Ennis & Ennis, P.A.
Attorneys at Law

Ortho Evra Patch News

ORTHO EVRA
(norelgestromin / ethinyl estradiol
TRANSDERMAL SYSTEM)
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
Rx only
DESCRIPTION
ORTHO EVRA is a combination transdermal contraceptive patch with a contact
surface area of 20 cm2. It contains 6.00 mg norelgestromin (NGMN) and 0.75 mg
ethinyl estradiol (EE). Systemic exposures (as measured by area under the curve
[AUC] and steady state concentration [Css]) of NGMN and EE during use of ORTHO
EVRA are higher and peak concentrations (Cmax) are lower than those produced by
an oral contraceptive containing norgestimate 250 µg / EE 35 µg. (See BOLDED
WARNING; CLINICAL PHARMACOLOGY, Transdermal versus Oral
Contraceptives).
ORTHO EVRAis a thin, matrix-type transdermal contraceptive patch consisting of
three layers. The backing layer is composed of a beige flexible film consisting of a
low-density 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 polyisobutylene/polybutene adhesive,
crospovidone, non-woven polyester fabric and lauryl lactate as inactive components.
The active components in this layer are the hormones, norelgestromin and ethinyl
estradiol. 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 polyethylene
terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in
contact with the middle adhesive layer.
The outside of the backing layer is heat-stamped “ORTHO EVRA 150/20.”
The structural formulas of the components are:
norelgestromin ethinyl estradiol
3
Molecular weight, norelgestromin: 327.47
Molecular weight, ethinyl estradiol: 296.41
Chemical name for norelgestromin: 18, 19-dinorpregn-4-en-20-yn-3-one,
13-ethyl- 17-hydroxy-, 3-oxime, (17)
Chemical name for ethinyl estradiol: 19-Norpregna-1, 3, 5 (10)-trien-20-yne-3,
17-diol, (17)
CLINICAL PHARMACOLOGY
Pharmacodynamics
Norelgestromin is the active progestin largely responsible for the progestational
activity that occurs in women following application of ORTHO EVRA.
Norelgestromin is also the primary active metabolite produced following oral
administration of norgestimate (NGM), the progestin component of the oral
contraceptive products ORTHO-CYCLEN® and ORTHO TRI-CYCLEN®.
Combination oral 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).
Receptor and human sex hormone-binding globulin (SHBG) binding studies, as well
as studies in animals and humans, have shown that both NGM and NGMN exhibit
high progestational activity with minimal intrinsic androgenicity90-93.
Transdermally-administered norelgestromin, in combination with ethinyl estradiol,
does not counteract the estrogen-induced increases in SHBG, resulting in lower levels
of free testosterone in serum compared to baseline.
One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function
post-therapy and found that FSH, LH, and Estradiol mean values, though suppressed
during therapy, returned to near baseline values during the 6 weeks post therapy.
Pharmacokinetics
Absorption
Following a single application of ORTHO EVRA, 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. The mean
steady state Css concentrations ranged from 0.305 –1.53 ng/mL for NGMN and from
11.2 – 137 pg/mL for EE.
Absorption of NGMN and EE following application of ORTHO EVRA to the
buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined.
4
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) pharmacokinetic parameters Css and AUC0-168 for NGMN and EE
following a single buttock application of ORTHO EVRA are summarized in
Table 1.
In multiple dose studies, AUC0-168 for NGMN and EE was found to increase over
time (Table 1). In a three-cycle study, these pharmacokinetic parameters reached
steady-state conditions during Cycle 3 (Figures 1 and 2). Upon removal of the patch,
serum levels of EE and NGMN reach very low or non-measurable levels within
3 days.
Table 1: Mean (%CV*) Pharmacokinetic Parameters of Norelgestromin (NGMN) and Ethinyl
Estradiol (EE) Following 3 Consecutive Cycles of ORTHO EVRA® 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)
t1/2 (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)
t1/2
(h) nc nc nc 21.0 (43.2)
nc = not calculated,*%CV is % of Coefficient of variation = 100 (standard
deviation/mean)
5
Figure 1: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following
Application of ORTHO EVRA on the Buttock for Three Consecutive Cycles (Vertical
arrow indicates time of patch removal)
Time (h)
0 24 48 72 96 120 144 168 192 216 240
NGMN Concentration (ng/mL)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cycle 1 Week 1
Cycle 3 Week 1
Cycle 3 Week 2
Cycle 3 Week 3
Figure 2: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following
Application of ORTHO EVRA on the Buttock for Three Consecutive Cycles (Vertical
arrow indicates time of patch removal.)
Time (h)
0 24 48 72 96 120 144 168 192 216 240
EE Concentration (pg/mL)
0
10
20
30
40
50
60
70
Cycle 1 Week 1
Cycle 3 Week 1
Cycle 3 Week 2
Cycle 3 Week 3
The absorption of NGMN and EE following application of ORTHO EVRA 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,
6
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 ORTHO EVRA 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.
Metabolism
Since ORTHO EVRA is applied transdermally, first-pass metabolism (via the
gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral
administration is avoided. Hepatic metabolism of NGMN occurs and metabolites
include norgestrel, which is highly bound to SHBG, and various hydroxylated and
conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated
products and their glucuronide and sulfate conjugates.
Distribution
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. Ethinyl estradiol is
extensively bound to serum albumin and induces an increase in the serum
concentrations of SHBG (See CLINICAL PHARMACOLOGY, Transdermal versus
Oral Contraceptives, Table 3).
Elimination
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.
Transdermal versus Oral Contraceptives
The ORTHO EVRA transdermal patch was designed to deliver EE and NGMN over
a seven-day period while oral contraceptives (containing NGM 250 µg / EE 35 µg)
are administered on a daily basis. Figures 3 and 4 present mean pharmacokinetic (PK)
profiles for EE and NGMN following administration of an oral contraceptive
(containing NGM 250 µg / EE 35 µg) compared to the 7-day transdermal
ORTHO EVRA patch (containing NGMN 6.0 mg / EE 0.75 mg) during cycle 2 in
32 healthy female volunteers.
7
Figure 3: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration
of an Oral Contraceptive for 2 cycles or Application of ORTHO EVRA® for 2 cycles to the
Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15-21,
ORTHO EVRA® : Cycle 2, week 3]
Time (h)
0 24 48 72 96 120 144 168 192 216 240
NGMN Concentration (ng/mL)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
ORTHO EVRA - Application to the Buttock
Oral Contraceptive (NGM 250 µg/ EE 35 µg)
Oral Contraceptive (NGM 250 µg/ EE 35 µg) - Estimated Steady State Data Based on Day 21
Figure 4: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of
an Oral Contraceptive for 2 cycles or Application of ORTHO EVRA® for 2 cycles to the
Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15-21,
ORTHO EVRA® : Cycle 2, week 3]
Time (h)
0 24 48 72 96 120 144 168 192 216 240
EE Concentration (
pg/mL) 0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
ORTHO EVRA - Application to the Buttock
Oral Contraceptive (NGM 250 µg/ EE 35 µg)
Oral Contraceptive (NGM 250 µg/ EE 35 µg) - Estimated Steady State Data Based on Day 21
Table 2 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK)
parameters.
8
Table 2: Mean (%CV) NGMN and EE Steady State Pharmacokinetic Parameters Following
Application of ORTHO EVRA® and Once-daily Administration of an Oral Contraceptive
(containing NGM 250 µg / EE 35 µg) in Healthy Female Volunteers
Parameter ORTHO EVRAe ORAL CONTRACEPTIVE d
NGMN a
Cmax (ng/mL) 1.12 (33.6) 2.16 (25.2)
AUC0-168 (ng.h/mL) 145 (36.8) 123 (30.2)b
Css (ng/mL) 0.888 (36.6) 0.732 (30.2) c
EE
Cmax (pg/mL) 97.4 (31.6) 133 (27.7)
AUC0-168 (pg.h/mL) 12,971 (33.1) 8,281(26.9)b
Css (pg/mL) 80.0 (33.5) 49.3 (26.9)c
a NGM is rapidly metabolized to NGMN following oral administration
b Average weekly exposure, calculated as AUC24 x 7
c Cavg
d Cycle 2, Day 21
e Cycle 2, Week 3
In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects
treated with ORTHO EVRA 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 ORTHO EVRA
was higher relative to the variability determined from the oral contraceptive. The
mean pharmacokinetic profiles are different between the two products and caution
should be exercised when making a direct comparison of these PK parameters.
In Table 3, 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 ORTHO EVRA users
compared to women taking the oral contraceptive; percent change in CBG
concentrations were similar for ORTHO EVRA and oral contraceptive users. Within
each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and
Cycle 2, Day 22.
9
Table 3: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following
Once-daily Administration of an Oral Contraceptive (containing NGM 250 µg /
EE 35 µg) for One Cycle and Application of ORTHO EVRA® for One Cycle in
Healthy Female Volunteers
Parameter ORTHO EVRA
(% 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)
Special Populations
Effects of Age, Body Weight, Body Surface Area and Race:
The effects of age, body weight, body surface area and race on the pharmacokinetics
of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic
studies of single 7-day applications of ORTHO EVRA. 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 (10-25%) of the
overall variability in the pharmacokinetics of NGMN and EE following application of
ORTHO EVRA 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.
Renal and Hepatic Impairment
No formal studies were conducted with ORTHO EVRA to evaluate the
pharmacokinetics, safety, and efficacy in women with renal or hepatic impairment.
Steroid hormones may be poorly metabolized in patients with impaired liver function
(see PRECAUTIONS).
Drug Interactions
The metabolism of hormonal contraceptives may be influenced by various drugs. Of
potential clinical importance are drugs that cause the induction of enzymes that are
responsible for the degradation of estrogens and progestins, and drugs that interrupt
entero-hepatic recirculation of estrogen (e.g. certain antibiotics)72.
The proposed mechanism of interaction of antibiotics is different from that of liver
enzyme-inducing drugs. Literature suggests possible interactions with the
concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a
pharmacokinetic drug interaction study, oral administration of tetracycline HCl,
500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA did not
significantly affect the pharmacokinetics of NGMN or EE.
10
The major target for enzyme inducers is the hepatic microsomal
estrogen-2-hydroxylase (cytochrome P450 3A4)99. See also PRECAUTIONS, Drug
Interactions.
Patch Adhesion
In the clinical trials with ORTHO EVRA, approximately 2% of the cumulative
number of patches completely detached. The proportion of subjects with at least
1 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 the DOSAGE AND ADMINISTRATION section.
INDICATIONS AND USAGE
ORTHO EVRA is indicated for the prevention of pregnancy in women who elect to
use a transdermal patch as a method of contraception.
The pharmacokinetic profile for the ORTHO EVRA transdermal patch is different
from that of an oral contraceptive. Healthcare professionals should balance the higher
estrogen exposure with ORTHO EVRA® against the chance of pregnancy if a
contraceptive pill is not taken daily. It is not known whether there are differences in
the risk of serious adverse events (See BOLDED WARNING; CLINICAL
PHARMACOLOGY, Transdermal versus Oral Contraceptives).
Like oral contraceptives, ORTHO EVRA is highly effective if used as
recommended in this label.
In 3 large clinical trials in North America, Europe and South Africa, 3,330 women
(ages 18-45) completed 22,155 cycles of ORTHO EVRA use, pregnancy rates were
approximately 1 per 100 women-years of ORTHO EVRA 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 ORTHO EVRA use
were among women with a baseline body weight 198 lbs. (90kg), 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 ORTHO EVRA may
be less effective in these women.
Health Care Professionals who consider ORTHO EVRA for women at or above
198 lbs. should discuss the patient's individual needs in choosing the most appropriate
contraceptive option.
Table 4 lists the accidental pregnancy rates for users of various methods of
contraception. The efficacy of these contraceptive methods, except sterilization, IUD,
11
and Norplant depends upon the reliability with which they are used. Correct and
consistent use of methods can result in lower failure rates.
Table 4: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of
Typical Use and the First Year of Perfect Use of Contraception and the Percentage
Continuing Use at the End of the First Year. United States.
% of Women Experiencing an Unintended Pregnancy within the
First Year of Use
% of Women
Continuing Use at
One Year3
Method
(1)
Typical Use1
(2)
Perfect Use2
(3) (4)
Chance4 85 85
Spermicides5 26 6 40
Periodic abstinence 25 63
Calendar 9
Ovulation Method 3
Sympto-Thermal6 2
Post-Ovulation 1
Cap7
Parous Women 40 26 42
Nulliparous Women 20 9 56
Sponge
Parous Women 40 20 42
Nulliparous Women 20 9 56
Diaphragm7 20 6 56
Withdrawal 19 4
Condom8
Female (Reality) 21 5 56
Male 14 3 61
Pill 5 71
Progestin Only 0.5
Combined 0.1
IUD
Progesterone T 2.0 1.5 81
Copper T380A 0.8 0.6 78
LNg 20 0.1 0.1 81
Depo-Provera 0.3 0.3 70
Norplant and Norplant-2 0.05 0.05 88
Female Sterilization 0.5 0.5 100
Male Sterilization 0.15 0.10 100
Hatcher et al, 1998, Ref. # 1.
Emergency Contraceptive Pills:
Treatment initiated within 72 hours after unprotected intercourse reduces the risk of
pregnancy by at least 75%.9
Lactational Amenorrhea Method:
LAM is highly effective, temporary method of contraception.10
12
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F,
Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth
Revised Edition. New York NY: Irvington Publishers, 1998.
1 Among typical couples who initiate use of a method (not necessarily for the first
time), the percentage who experience an accidental pregnancy during the first year
if they do not stop use for any other reason.
2 Among couples who initiate use of a method (not necessarily for the first time) and
who use it perfectly (both consistently and correctly), the percentage who
experience an accidental pregnancy during the first year if they do not stop use for
any other reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use
a method for one year.
4 The percents becoming pregnant in columns (2) and (3) are based on data from
populations where contraception is not used and from women who cease using
contraception in order to become pregnant. Among such populations, about 89%
become pregnant within one year. This estimate was lowered slightly (to 85%) to
represent the percent who would become pregnant within one year among women
now relying on reversible methods of contraception if they abandoned
contraception altogether.
5 Foams, creams, gels, vaginal suppositories, and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory
and basal body temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 The treatment schedule is one dose within 72 hours after unprotected intercourse,
and a second dose 12 hours after the first dose. The Food and Drug Administration
has declared the following brands of oral contraceptives to be safe and effective for
emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink
pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is
4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
10 However, to maintain effective protection against pregnancy, another method of
contraception must be used as soon as menstruation resumes, the frequency or
duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches
six months of age.
ORTHO EVRA has not been studied for and is not indicated for use in emergency
contraception.
13
CONTRAINDICATIONS
ORTHO EVRA should not be used in women who currently have the following
conditions:
• Thrombophlebitis, thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebrovascular or coronary artery disease (current or past history)
• Valvular heart disease with complications103
• Severe hypertension103
• Diabetes with vascular involvement103
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast or personal history of breast cancer
• Carcinoma of the endometrium or other known or suspected estrogen-dependent
neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive
use
• Acute or chronic hepatocellular disease with abnormal liver function103
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side effects from
hormonal contraceptive use. This risk increases with age and with heavy
smoking (15 or more cigarettes per day) and is quite marked in women over
35 years of age. Women who use hormonal contraceptives, including
ORTHO EVRA®, should be strongly advised not to smoke.
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. 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 EE 35 µg. In contrast, peak concentrations for EE are
approximately 25% lower in women using ORTHO EVRA®. Inter-subject
variability results in increased exposure to EE in some women using either
14
ORTHO EVRA®
or oral contraceptives. However, inter-subject variability in
women using ORTHO EVRA® is higher. In general, increased estrogen exposure
may increase the risk of adverse events. However, it is not known whether there
are changes in the risk of serious adverse events based on the differences in
pharmacokinetic profiles of EE in women using ORTHO EVRA® compared with
women using oral contraceptives containing 35 µg of EE. (See CLINICAL
PHARMACOLOGY, Transdermal versus Oral Contraceptives).
ORTHO EVRA and other contraceptives that contain both an estrogen and a
progestin are called combination hormonal contraceptives. There is limited
epidemiologic data available to determine whether safety with the transdermal route
of administration is different than the oral route. Practitioners prescribing
ORTHO EVRA should be familiar with the following information relating to risks.
The use of combination hormonal contraceptives is associated with increased risks of
several serious conditions including myocardial infarction, thromboembolism, stroke,
hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or
mortality is very small in healthy women without underlying risk factors. The risk of
morbidity and mortality increases significantly in the presence of other underlying
risk factors such as hypertension, hyperlipidemias, obesity and diabetes.
The information contained in this package insert is principally based on studies
carried out in women who used combination oral contraceptives with higher
formulations of estrogens and progestins than those in common use today. The effect
of long-term use of combination hormonal contraceptives with lower doses of both
estrogen and progestin administered by any route remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types:
retrospective or case control studies and prospective or cohort studies. Case control
studies provide a measure of the relative risk of a disease, namely, a ratio of the
incidence of a disease among oral contraceptive users to that among nonusers. The
relative risk does not provide information on the actual clinical occurrence of a
disease. Cohort studies provide a measure of attributable risk, which is the difference
in the incidence of disease between hormonal contraceptive users and nonusers. The
attributable risk does provide information about the actual occurrence of a disease in
the population (adapted from refs. 2 and 3 with the author's permission). For further
information, the reader is referred to a text on epidemiological methods.
15
1. Thromboembolic Disorders and Other Vascular Problems
a. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use
of hormonal contraceptives is well established. Case control studies have found the
relative risk of users compared to nonusers to be 3 for the first episode of superficial
venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and
1.5 to 6 for women with predisposing conditions for venous thromboembolic
disease2,3,19-24. Cohort studies have shown the relative risk to be somewhat lower,
about 3 for new cases and about 4.5 for new cases requiring hospitalization25. The
risk of thromboembolic disease associated with hormonal contraceptives is not related
to length of use and disappears after hormonal contraceptive use is stopped2. A two-
to four-fold increase in relative risk of post-operative thromboembolic complications
has been reported with the use of hormonal contraceptives9,26. The relative risk of
venous thrombosis in women who have predisposing conditions is twice that of
women without such medical conditions9,26. If feasible, hormonal contraceptives
should be discontinued at least four weeks prior to and for two weeks after elective
surgery of a type associated with an increase in risk of thromboembolism and during
and following prolonged immobilization. Since the immediate postpartum period is
also associated with an increased risk of thromboembolism, hormonal contraceptives
should be started no earlier than four weeks after delivery in women who elect not to
breast-feed.
In the large clinical trials (N= 3,330 with 1,704 women-years of exposure), one case
of non-fatal pulmonary embolism occurred during ORTHO EVRA use, and one case
of post-operative non-fatal pulmonary embolism was reported following
ORTHO EVRA use. It is unknown if the risk of venous thromboembolism with
ORTHO EVRA use is different than with use of combination oral contraceptives.
As with any combination hormonal contraceptives, the clinician should be alert to the
earliest manifestations of thrombotic disorders (thrombophlebitis, pulmonary
embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these
occur or be suspected, ORTHO EVRA should be discontinued immediately.
b. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to hormonal
contraceptive use. This risk is primarily in smokers or women with other underlying
risk factors for coronary artery disease such as hypertension, hypercholesterolemia,
morbid obesity, and diabetes. The relative risk of heart attack for current hormonal
contraceptive users has been estimated to be two to six4-10 compared to non-users.
The risk is very low under the age of 30.
16
Smoking in combination with oral contraceptive use has been shown to contribute
substantially to the incidence of myocardial infarctions in women in their mid-thirties
or older with smoking accounting for the majority of excess cases11. Mortality rates
associated with circulatory disease have been shown to increase substantially in
smokers, especially in those 35 years of age and older among women who use oral
contraceptives. (See Figure 5)
Figure 5: Circulatory Disease Mortality Rates Per 100,000 Women-Years by Age, Smoking Status
and Oral Contraceptive Use
Hormonal contraceptives may compound the effects of well-known risk factors, such
as hypertension, diabetes, hyperlipidemias, age and obesity13. In particular, some
progestins are known to decrease HDL cholesterol and cause glucose intolerance,
while estrogens may create a state of hyperinsulinism14-18. Hormonal contraceptives
have been shown to increase blood pressure among some users (see Section 9 in
WARNINGS). Similar effects on risk factors have been associated with an increased
risk of heart disease. Hormonal contraceptives, including ORTHO EVRA, must be
used with caution in women with cardiovascular disease risk factors.
Norgestimate and norelgestromin have minimal androgenic activity (see CLINICAL
PHARMACOLOGY). There is some evidence that the risk of myocardial infarction
associated with hormonal contraceptives is lower when the progestin has minimal
androgenic activity than when the activity is greater97.
c. Cerebrovascular Diseases
Hormonal contraceptives have been shown to increase both the relative and
attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes),
17
although, in general, the risk is greatest among older (>35 years), hypertensive
women who also smoke. Hypertension was found to be a risk factor for both users
and nonusers, for both types of strokes, and smoking interacted to increase the risk of
stroke27-29.
In a large study, the relative risk of thrombotic strokes has been shown to range from
3 for normotensive users to 14 for users with severe hypertension30. The relative risk
of hemorrhagic stroke is reported to be 1.2 for non-smokers who used hormonal
contraceptives, 2.6 for smokers who did not use hormonal contraceptives, 7.6 for
smokers who used hormonal contraceptives, 1.8 for normotensive users and 25.7 for
users with severe hypertension30. The attributable risk is also greater in older women3.
d. Dose-Related Risk of Vascular Disease From Hormonal
Contraceptives
A positive association has been observed between the amount of estrogen and
progestin in hormonal contraceptives and the risk of vascular disease31-33. A decline
in serum high-density lipoproteins (HDL) has been reported with many progestational
agents14-16. A decline in serum high-density lipoproteins has been associated with an
increased incidence of ischemic heart disease. Because estrogens increase HDL
cholesterol, the net effect of a hormonal contraceptive depends on a balance achieved
between doses of estrogen and progestin and the activity of the progestin used in the
contraceptives. The activity and amount of both hormones should be considered in
the choice of a hormonal contraceptive.
e. Persistence of Risk of Vascular Disease
There are two studies that have shown persistence of risk of vascular disease for everusers
of combination hormonal contraceptives. In a study in the United States, the
risk of developing myocardial infarction after discontinuing combination hormonal
contraceptives persists for at least 9 years for women 40-49 years who had used
combination hormonal contraceptives for five or more years, but this increased risk
was not demonstrated in other age groups8. In another study in Great Britain, the risk
of developing cerebrovascular disease persisted for at least 6 years after
discontinuation of combination hormonal contraceptives, although excess risk was
very small34. However, both studies were performed with combination hormonal
contraceptive formulations containing 50 micrograms or higher of estrogens.
It is unknown whether ORTHO EVRA is distinct from other combination hormonal
contraceptives with regard to the occurrence of venous and arterial thrombosis.
18
2. Estimates of Mortality From Combination Hormonal Contraceptive
Use
One study gathered data from a variety of sources that have estimated the mortality
rate associated with different methods of contraception at different ages (Table 5).
These estimates include the combined risk of death associated with contraceptive
methods plus the risk attributable to pregnancy in the event of method failure. Each
method of contraception has its specific benefits and risks. The study concluded that
with the exception of combination oral contraceptive users 35 and older who smoke,
and 40 and older who do not smoke, mortality associated with all methods of birth
control is low and below that associated with childbirth.
The observation of a possible increase in risk of mortality with age for combination
oral contraceptive users is based on data gathered in the 1970's but not reported until
198335. Current clinical recommendation involves the use of lower estrogen dose
formulations and a careful consideration of risk factors. In 1989, the Fertility and
Maternal Health Drugs Advisory Committee was asked to review the use of
combination hormonal contraceptives in women 40 years of age and over. The
Committee concluded that although cardiovascular disease risks may be increased
with combination hormonal contraceptive use after age 40 in healthy non-smoking
women (even with the newer low-dose formulations), there are also greater potential
health risks associated with pregnancy in older women and with the alternative
surgical and medical procedures that may be necessary if such women do not have
access to effective and acceptable means of contraception. The Committee
recommended that the benefits of low-dose combination hormonal contraceptive use
by healthy non-smoking women over 40 may outweigh the possible risks36, 37.
Although the data are mainly obtained with oral contraceptives, this is likely to apply
to ORTHO EVRA as well. Women of all ages who use combination hormonal
contraceptives, should use the lowest possible dose formulation that is effective and
meets the individual patient needs.
19
Table 5: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of
Fertility Per 100,000 Non-Sterile Women, by Fertility Control Method According to Age
Method of control and
outcome 15-19 20-24 25-29 30-34 35-39 40-44
No fertility control
methods*
7.0 7.4 9.1 14.8 25.7 28.2
Oral contraceptives,
non-smoker**
0.3 0.5 0.9 1.9 13.8 31.6
Oral contraceptives,
smoker**
2.2 3.4 6.6 13.5 51.1 117.2
IUD** 0.8 0.8 1.0 1.0 1.4 1.4
Condom* 1.1 1.6 0.7 0.2 0.3 0.4
Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8
Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. # 35.
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies give conflicting reports on the relationship
between breast cancer and COC use. The risk of having breast cancer diagnosed may
be slightly increased among current and recent users of combination oral
contraceptives. However, this excess risk appears to decrease over time after COC
discontinuation and by 10 years after cessation the increased risk disappears. Some
studies report an increased risk with duration of use while other studies do not and no
consistent relationships have been found with dose or type of steroid. Some studies
have found a small increase in risk for women who first use COCs before age 20.
Most studies show a similar pattern of risk with COC use regardless of a woman’s
reproductive history or her family breast cancer history.
In addition, breast cancers diagnosed in current or ever oral contraceptive users may
be less clinically advanced than in never-users.
Women who currently have or have had breast cancer should not use hormonal
contraceptives because breast cancer is usually a hormonally sensitive tumor.
Some studies suggest that combination oral contraceptive use has been associated
with an increase in the risk of cervical intraepithelial neoplasia in some populations of
women45-48. However, there continues to be controversy about the extent to which
such findings may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast
and cervical cancers, a cause-and-effect relationship has not been established. It is not
known whether ORTHO EVRA is distinct from oral contraceptives with regard to
the above statements.
20
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with hormonal contraceptive use, although
the incidence of benign tumors is rare in the United States. Indirect calculations have
estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk
that increases after four or more years of use, especially with hormonal contraceptives
containing 50 micrograms or more of estrogen49. Rupture of benign, hepatic
adenomas may cause death through intra-abdominal hemorrhage50,51.
Studies from Britain and the US have shown an increased risk of developing
hepatocellular carcinoma in long term ( 8 years)52-54,96 oral contraceptive users.
However, these cancers are extremely rare in the U.S. and the attributable risk (the
excess incidence) of liver cancers in oral contraceptive users approaches less than one
per million users. It is unknown whether ORTHO EVRA is distinct from oral
contraceptives in this regard.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of
hormonal contraceptives. ORTHO EVRA should be discontinued if there is
unexplained partial or complete loss of vision; onset of proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic
measures should be undertaken immediately.
6. Hormonal Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in
women who have used oral contraceptives prior to pregnancy56,57. Studies also do not
indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb
reduction defects are concerned55,56,58,59, when oral contraceptives are taken
inadvertently during early pregnancy.
Combination hormonal contraceptives such as ORTHO EVRA should not be used to
induce withdrawal bleeding as a test for pregnancy. ORTHO EVRA should not be
used during pregnancy to treat threatened or habitual abortion. It is recommended that
for any patient who has missed two consecutive periods, pregnancy should be ruled
out. If the patient has not adhered to the prescribed schedule for the use of ORTHO
EVRA the possibility of pregnancy should be considered at the time of the first
missed period. Hormonal contraceptive use should be discontinued if pregnancy is
confirmed.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery
in users of hormonal contraceptives and estrogens60,61. More recent studies, however,
21
have shown that the relative risk of developing gallbladder disease among hormonal
contraceptive users may be minimal62-64. The recent findings of minimal risk may be
related to the use of hormonal contraceptive formulations containing lower hormonal
doses of estrogens and progestins.
Combination hormonal contraceptives such as ORTHO EVRA may worsen existing
gallbladder disease and may accelerate the development of this disease in previously
asymptomatic women. Women with a history of combination hormonal
contraceptive-related cholestasis are more likely to have the condition recur with
subsequent combination hormonal contraceptive use.
8. Carbohydrate and Lipid Metabolic Effects
Hormonal contraceptives have been shown to cause a decrease in glucose tolerance in
some users17. However, in the non-diabetic woman, combination hormonal
contraceptives appear to have no effect on fasting blood glucose67. Prediabetic and
diabetic women in particular should be carefully monitored while taking combination
hormonal contraceptives such as ORTHO EVRA.
In clinical trials with oral contraceptives containing ethinyl estradiol and norgestimate
there were no clinically significant changes in fasting blood glucose levels. There
were no clinically significant changes in glucose levels over 24 cycles of use.
Moreover, glucose tolerance tests showed no clinically significant changes from
baseline to cycles 3, 12 and 24. In a 6-cycle clinical trial with ORTHO EVRA there
were no clinically significant changes in fasting blood glucose from baseline to end of
treatment.
A small proportion of women will have persistent hypertriglyceridemia while taking
hormonal contraceptives. As discussed earlier (see WARNINGS 1a and 1d), changes
in serum triglycerides and lipoprotein levels have been reported in hormonal
contraceptive users.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal
contraception103. Women with a history of hypertension or hypertension-related
diseases, or renal disease70 should be encouraged to use another method of
contraception. If women elect to use ORTHO EVRA, they should be monitored
closely and if a clinically significant elevation of blood pressure occurs,
ORTHO EVRA should be discontinued. For most women, elevated blood pressure
will return to normal after stopping hormonal contraceptives, and there is no
difference in the occurrence of hypertension between former and never users68-71.
22
An increase in blood pressure has been reported in women taking hormonal
contraceptives68 and this increase is more likely in older hormonal contraceptive
users69 and with extended duration of use61. Data from the Royal College of General
Practitioners12 and subsequent randomized trials have shown that the incidence of
hypertension increases with increasing progestational activity.
10. Headache
The onset or exacerbation of migraine headache or the development of headache with
a new pattern that is recurrent, persistent or severe requires discontinuation of
ORTHO EVRA and evaluation of the cause.
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in women using
ORTHO EVRA. Non-hormonal causes should be considered and adequate
diagnostic measures taken to rule out malignancy, other pathology, or pregnancy in
the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding.
If pathology has been excluded, time or a change to another contraceptive product
may resolve the bleeding. In the event of amenorrhea, pregnancy should be ruled out
before initiating use of ORTHO EVRA.
Some women may encounter amenorrhea or oligomenorrhea after discontinuation of
hormonal contraceptive use, especially when such a condition was pre-existent.
Bleeding Patterns:
In the clinical trials most women started their 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 withdrawal flow and breakthrough bleeding and/or
spotting).
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
Women should be counseled that ORTHO EVRA does not protect against HIV
infection (AIDS) and other sexually transmitted infections.
1. Body Weight 198 lbs. (90 kg)
Results of clinical trials suggest that ORTHO EVRA may be less effective in
women with body weight 198 lbs. (90 kg) than in women with lower body weights.
23
2. Physical Examination and Follow-Up
It is good medical practice for women using ORTHO EVRA, as for all women, to
have annual medical evaluation and physical examinations. The physical
examination, however, may be deferred until after initiation of hormonal
contraceptives if requested by the woman and judged appropriate by the clinician.
The physical examination should include special reference to blood pressure, breasts,
abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests.
In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate
measures should be conducted to rule out malignancy or other pathology. Women
with a strong family history of breast cancer or who have breast nodules should be
monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they
elect to use ORTHO EVRA. Some progestins may elevate LDL levels and may
render the control of hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman using ORTHO EVRA, the medication should be
discontinued. The hormones in ORTHO EVRA may be poorly metabolized in
patients with impaired liver function.
5. Fluid Retention
Steroid hormones like those in ORTHO EVRA may cause some degree of fluid
retention. ORTHO EVRA should be prescribed with caution, and only with careful
monitoring, in patients with conditions which might be aggravated by fluid retention.
6. Emotional Disorders
Women who become significantly depressed while using combination hormonal
contraceptives such as ORTHO EVRA should stop the medication and use another
method of contraception in an attempt to determine whether the symptom is drug
related. Women with a history of depression should be carefully observed and
ORTHO EVRA discontinued if significant depression occurs.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should
be assessed by an ophthalmologist.
24
8. Drug Interactions
Changes in Contraceptive Effectiveness Associated With
Co-Administration of Other Drugs:
Contraceptive effectiveness may be reduced when hormonal contraceptives are
co-administered with some antibiotics, antifungals, anticonvulsants, and other drugs
that increase metabolism of contraceptive steroids. This could result in unintended
pregnancy or breakthrough bleeding. Examples include barbiturates, griseofulvin,
rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine,
topiramate and possibly with ampicillin.
The proposed mechanism of interaction of antibiotics is different from that of liver
enzyme-inducing drugs. Literature suggests possible interactions with the
concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a
pharmacokinetic drug interaction study, oral administration of tetracycline HCl,
500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA did not
significantly affect the pharmacokinetics of norelgestromin or EE.
Several of the anti-HIV protease inhibitors have been studied with co-administration
of oral combination hormonal contraceptives; significant changes (increase and
decrease) in the mean AUC of the estrogen and progestin have been noted in some
cases. The efficacy and safety of oral contraceptive products may be affected; it is
unknown whether this applies to ORTHO EVRA. Healthcare professionals should
refer to the label of the individual anti-HIV protease inhibitors for further drug-drug
interaction information.
Herbal products containing St. John’s Wort (hypericum perforatum) may induce
hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce
the effectiveness of contraceptive steroids. This may also result in breakthrough
bleeding.
Increase in Plasma Hormone Levels Associated With Co-Administered Drugs:
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl
estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic
acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by
inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole
may increase plasma hormone levels.
Changes in Plasma Levels of Co-Administered Drugs:
Combination hormonal contraceptives containing some synthetic estrogens
(e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased
plasma concentrations of cyclosporine, prednisolone, and theophylline have been
25
reported with concomitant administration of oral contraceptives. In addition, oral
contraceptives may induce the conjugation of other compounds. Decreased plasma
concentrations of acetaminophen and increased clearance of temazepam, salicylic
acid, morphine and clofibric acid have been noted when these drugs were
administered with oral contraceptives.
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in
human liver microsomes, the clinical consequence of such an interaction on the levels
of other concomitant medications is likely to be insignificant. Under the
recommended dosing regimen, the in vivo concentrations of norelgestromin and its
metabolites, even at the peak serum levels, are relatively low compared to the
inhibitory constant (Ki) (based on results of in vitro studies).
Health care professionals are advised to also refer to prescribing information of
co-administered drugs for recommendations regarding management of concomitant
therapy.
9. Interactions With Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by
hormonal contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased
antithrombin 3; increased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating
total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by
column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting
the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex hormone binding globulins are increased and result in elevated levels of
total circulating endogenous sex steroids and corticoids; however, free or
biologically active levels either decrease or remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and
lipoproteins may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by hormonal contraceptive therapy.
This may be of clinical significance if a woman becomes pregnant shortly
after discontinuing ORTHO EVRA.
10. Carcinogenesis
No carcinogenicity studies were conducted with norelgestromin. However, bridging
PK studies were conducted using doses of NGM/EE which were used previously in
the 2-year rat carcinogenicity study and 10-year monkey toxicity study to support the
approval of ORTHO-CYCLEN and ORTHO TRI-CYCLEN under NDAs 19-653
and 19-697, respectively. The PK studies demonstrated that rats and monkeys were
26
exposed to 16 and 8 times the human exposure, respectively, with the proposed
ORTHO EVRA transdermal contraceptive system.
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.
See WARNINGS Section.
11. Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections.
Norelgestromin was tested for its reproductive toxicity in a rabbit developmental
toxicity study by the SC route of administration. Doses of 0, 1, 2, 4 and 6 mg/kg body
weight, which gave systemic exposure of approximately 25 to 125 times the human
exposure with ORTHO EVRA, were administered daily on gestation days 7–19.
Malformations reported were paw hyperflexion at 4 and 6 mg/kg and paw
hyperextension and cleft palate at 6 mg/kg.
12. Nursing Mothers
The effects of ORTHO EVRA in nursing mothers have not been evaluated and are
unknown. Small amounts of combination hormonal contraceptive steroids have been
identified in the milk of nursing mothers and a few adverse effects on the child have
been reported, including jaundice and breast enlargement. In addition, combination
hormonal contraceptives given in the postpartum period may interfere with lactation
by decreasing the quantity and quality of breast milk. Long-term follow-up of infants
whose mothers used combination hormonal contraceptives while breast feeding has
shown no deleterious effects. However, the nursing mother should be advised not to
use ORTHO EVRA but to use other forms of contraception until she has completely
weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO EVRA have been established in women of
reproductive age. Safety and efficacy are expected to be the same for post-pubertal
adolescents under the age of 16 and for users 16 years and older. Use of this product
before menarche is not indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated
in this population.
27
15. Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection
(AIDS) and other sexually transmitted diseases.
16. Patch Adhesion
Experience with more than 70,000 ORTHO EVRA patches worn for contraception
for 6-13 cycles showed that 4.7% of patches were replaced because they either fell off
(1.8%) or were partly detached (2.9%). Similarly, in a small study of patch wear
under conditions of physical exertion and variable temperature and humidity, less
than 2% of patches were replaced for complete or partial detachment.
If the ORTHO EVRA 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, if it has become stuck to itself or another surface, if it has other material
stuck to it, or if it 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 to hold the ORTHO EVRA patch in place.
If a patch is partially or completely detached for more than one day (24 hours or
more) OR if the woman is not sure how long the patch has been detached, she may
not be protected from pregnancy. She should stop the current contraceptive cycle and
start a new cycle immediately by applying a new patch. Back-up contraception, such
as condoms, spermicide, or diaphragm, must be used for the first week of the new
cycle.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
The most common adverse events reported by 9 to 22% of women using
ORTHO EVRA in clinical trials (N= 3,330) were the following, in order of
decreasing incidence: breast symptoms, headache, application site reaction, nausea,
upper respiratory infection, menstrual cramps, and abdominal pain.
The most frequent adverse events leading to discontinuation in 1 to 2.4% of women
using ORTHO EVRA in the trials included the following: nausea and/or vomiting,
application site reaction, breast symptoms, headache, and emotional lability.
Listed below are adverse events that have been associated with the use of
combination hormonal contraceptives. These are also likely to apply to combination
transdermal hormonal contraceptives such as ORTHO EVRA.
28
An increased risk of the following serious adverse reactions has been associated with
the use of combination hormonal contraceptives (see WARNINGS Section).
• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of
combination hormonal contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in users of combination hormonal
contraceptives and are believed to be drug-related:
• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
29
• Migraine
• Rash (allergic)
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
The following adverse reactions have been reported in users of combination hormonal
contraceptives and a cause and effect association has been neither confirmed nor
refuted:
• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome
OVERDOSAGE
Serious ill effects have not been reported following accidental ingestion of large
doses of hormonal contraceptives. Overdosage may cause nausea and vomiting, and
30
withdrawal bleeding may occur in females. Given the nature and design of the
ORTHO EVRA patch, it is unlikely that overdosage will occur. Serious ill effects
have not been reported following acute ingestion of large doses of oral contraceptives
by young children. In case of suspected overdose, all ORTHO EVRA patches
should be removed and symptomatic treatment given.
DOSAGE AND ADMINISTRATION
To achieve maximum contraceptive effectiveness, ORTHO EVRA must be used
exactly as directed.
Complete instructions to facilitate patient counseling on proper system usage may be
found in the Detailed Patient Labeling.
Transdermal Contraceptive System Overview
ORTHO EVRA® is a combination transdermal contraceptive that contains 6.00 mg
norelgestromin (NGMN) and 0.75mg ethinyl estradiol (EE). Systemic exposures (as
measured by AUC and Css) of NGMN and EE during use of ORTHO EVRA® are
higher and peak concentrations (Cmax) are lower than those produced by an oral
contraceptive containing norgestimate 250 µg / EE 35 µg. (See BOLDED
WARNING; CLINICAL PHARMACOLOGY, Transdermal versus Oral
Contraceptives).
This system uses a 28-day (four-week) cycle. A new patch is applied each week for
three weeks (21 total days). Week Four 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.
The ORTHO EVRA® patch should not be cut, damaged or altered in any way. If the
ORTHO EVRA® patch is cut, damaged or altered in size, contraceptive efficacy may
be impaired.
On the day after Week Four ends a new four-week cycle is started by applying a new
patch. Under no circumstances should there be more than a seven-day patch-free
interval between dosing cycles.
31
If the woman is starting ORTHO EVRA for
the first time, she should wait until the day
she begins her menstrual period. Either a
First Day start or Sunday start may be chosen
(see below). The day she applies her first
patch will be Day 1. Her “Patch Change Day”
will be on this day every week.
• for First Day Start: the patient should
apply her first patch during the first
24 hours of her menstrual period.
If therapy starts after Day 1 of the menstrual
cycle, a non-hormonal back-up contraceptive
(such as a condoms, spermicide, or
diaphragm) should be used concurrently for
the first 7 consecutive days of the first
treatment cycle.
• for Sunday Start: the woman should
apply her first patch on the first Sunday
after her menstrual period starts. She must
use back-up contraception for the first
week of her first cycle.
If the menstrual period begins on a Sunday,
the first patch should be applied on that day,
and no back-up contraception is needed.
Where to apply the patch. The patch should
be applied to clean, dry, intact healthy skin on
the buttock, abdomen, upper outer arm or
upper torso, in a place where it won’t be
rubbed by tight clothing. ORTHO EVRA
should not be placed on skin that is red,
irritated or cut, nor should it be placed on the
breasts.
To prevent interference with the adhesive
properties of ORTHO EVRA, no make-up,
creams, lotions, powders or other topical
products should be applied to the skin area
where the ORTHO EVRA patch is or will be
32
placed.
Application of the ORTHO EVRA patch
The foil pouch is opened by tearing it along
the edge using the fingers.
The foil pouch should be peeled apart and
open flat
A corner of the patch is grasped firmly and it
is gently removed from the foil pouch.
The woman should be instructed to use her
fingernail, to lift one corner of the patch and
peel the patch and the plastic liner off the foil
liner. Sometimes patches can stick to the
inside of the pouch – the woman should be
careful not to accidentally remove the clear
liner as she removes the patch.
33
Half of the clear protective liner is to be
peeled away. (The woman should avoid
touching the sticky surface of the patch).
The sticky surface of the patch is applied to
the skin and the other half of the liner is
removed. The woman should press down
firmly on the patch with the palm of her hand
for 10 seconds, making sure that the edges
stick well. She should check her patch every
day to make sure it is sticking.
The patch is worn for seven days (one week).
On the “Patch Change Day”, Day 8, the used
patch is removed and a new one is applied
immediately. The used patch still contains
some active hormones – it should be carefully
folded in half so that it sticks to itself before
safely disposing of it in the trash. Used
patches should not be flushed down the toilet.
A new patch is applied for Week Two (on
Day 8) and again for Week Three (on Day
15), on the usual “Patch Change Day”. Patch
changes may occur at any time on the Change
Day. Each new ORTHO EVRA patch
should be applied to a new spot on the skin to
help avoid irritation, although they may be
kept within the same anatomic area.
34
Week Four is patch-free (Day 22 through
Day 28), thus completing the four-week
contraceptive cycle. Bleeding is expected to
begin during this time.
The next four-week cycle is started by
applying a new patch on the usual “Patch
Change Day,” the day after Day 28, no matter
when the menstrual period begins or ends.
Under no circumstances should there be more
than a seven-day patch-free interval between
patch cycles.
If the ORTHO EVRA patch becomes partially or completely detached and remains
detached, insufficient drug delivery occurs.
If a patch is partially or completely detached:
• for less than one day (up to 24 hours), the woman should try to reapply it to the
same place or replace it with a new patch immediately. No back-up contraception
is needed. The woman’s “Patch Change Day” will remain the same.
• for more than one day (24 hours or more) OR if the woman is not sure how
long the patch has been detached, SHE MAY NOT BE PROTECTED FROM
PREGNANCY. She should stop the current contraceptive cycle and start a new
cycle immediately by applying a new patch. There is now a new “Day 1” and a
new “Patch Change Day.” Back-up contraception, such as condoms, spermicide,
or diaphragm, must be used for the first week of the new cycle.
A patch should not be re-applied if it is no longer sticky, if it has become stuck to
itself or another surface, if it has other material stuck to it or if it has previously
become loose or fallen off. If a patch cannot be re-applied, a new patch should be
applied immediately. Supplemental adhesives or wraps should not be used to hold the
ORTHO EVRA patch in place.
If the woman forgets to change her patch…
• at the start of any patch cycle (Week One /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”
35
and a new “Day 1.” The woman must use back-up contraception, such as
condoms, spermicide, or diaphragm, for the first week of the new cycle.
• in the middle of the patch cycle (Week Two/Day 8 or Week Three/Day 15),
- for one or two 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 two days (48 hours or more), SHE MAY NOT BE
PROTECTED FROM PREGNANCY. She should stop the current contraceptive
cycle and start a new four-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 one week.
• at the end of the patch cycle (Week Four/Day 22),
Week Four (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.
Under no circumstances should there be more than a seven-day patch-free
interval between cycles. If there are more than seven patch-free days, THE
WOMAN MAY NOT BE PROTECTED FROM PREGNANCY and back-up
contraception, such as condoms, spermicide, or diaphragm, must be used for seven
days. As with combined oral contraceptives, the risk of ovulation increases with each
day beyond the recommended drug-free period. If coital exposure has occurred during
such an extended patch-free interval, the possibility of fertilization should be
considered.
Change Day Adjustment
If the woman wishes to change her Patch Change Day she should complete her
current cycle, removing the third ORTHO EVRA patch on the correct day. During
the patch-free week, she may select an earlier Patch Day Change by applying a new
ORTHO EVRA patch on the desired day. In no case should there be more than
7 consecutive patch-free days.
Switching From an Oral Contraceptive
Treatment with ORTHO EVRA should begin on the first day of withdrawal
bleeding. If there is no withdrawal bleeding within 5 days of the last active (hormonecontaining)
tablet, pregnancy must be ruled out. If therapy starts later than the first
day of withdrawal bleeding, a non-hormonal contraceptive should be used
concurrently for 7 days. If more than 7 days elapse after taking the last active oral
contraceptive tablet, the possibility of ovulation and conception should be considered.
36
Use After Childbirth
Women who elect not to breast-feed should start contraceptive therapy with
ORTHO EVRA no sooner than 4 weeks after childbirth. If a woman begins using
ORTHO EVRA postpartum, and has not yet had a period, the possibility of
ovulation and conception occurring prior to use of ORTHO EVRA should be
considered, and she should be instructed to use an additional method of contraception,
such as condoms, spermicide, or diaphragm, for the first seven days. (See
Precautions: Nursing Mothers, and Warnings: Thromboembolic and Other Vascular
Problems.)
Use After Abortion or Miscarriage106
After an abortion or miscarriage that occurs in the first trimester, ORTHO EVRA
may be started immediately. An additional method of contraception is not needed if
ORTHO EVRA is started immediately. If use of ORTHO EVRA is not started
within 5 days following a first trimester abortion, the woman should follow the
instructions for a woman starting ORTHO EVRA 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.
ORTHO EVRA should be started no earlier than 4 weeks after a second trimester
abortion or miscarriage. When ORTHO EVRA is used postpartum or postabortion,
the increased risk of thromboembolic disease must be considered. (See
CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease.
See PRECAUTIONS for “Nursing Mothers”.)
Breakthrough Bleeding or Spotting
In the event of breakthrough bleeding or spotting (bleeding that occurs on the days
that ORTHO EVRA is worn), treatment should be continued. If breakthrough
bleeding persists longer than a few cycles, a cause other than ORTHO EVRA should
be considered.
In the event of no withdrawal bleeding (bleeding that should occur during the patchfree
week), treatment should be resumed on the next scheduled Change Day. If
ORTHO EVRA has been used correctly, the absence of withdrawal bleeding is not
necessarily an indication of pregnancy. Nevertheless, the possibility of pregnancy
should be considered, especially if absence of withdrawal bleeding occurs in
2 consecutive cycles. ORTHO EVRA should be discontinued if pregnancy is
confirmed.
37
In Case of Vomiting or Diarrhea
Given the nature of transdermal application, dose delivery should be unaffected by
vomiting.
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. Only one
patch should be worn at a time.
ADDITIONAL INSTRUCTIONS FOR DOSING
Breakthrough 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, nonfunctional causes should considered.
In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina,
adequate diagnostic measures are indicated 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, the possibility of
pregnancy should be considered at the time of the first missed period.
Hormonal contraceptive use should be discontinued 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.
3. If the woman has adhered to the prescribed regimen and misses two
consecutive periods, pregnancy should be ruled out. ORTHO EVRA use
should be discontinued if pregnancy is confirmed.
HOW SUPPLIED
Each beige ORTHO EVRA patch contains 6.00mg norelgestromin and 0.75 mg EE..
Each patch surface is heat stamped with ORTHO EVRA 150/20. Each patch is
packaged in a protective pouch.
ORTHO EVRA is available in folding cartons of 1 cycle each (NDC # 0062-1920-
15); each cycle contains 3 patches.
38
ORTHO EVRA is also available in folding cartons containing a single patch
(NDC # 0062-1920-01), intended for use as a replacement in the event that a patch is
inadvertently lost or destroyed.
Special Precautions for Storage and Disposal
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
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. Each patch should be carefully
folded in half so that it sticks to itself before safely disposing of it in the trash. Used
patches should not be flushed down the toilet.
REFERENCES
1. Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W,
Stewart GK, Kowal D, Guest F. Contraceptive Technology: Seventeenth Revised
Edition. New York NY: Irvington Publishers, 1998. 2. Stadel BV. Oral contraceptives
and cardiovascular disease. (Pt.1). N Engl J Med 1981; 305:612-618. 3. Stadel BV.
Oral contraceptives and cardiovascular disease. (Pt.2). N Engl J Med 1981; 305:672-
677. 4. Adam SA, Thorogood M. Oral contraception and myocardial infarction
revisited: the effects of new preparations and prescribing patterns. Br J Obstet
Gynaecol 1981; 88:838-845. 5. Mann Jl, Inman WH. Oral contraceptives and death
from myocardial infarction. Br Med J 1975; 2(5965):245-248. 6. Mann Jl, Vessey
MP, Thorogood M, Doll R. Myocardial infarction in young women with special
reference to oral contraceptive practice. Br Med J 1975; 2(5956):241-245. 7. Royal
College of General Practitioners’ Oral Contraception Study: Further analyses of
mortality in oral contraceptive users. Lancet 1981; 1:541-546. 8. Slone D, Shapiro S,
Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction
in relation to current and discontinued use of oral contraceptives. N Engl J Med
1981:305:420-424. 9. Vessey MP. Female hormones and vascular disease-an
epidemiological overview. Br J Fam Plann 1980; 6 (Supplement): 1-12.
10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS.
Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent
Med 1986; 15:352-362. 11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM.
The relative impact of smoking and oral contraceptive use on women in the United
States. JAMA 1987; 258:1339-1342. 12. Layde PM, Beral V. Further analyses of
mortality in oral contraceptive users; Royal College of General Practitioners’ Oral
Contraception Study. (Table 5) Lancet 1981; 1:541-546. 13. Knopp RH.
39
Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J
Reprod Med 1986; 31(9) (Supplement):913-921. 14. Krauss RM, Roy S, Mishell DR,
Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids
and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J
Obstet 1983; 145:446-452. 15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R,
Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein
cholesterol. N Engl J Med 1983; 308:862-867. 16. Wynn V, Niththyananthan R. The
effect of progestin in combined oral contraceptives on serum lipids with special
reference to high density lipoproteins. Am J Obstet Gynecol 1982;142:766-771.
17. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism.
J Reprod Med 1986;31(9)(Supplement):892-897. 18. LaRosa JC. Atherosclerotic risk
factors in cardiovascular disease. J Reprod Med 1986;31(9)(Supplement):906-912.
19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and
cerebral thrombosis and embolism in women of child-bearing age. Br Med J
1968;2(5599):193-199. 20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD,
Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further
report. Am J Epidemiol 1979;110(2):188-195. 21. Petitti DB, Wingerd J, Pellegrin F,
Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives,
noncontraceptive estrogens, and other factors. JAMA 1979;242:1150-1154.
22. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives
and thromboembolic disease. Br Med J 1968;2(5599):199-205. 23. Vessey MP, Doll
R. Investigation of relation between use of oral contraceptives and thromboembolic
disease. A further report. Br Med J 1969; 2(5658):651-657. 24. Porter JB, Hunter JR,
Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular
disease-recent experience. Obstet Gynecol 1982;59(3):299-302. 25. Vessey M, Doll
R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using
different methods of contraception: an interim report. J Biosocial Sci 1976;8:375-427.
26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis,
and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399. 27. Collaborative
Group for the Study of Stroke in Young Women: Oral contraception and increased
risk of cerebral ischemia or thrombosis. N Engl J Med 1973;288:871-878. 28. Petitti
DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of
subarachnoid hemorrhage. Lancet 1978;2:234-236. 29. Inman WH. Oral
contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979:2(6203):1468-
1470. 30. Collaborative Group for the Study of Stroke in Young Women: Oral
Contraceptives and stroke in young women: associated risk factors. JAMA 1975;
231:718-722. 31. Inman WH, Vessey MP, Westerholm B, Engelund A.
Thromboembolic disease and the steroidal content of oral contraceptives. A report to
the Committee on Safety of Drugs. Br Med J 1970;2:203-209. 32. Meade TW,
40
Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated
with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen
preparations. Br Med J 1980;280(6224):1157-1161. 33. Kay CR. Progestogens and
arterial disease-evidence from the Royal College of General Practitioners’ Study. Am
J Obstet Gynecol 1982;142:762-765. 34. Royal College of General Practitioners:
Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract
1983;33:75-82. 35. Ory HW. Mortality associated with fertility and fertility control:
1983. Family Planning Perspectives 1983;15:50-56. 36. The Cancer and Steroid
Hormone Study of the Centers for Disease Control and the National Institute of Child
Health and Human Development: Oral contraceptive use and the risk of breast cancer.
N Engl J Med 1986;315:405-411. 37. Pike MC, Henderson BE, Krailo MD, Duke A,
Roy S. Breast cancer in young women and use of oral contraceptives: possible
modifying effect of formulation and age at use. Lancet 1983;2:926-929. 38. Paul C,
Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national
study. Br Med J 1986; 293:723-725. 39. Miller DR, Rosenberg L, Kaufman DW,
Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral
contraceptive use. Obstet Gynecol 1986;68:863-868. 40. Olson H, Olson KL, Moller
TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in
Sweden (letter). Lancet 1985; 2:748-749. 41. McPherson K, Vessey M, Neil A, Doll
R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another
case-control study. Br J Cancer 1987; 56:653-660. 42. Huggins GR, Zucker PF. Oral
contraceptives and neoplasia; 1987 update. Fertil Steril 1987; 47:733-761.
43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty Br Med
J 1986; 293:709-710. 44. Shapiro S. Oral contraceptives-time to take stock. N Engl J
Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW.
Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am
J Obstet Gynecol 1976; 124:573-577. 46. Vessey MP, Lawless M, McPherson K,
Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of
the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K,
Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives
and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344. 48. WHO
Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical
cancer and combined oral contraceptives. Br Med J 1985; 290:961-965. 49. Rooks
JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW.
Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA
1979; 242:644-648. 50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage
from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-
435. 51. Klatskin G. Hepatic tumors: possible relationship to use of oral
contraceptives. Gastroenterology 1977; 73:386-394. 52. Henderson BE, Preston-
41
Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral
contraceptives. Br J Cancer 1983;48:437-440. 53. Neuberger J, Forman D, Doll R,
Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986;
292:1355-1357. 54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral
contraceptives. Br Med J 1986; 292:1357-1361. 55. Harlap S, Eldor J. Births
following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.
56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives
analyzed in a national malformation register. Am J Obstet Gynecol 1981: 140:521-
524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects.
Am J Epidemiol 1980; 112:73-79. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin
JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease.
Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg
MB. Exogenous hormones and other drug exposures of children with congenital heart
disease. Am J Epidemiol 1979; 109:433-439. 60. Boston Collaborative Drug
Surveillance Program: Oral contraceptives and venous thromboembolic disease,
surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-
1404. 61. Royal College of General Practitioners: Oral contraceptives and health.
New York, Pittman 1974. 62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder
disease: a cohort study of young women attending family planning clinics. J
Epidemiol Community Health 1982; 36:274-278. 63. Rome Group for Epidemiology
and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an
Italian adult female population. Am J Epidemiol 1984; 119:796-805. 64. Strom BL,
Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral
contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther
1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J,
Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different
combined oral contraceptive formulations on carbohydrate and lipid metabolism.
Lancet 1979; 1:1045-1049. 66. Wynn V. Effect of progesterone and progestins on
carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E,
Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395-410. 67. Perlman JA,
Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the
potency of oral contraceptive progestogens. J Chronic Dis 1985;38:857-864. 68.
Royal College of General Practitioners’ Oral Contraception Study: Effect on
hypertension and benign breast disease of progestogen component in combined oral
contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and
blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive
induced hypertension-nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71.
Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the
Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid
42
contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977;
pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research
Milan.) 72. Stockley I. Interactions with oral contraceptives. J Pharm 1976;216:140-
143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control
and the National Institute of Child Health and Human Development: Oral
contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.
74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and
the National Institute of Child Health and Human Development: Combination oral
contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75.
Ory HW. Functional ovarian cysts and oral contraceptives: negative association
confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW, Cole P, MacMahon B,
Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J
Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral
contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD,
Lincoln R. Making choices: Evaluating the health risks and benefits of birth control
methods. New York, The Alan Guttmacher Institute, 1983; p.1. 79. Schlesselman J,
Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral
contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick
RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control
study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42.
81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F,
Tognoni G. Oral contraceptives and cancers of the breast and of the female genital
tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317. 82.
Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
contraceptive use and breast cancer in young women. A Joint National Case-control
study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC.
Breast cancer and the pill-A further report from the Royal College of General
Practitioners’ oral contraception study. Br J Cancer 1988; 58:675-680. 84. Stadel BV,
Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast
cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR,
Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer
before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989;
129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive
use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87.
Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral
contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-
Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a
large cohort study. Br J Cancer 1989; 59:613-617. 89. Jick SS, Walker AM,
Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989;
43
59:618-621. 90. Anderson FD, Selectivity and minimal androgenicity of norgestimate
in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992;
156 (Supplement):15-21. 91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical
evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989;
34(51):347-352. 92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL.
Progestational and androgenic receptor binding affinities and in vivo activities of
norgestimate and other progestins. Contraception 1989; 41(4):399-409. 93. Phillips
A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of
progestogens used in contraceptives. Contraception 1987; 36(2):181-192. 94. Janaud
A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen
metabolism with triphasic oral contraceptive formulations containing norgestimate or
levonorgestrel Acta Obstet Gynecol Scand 1992; 156 (Supplement):34-38.
95. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and
hormonal contraceptives: collaborative reanalysis of individual data on 53 297
women with breast cancer and 100 239 women without breast cancer from 54
epidemiological studies. Lancet 1996; 347:1713-1727. 96. Palmer JR, Rosenberg L,
Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and
Liver Cancer. Am J Epidemiol 1989;130:878-882. 97. Lewis M, Spitzer WO,
Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of
Transnational Research Group on Oral Contraceptives and Health of Young Women.
Third generation oral contraceptives and risk of myocardial infarction: an
international case-control study. Br Med J, 1996;312:88-90. 98. Vessey MP, Smith
MA, Yeates D. Return of fertility after discontinuation of oral contraceptives:
influence of age and parity. Brit J Fam Plan; 1986; 11:120-124. 99. Back DJ, Orme
M.L’E. Pharmacokinetic drug interactions with oral contraceptives. Clin
Pharmacokinet 1990; 18:472-484. 100. Rosenfeld WE, Doose DR, Walker SA,
Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive
containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia
1997 Mar;38(3):317-323. 101. Shenfield GM. Oral Contraceptives. Are drug
interaction of clinical significance Drug Saf 1993 Jul;9(1):21-37. 102. Ouellet D,
Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, Leonard JM, Granneman GR.
Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female
volunteers. Br J Clin Pharmacol 1998;46(2):111-116. 103. Improving access to
quality care in family planning: Medical eligibility criteria for contraceptive use.
Geneva, WHO, Family and Reproductive Health, 1996 (WHO/FRH/FPP/96.9). 104.
Skolnick JL, Stoler BS, Katz DG, Anderson WH. Rifampicin, oral contraceptives and
pregnancy. J Am Med Assoc 1976;236-1382. 105. Henney JE. Risk of drug
interactions with St. John’s Wort. JAMA 2000;283(13). 106. Lahteennmaki P et al,
Coagulation factors in women using oral contraceptives or intrauterine devices
44
immediately after abortion. American Journal of Obstetrics and Gynecology, (1981);
141: 175-179.
DETAILED PATIENT LABELING
ORTHO EVRA (norelgestromin/ethinyl estradiol transdermal system)
Rx only
This product is intended to prevent pregnancy. It does not protect against HIV
(AIDS) or other sexually transmitted diseases.
DESCRIPTION
The contraceptive patch ORTHO EVRA is a thin, beige, plastic patch that sticks to
the skin. The sticky part of the patch contains the following hormones:
norelgestromin (progestin) and ethinyl estradiol (estrogen). These hormones are
absorbed continuously through the skin and into the bloodstream. On average, the
amount of estrogen delivered through the skin produces estrogen exposure that is
higher than the exposure when taking a birth control pill containing 35 micrograms of
estrogen. Each patch is sealed in a pouch that protects it until you are ready to wear it.
INTRODUCTION
Any woman who considers using the contraceptive patch ORTHO EVRA should
understand the benefits and risks of using this form of birth control. This leaflet will
give you much of the information you will need to make this decision and will also
help you determine if you are at risk of developing any serious side effects. It will tell
you how to use the contraceptive patch properly so that it will be as effective as
possible. However, this leaflet is not a replacement for a careful discussion between
you and your health care professional. You should discuss the information provided
in this leaflet with him or her, both when you first start using the contraceptive patch
ORTHO EVRA and during your revisits. You should also follow your health care
professional’s advice with regard to regular check-ups while you are using the
contraceptive patch.
EFFECTIVENESS OF HORMONAL CONTRACEPTIVE METHODS
Hormonal contraceptives, including ORTHO EVRA, are used to prevent pregnancy
and are more effective than most other non-surgical methods of birth control. When
ORTHO EVRA is used correctly, the chance of becoming pregnant is approximately
1% (1 pregnancy per 100 women per year of use when used correctly), which is
comparable to that of the pill. The chance of becoming pregnant increases with
incorrect use.
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Clinical trials suggested that ORTHO EVRA may be less effective in women
weighing more than 198 lbs. (90 kg). If you weigh more than 198 lbs. (90 kg) you
should talk to your health care professional about which method of birth control may
be best for you.
Typical failure rates for other methods of birth control during the first year of use are
as follows:
Implant: <1%
Injection: <1%
IUD: <1-2%
Diaphragm with spermicides: 20%
Spermicides alone: 26%
Female sterilization: <1%
Male sterilization: <1%
Cervical Cap with spermicide: 20 to 40%
Condom alone (male): 14%
Condom alone (female): 21%
Periodic abstinence: 25%
No birth control method: 85%
Withdrawal: 19%
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:
Cigarette smoking increases the risk of serious cardiovascular side effects from
hormonal contraceptive use. This risk increases with age and with heavy
smoking (15 or more cigarettes per day) and is quite marked in women over
35 years of age. Women who use hormonal contraceptives, including
ORTHO EVRA, are strongly advised not to smoke.
Some women should not use the ORTHO EVRA contraceptive patch. For example,
you should not use ORTHO EVRA if you are pregnant or think you may be
pregnant. You should also not use ORTHO EVRA if you have any of the following
conditions:
• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• Chest pain (angina pectoris)
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• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or
vagina.
• Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
• Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during
pregnancy or during previous use of hormonal contraceptives such as
ORTHO EVRA, NORPLANT, or the birth control pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• Severe high blood pressure
• Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
• Headaches with neurological symptoms
• Use of oral contraceptives (birth control pills)
• Disease of heart valves with complications
• Need for a prolonged period of bed rest following major surgery
• An allergic reaction to any of the components of ORTHO EVRA
Tell your health care professional if you have ever had any of these conditions. Your
health care professional can recommend a non-hormonal method of birth control.
OTHER CONSIDERATIONS BEFORE USING ORTHO EVRA
Hormones from patches applied to the skin get into the blood stream and are removed
from the body differently than hormones from birth control pills taken by mouth. 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 exposure may increase the risk of side effects. However,
it is not known if there are differences in the risk of serious side effects based on the
differences between ORTHO EVRA® and a birth control pill containing
35 micrograms of estrogen. Talk to your healthcare provider about how this
information relates to your use of ORTHO EVRA®.
Also talk to your health care professional about using ORTHO EVRA if:
• you smoke
• you are recovering from the birth of a baby
• you are recovering from a second trimester miscarriage or abortion
• you are breast-feeding
• you weigh 198 pounds or more
• you are taking any other medications
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• Also, tell your health care professional if you have or have had:
• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
• A family history of breast cancer
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Depression
• Gallbladder disease
• Liver disease
• Heart disease
• Kidney disease
• Scanty or irregular menstrual periods
If you have any of these conditions you should be checked often by your health care
professional if you use the contraceptive patch.
RISKS OF USING HORMONAL CONTRACEPTIVES, INCLUDING
ORTHO EVRA
The following information is derived primarily from studies of birth control pills.
Since ORTHO EVRA contains hormones similar to those found in birth control
pills, it is expected to be associated with similar risks:
1. Risk of Developing Blood Clots
Blood clots and blockage of blood vessels that can cause death or serious disability
are some of the most serious side effects of using hormonal contraceptives, including
the ORTHO EVRA contraceptive patch. In particular, a clot in the legs can cause
thrombophlebitis, and a clot that travels to the lungs can cause sudden blocking of the
vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye
and may cause blindness, double vision, or impaired vision.
If you use ORTHO EVRA and need elective surgery, need to stay in bed for a
prolonged illness or injury or have recently delivered a baby, you may be at risk of
developing blood clots. You should consult your doctor about stopping
ORTHO EVRA four weeks before surgery and not using it for two weeks after
surgery or during bed rest. You should also not use ORTHO EVRA soon after
delivery of a baby. It is advisable to wait for at least four weeks after delivery if you
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are not breast- feeding. If you are breast-feeding, you should wait until you have
weaned your child before using ORTHO EVRA. (See also the section on Breast-
Feeding in General Precautions.)
2. Heart Attacks and Strokes
Hormonal contraceptives, including ORTHO EVRA, may increase the risk of
developing strokes (blockage or rupture of blood vessels in the brain) and angina
pectoris and heart attacks (blockage of blood vessels in the heart). Any of these
conditions can cause death or serious disability.
Smoking and the use of hormonal contraceptives including ORTHO EVRA greatly
increase the chances of developing and dying of heart disease. Smoking also greatly
increases the possibility of suffering heart attacks and strokes.
3. Gallbladder Disease
Women who use hormonal contraceptives, including ORTHO EVRA, probably have
a greater risk than nonusers of having gallbladder disease.
4. Liver Tumors
In rare cases, combination oral contraceptives can cause benign but dangerous liver
tumors. Since ORTHO EVRA contains hormones similar to those in birth control
pills, this association may also exist with ORTHO EVRA. These benign liver
tumors can rupture and cause fatal internal bleeding. In addition, some studies report
an increased risk of developing liver cancer. However, liver cancers are rare.
5. Cancer of the Reproductive Organs and Breasts
Various studies give conflicting reports on the relationship between breast cancer and
hormonal contraceptive use. Combination hormonal contraceptives, including
ORTHO EVRA, may slightly increase your chance of having breast cancer
diagnosed, particularly after using hormonal contraceptives at a younger age. After
you stop using hormonal contraceptives, the chances of having breast cancer
diagnosed begin to go back down. You should have regular breast examinations by a
health care professional and examine your own breasts monthly. Tell your health care
professional if you have a family history of breast cancer or if you have had breast
nodules or an abnormal mammogram.
Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives, although this finding may be related to factors
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other than the use of oral contraceptives. However, there is insufficient evidence to
rule out the possibility that oral contraceptives may cause such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR
PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing
certain diseases that may lead to disability or death. An estimate of the number of
deaths associated with different methods of birth control and pregnancy has been
calculated and is shown in the following table.
ORTHO EVRA is expected to be associated with similar risks as oral
contraceptives:
Annual Number of Birth-Related or Method-Related Deaths Associated With
Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method
According to Age
Method of control
and outcome 15-19 20-24 25-29 30-34 35-39 40-44
No fertility control
methods* 7.0 7.4 9.1 14.8 25.7 28.2
Oral contraceptives
non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6
Oral contraceptives
smoker** 2.2 3.4 6.6 13.5 51.1 117.2
IUD** 0.8 0.8 1.0 1.0 1.4 1.4
Condom* 1.1 1.6 0.7 0.2 0.3 0.4
Diaphragm /
spermicide* 1.9 1.2 1.2 1.3 2.2 2.8
Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
In the above table, the risk of death from any birth control method is less than the risk
of childbirth, except for oral contraceptive users over the age of 35 who smoke and
pill users over the age of 40 even if they do not smoke. It can be seen in the table that
for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths
per 100,000 women, depending on age). Among pill users who do not smoke, the risk
of death is always lower than that associated with pregnancy for any age group,
although over the age of 40, the risk increases to 32 deaths per 100,000 women,
compared to 28 associated with pregnancy at that age. However, for pill users who
smoke and are over the age of 35, the estimated number of deaths exceeds those for
other methods of birth control. If a woman is over the age of 40 and smokes, her
estimated risk of death is four times higher (117/100,000 women) than the estimated
risk associated with pregnancy (28/100,000 women) in that age group.
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In 1989 an Advisory Committee of the FDA concluded that