IMPORTANT SAFETY UPDATE FOR U.S. Healthcare Professionals ORTHO EVRA®

IMPORTANT SAFETY UPDATE FOR US Healthcare
Professionals ORTHO EVRA®

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March 23, 2011 - At the request of the FDA, the product labeling for ORTHO EVRA® has been revised to include the following in the Boxed WARNING: potential risk of venous thromboembolism and the pharmacokinetic profile of ethinyl estradiol associated with the use of ORTHO EVRA®. Additionally, the Boxed WARNING has been revised to state that women who are over 35 years old should not use ORTHO EVRA®.


The ORTHO EVRA® product labeling has been revised as follows:

  • The revised Boxed WARNINGS has been moved to the beginning of the Physician Labeling.
  • The warning regarding cigarette smoking and the associated risk of serious cardiovascular events currently in the Boxed WARNINGS of Physician and Detailed Patient Labeling has been modified to advise patients who are >35 years of age and smoke not use ORTHO EVRA®.
  • The potential risk of venous thromboembolism and the pharmacokinetic profile of ethinyl estradiol associated with the use of ORTHO EVRA®, which were already described in the WARNINGS and CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives sections of Physician Labeling, have been moved to appear in the Boxed WARNINGS.
  • The narrative description of the epidemiologic findings described in Table 5 in the WARNINGS section has been slightly modified.

WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, AND
PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOL


Cigarette Smoking and Serious Cardiovascular Risks

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 ORTHO EVRA®, should not be used by women who are over 35 years of age and smoke.


Risk of Venous Thromboembolism

The risk of venous thromboembolism (VTE) among women aged 15-44 who used the ORTHO EVRA® patch compared to women who used oral contraceptives containing 30-35 mcg of ethinyl estradiol (EE) and either levonorgestrel or norgestimate was assessed in four U.S. case-control studies using electronic healthcare claims data. The odds ratios ranged from 1.2 to 2.2; one of the studies found a statistically significant increased risk of VTE for current users of ORTHO EVRA® (see WARNINGS - Table 5).


Pharmacokinetic Profile of Ethinyl Estradiol

The pharmacokinetic (PK) profile for the ORTHO EVRA® patch is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. Area under the time-concentration curve (AUC) and average concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using ORTHO EVRA® compared with women using an oral contraceptive containing 35 mcg of EE. In contrast, peak concentrations for EE are approximately 25% lower in women using ORTHO EVRA®. 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 ORTHO EVRA® compared with women using oral contraceptives containing 30-35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See WARNINGS and CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives.)


WHO SHOULD NOT USE ORTHO EVRA®

Hormonal contraceptives include birth control pills, injectables, implants, the vaginal ring, and the contraceptive patch. The following information is derived primarily from studies of birth control pills. The contraceptive patch is expected to be associated with similar risks:


Do not use ORTHO EVRA® if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from hormonal contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

EPIDEMIOLOGY STUDIES: Evaluation of the risk of venous thromboembolism (VTE) among women aged 15-44 who used ORTHO EVRA®


Four epidemiologic, case-control studies107-111,113-115 were conducted in the U.S. using electronic healthcare claims data to evaluate the risk of venous thromboembolism (VTE) among women aged 15-44 who used ORTHO EVRA® compared to women who used oral contraceptives containing 30-35 mcg of ethinyl estradiol (EE) and either levonorgestrel (LNG) or norgestimate (NGM). NGM is the prodrug for norelgestromin, the progestin in ORTHO EVRA®.


These studies (see Table 5) used slightly different designs and reported odds ratios ranging from 1.2 to 2.2. The interpretations of these odds ratios 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 ORTHO EVRA®.


The four studies are:

  • The i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including a 24-month extension, based on the Ingenix Research Datamart; only this study included patient chart review to confirm the VTE occurrence.
  • The Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database
  • BCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database
  • BCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan

A summary of the study published by Jick SS, Kaye JA, Russmann S, Jick H (Contraception. 2006;73:223-228). Risk of nonfatal venous thromboembolism in women using a contraceptive trandsdermal patch and oral contraceptives containing norgestimate and 35µg of ethinyl estradiol can be found by clicking the following link: http://www.ncbi.nlm.nih.gov/pubmed/16472560


A summary of the study published by Cole JA, Norman H, Doherty M, Walker AM (Obstetrics and Gynecology. 2007;109:339-346). Venous Thromboembolism, Myocardial Infarction, and Stroke Among Transdermal Contraceptive System Users can be found by clicking the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=339%5Bpage%5D%20AND%202007%5Bpdat%5D%20AND%20Cole%5Bfirst%20author%5D


A summary of the publication by Jick S, Kaye JA, Li L, Jick H (Contraception. 2007;76:4-7). Further Results on the Risk of Non-Fatal Venous Thromboembolism in users of the contraceptive patch compared to users of oral contraceptives containing Norgestimate and 35µg of EE can be found by clicking the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=4%5Bpage%5D%20AND%202007%5Bpdat%5D%20AND%20Jick%5Bfirst%20author%5D


A summary of the Boston Collaborative Drug Surveillance Program (BCDSP) study published by Jick SS, Hagberg KW, Hernandez RK, Kaye JA (Contraception. 2010;81(1):16-21.) entitled "Postmarketing study of ORTHO EVRA® and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism" can be found by clicking the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=16%5Bpage%5D%20AND%202010%5Bpdat%5D%20AND%20Jick%5Bfirst%20author%5D


For additional information, please call the Medical Information Center at 1-800-526-7736. Click here for FULL PRESCRIBING INFORMATION, including Boxed WARNINGS.


Important Safety Information


Serious as well as minor side effects have been reported with the use of the Patch. Serious risks, which can be life threatening, include blood clots, stroke and heart attacks and are increased if you smoke cigarettes. Cigarette smoking increases the risk of serious cardiovascular side effects, especially if you are over 35. Women who use the Patch are strongly advised not to smoke. Some women should not use the Patch, including women who have blood clots, certain cancers, a history of heart attack, blood clots, or stroke, as well as those who are or may be pregnant.


Hormones from ORTHO EVRA® get into the bloodstream 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 ORTHO EVRA® 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. The risk of venous thromboembolic events (blood clots in the legs and/or the lungs) may be increased with ORTHO EVRA® use compared with use of birth control pills. Studies examined the risk of these serious blood clots in women who used either ORTHO EVRA® or birth control pills containing one of two progestins (levonorgestrel or norgestimate) and 30–35 micrograms of estrogen. Results of these studies ranged from an approximate doubling of risk of serious blood clots to no increase in risk in women using ORTHO EVRA® compared to women using birth control pills.


You should discuss with your healthcare professional whether ORTHO EVRA® is a good method of contraception for you.


The Patch does not protect against HIV or sexually transmitted diseases.


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.


Please see the Detailed Patient Labeling from the full Product Information.

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