norelgestromin (Ortho-Evra). May 8, 2008. https://www.citizen.org/article/petition-to-ban-ethinyl-estradiol-norelgestromin-ortho-evra/. Accessed January 30, 2020.

[19] Food and Drug Administration. Supplement approval letter: Ortho-Evra (NDA 21-180/S-022). September 20, 2006. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021180s022ltr.pdf. Accessed January 30, 2020.

[20] Ortho-McNeil Pharmaceuticals. Label: norelgestromin/ethinyl estradiol transdermal system (ORTHO EVRA). September 2006. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021180s022lbl.pdf. Accessed January 30, 2020.

[21] Food and Drug Administration. Supplement Approval letter: Ortho-Evra (NDA 021180/S-039). March 23, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/021180s039ltr.pdf. Accessed January 30, 2020.

[22] Ortho-McNeil-Janssen Pharmaceuticals. Label: norelgestromin/ethinyl estradiol transdermal system (ORTHO EVRA). March 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021180s039lbl.pdf. Accessed January 30, 2020.