Norelgestromin and Ethinyl estradiol
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
DRUG 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 EVRA®is 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®.”
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?)
INDICATIONS
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 and the possible increased risk of venous thromboembolism with ORTHO EVRA® against the chance of pregnancy if a contraceptive pill is not taken daily. (See BOLDED WARNING; WARNINGS; 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, 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
Diaphram7 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.
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.
6Cervical 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.
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
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.
ORTHO EVRA® has not been studied for and is not indicated for use in emergency contraception.
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.
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 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.
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. Used patches should not be flushed down the toilet. For disposal directions, see HOW SUPPLIED: Special Precautions for Storage and Disposal.
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.
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” 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 (hormone- containing) 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.
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 PPRECAUTIONS: 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 patch- free 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.
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:
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.
If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches.
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.
SIDE EFFECTS
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® .
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
Migraine
Allergic reaction, including rash, urticaria and angioedema
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
DRUG INTERACTIONS
Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Drugs
If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:
barbiturates
bosentan
carbamazepine
felbamate
griseofulvin
oxcarbazepine
phenytoin
rifampin
St. John's wort
topiramate
HIV protease inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors.
Antibiotics:There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 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.
Consult the labeling of the concurrently-used drug to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
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 or induce the conjugation of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been 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).
Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by hormonal contraceptives:
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
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.
Other binding proteins may be elevated in serum.
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.
Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
Glucose tolerance may be decreased.
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®.
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 ORTHO EVRA® or oral contraceptives. However, inter-subject variability in women using ORTHO EVRA® is higher. 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. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives).
Epidemiologic, case-control studies107-111 were conducted in the U.S. using electronic healthcare claims data to evaluate the risk of venous thromboembolism (VTE) among women aged 15-44 who used ORTHO EVRA® compared to women who used oral contraceptives containing 30-35 mcg of ethinyl estradiol (EE) and either norgestimate (NGM) or levonorgestrel (LNG). NGM is the prodrug for norelgestromin, the progestin in ORTHO EVRA®. These studies (see Table 5) used slightly different designs and reported odds ratios ranging from 0.9 to 2.4. The interpretations of these odds ratios range from no increase in risk to an approximate doubling of risk. One study (i3 Ingenix) included patient chart review to confirm the VTE occurrence.
Table 5: Estimates (Odds Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA® Compared to Oral Contraceptive UsersEpidemiologic Study Comparator Product Odds Ratio (95% C.I.)
i3 Ingenix107 NGM/35 mcg EEA 2.4*(1.1-5.5)B
BCDSP
NGM108,109,111,c NGM/35 mcg EE 0.9 (0.5-1.6)108,D
1.1(0.6-2.1)109,E
2.4*(1.2-5.0)111, F
1.2(0.9-1.8)111, G
(pooled from three datasets above)
BCDSP
LNG110 LNGH/30 mcg EE 2.0 (0.9-4.1)I
*Increase in risk of VTE is statistically significant
A NGM = norgestimate; EE = ethinyl estradiol
B 33 months of data.
C BCDSP = Boston Collaborative Drug Surveillance Program
D Initial 36 months of data (reference 108).
E Reference 109: Separate estimate from 17 months of data on new cases not included in the previous estimate (reference 108).
F Reference 111: Separate estimate from 14 months of data on new cases not included in the previous estimates (references 108 and 109).
G Pooled odds ratio from references 108, 109 and 111.
H LNG = levonorgestrel
I 48 months of data
In 3 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.
ORTHO EVRA® and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives. As with any combination hormonal contraceptive, the clinician should be alert to the earliest manifestations of thromboembolic disorders (thrombophlebitis, VTE including pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, ORTHO EVRA® should be discontinued immediately.
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 that follows in this section of the 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 cohort studies. Case control studies provide an estimate of the relative risk or odds for developing a disease, namely, a ratio of the disease among oral contraceptive users to that among nonusers or users of a comparator drug product. The odds ratio does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of the incidence of a disease in an exposed population. The relative risk is the ratio of the incidence density in the exposed population relative to the incidence density in a comparator population. Cohort studies also provide a measure of attributable risk, which is the difference in the incidence of disease between hormonal contraceptive users and nonusers or comparator drug products. 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.
Thromboembolic Disorders and Other Vascular Problems
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.
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.
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 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.
Cerebrovascular Diseases
Hormonal contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), 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.
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 progestational14-16 agents . 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.
Persistence of Risk of Vascular Disease
There are two studies that have shown persistence of risk of vascular disease for ever- users 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.
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 6). 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.
Table 6: 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 AgeMethod 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.
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 women 45-48. 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.