ORTHO EVRA^®
(norelgestromin / ethinyl estradiol TRANSDERMAL SYSTEM)

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 risks^{36, 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.

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.

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 hemorrhage^50,51.

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.

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.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy^56,57. Studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned^55,56,58,59, 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.

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of hormonal contraceptives and estrogens^60,61. More recent studies, however, have shown that the relative risk of developing gallbladder disease among hormonal contraceptive users may be minimal^62-64. 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.

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.

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 users^68-71.

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.

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.

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.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Women should be counseled that ORTHO EVRA^® does not protect against HIV infection (AIDS) and other sexually transmitted infections.

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.

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.

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.

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.

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.

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.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

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^®.

No carcinogenicity studies were conducted with norelgestromin. However, bridging PK studies were conducted using doses of norgestimate (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 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.

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.

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.

This product has not been studied in women over 65 years of age and is not indicated in this population.

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

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.

See Patient Labeling printed below.

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
• 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

Serious ill effects have not been reported following accidental ingestion of large doses of hormonal contraceptives. Overdosage may cause nausea and vomiting, and 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.

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.

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 C_ss) of NGMN and EE during use of ORTHO EVRA^® are higher and peak concentrations (C_max) 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– 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.
	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.

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.

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.

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.)

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".)

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.

Given the nature of transdermal application, dose delivery should be unaffected by vomiting.

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.

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.

• 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.

Each beige ORTHO EVRA^® patch contains 6.00mg norelgestromin and 0.75 mg EE.

Each patch surface is heat stamped with ORTHO EVRA^®. 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.

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.

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.

• 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. 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 span of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970;2:203-209.
• 32.Meade TW, 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-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 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; 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 immediately after abortion. American Journal of Obstetrics and Gynecology, (1981); 141: 175-179.
• 107.<  I3 Drug Safety, The risk of venous thromboembolism, myocardial infarction, and ischemic stroke among women using the transdermal contraceptive system compared to women using norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol. (June 2006) Data on file.
• 108.<  Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using oral contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 73 (2006): 223–228.

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ORTHO EVRA^® (norelgestromin/ethinyl estradiol transdermal system)

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.

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Issued September 2006

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