Ortho Evra

Ortho Evra is a prescription medication used to prevent pregnancy. It contains two medications, norelgestromin and ethinyl estradiol, which belong to a group of drugs called hormonal contraceptives. These hormones prevent pregnancy by stopping ovulation and by altering cervical mucus and the lining of the uterus.

This medication comes in the form of a skin patch to be placed on the skin each week for the first 3 weeks of the menstrual cycle.

Common side effects include nausea, breast discomfort, and headache.

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

Some women should not use the Ortho Evra contraceptive patch. For example, you should not use Ortho Evra if you are pregnant or think you may be pregnant. You should also not use Ortho Evra if you have any of the following conditions:

• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• An inherited problem that makes your blood clot more than normal
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
• Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
• Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal contraceptives such as norelgestromin/ethinyl estradiol, Norplant, or the birth control pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• Severe high blood pressure
• Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
• Headaches with neurological symptoms
• Use of oral contraceptives (birth control pills)
• Disease of heart valves with complications
• Need for a prolonged period of bed rest following major surgery
• An allergic reaction to any of the components of norelgestromin/ethinyl estradiol

Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend a non-hormonal method of birth control.

Hormones from Ortho Evra get into the blood stream and are processed by the body differently than hormones from birth control pills. You will be exposed to about 60% more estrogen if you useOrtho Evra than if you use a typical birth control pill containing 35 micrograms of estrogen. In general, increased estrogen may increase the risk of side effects.

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

Talk to your healthcare professional about using Ortho Evra if:

• you smoke
• you are recovering from the birth of a baby
• you are recovering from a second trimester miscarriage or abortion
• you are breastfeeding
• you weigh 198 pounds or more
• you are taking any other medications

Also, tell your healthcare professional if you have or have had:

• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram
• A family history of breast cancer
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Depression
• Gallbladder disease
• Liver disease
• Heart disease
• Kidney disease
• Scanty or irregular menstrual periods

If you have any of these conditions you should be checked often by your healthcare professional if you use the contraceptive patch.

RISKS OF USING HORMONAL CONTRACEPTIVES, INCLUDING ORTHO EVRA 

The following information is derived primarily from studies of birth control pills. Since Ortho Evra contains hormones similar to those found in birth control pills, it is expected to be associated with similar risks:

1. Risk of Developing Blood Clots

Blood clots and blockage of blood vessels that can cause death or serious disability are some of the most serious side effects of using hormonal contraceptives, including the norelgestromin/ethinyl estradiol contraceptive patch. In particular, a clot in the legs can cause thrombophlebitis, and a clot that travels to the lungs can cause sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision.

The risk of venous thromboembolic disease (blood clots in the legs and/or the lungs) may be increased with norelgestromin/ethinyl estradiol compared with that of oral contraceptives containing norgestimate and 35 micrograms of estrogen. You should discuss this possible increased risk with your healthcare professional before using norelgestromin/ethinyl estradiol. 

If you use Ortho Evra and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor about stopping Ortho Evra four weeks before surgery and not using it for two weeks after surgery or during bed rest. You should also not use Ortho Evra soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using Ortho Evra.

2. Heart Attacks and Strokes

Hormonal contraceptives, including Ortho Evra, may increase the risk of developing strokes (blockage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability.

Smoking and the use of hormonal contraceptives including Ortho Evra greatly increase the chances of developing and dying of heart disease. Smoking also greatly increases the possibility of suffering heart attacks and strokes.

3. Gallbladder Disease

Women who use hormonal contraceptives, including Ortho Evra, probably have a greater risk than nonusers of having gallbladder disease.

4. Liver Tumors

In rare cases, combination oral contraceptives can cause benign but dangerous liver tumors. Since Ortho Evra contains hormones similar to those in birth control pills, this association may also exist with Ortho Evra. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.

5. Cancer of the Reproductive Organs and Breasts

Various studies give conflicting reports on the relationship between breast cancer and hormonal contraceptive use. Combination hormonal contraceptives, including Ortho Evra, may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives, although this finding may be related to factors other than the use of oral contraceptives. However, there is insufficient evidence to rule out the possibility that oral contraceptives may cause such cancers.

PREGNANCY DUE TO ORTHO EVRA FAILURE

The incidence of pregnancy from hormonal contraceptive failure is approximately one percent (i.e., one pregnancy per 100 women per year) if used correctly. The chance of becoming pregnant increases with incorrect use. If contraceptive patch failure does occur, the risk to the fetus is minimal.

PREGNANCY AFTER STOPPING ORTHO EVRA 

There may be some delay in becoming pregnant after you stop using Ortho Evra, especially if you had irregular menstrual cycles before you used hormonal contraceptives. It may be best to postpone conception until you begin menstruation regularly once you have stopped using Ortho Evra and want to become pregnant.

There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping hormonal contraceptives.

Ortho Evra keeps you from becoming pregnant by transferring hormones to your body through your skin. The patch must stick securely to your skin in order for it to work properly.

This method uses a 28 day (four week) cycle. You should apply a new patch each week for three weeks (21 total days). You should not apply a patch during the fourth week. Your menstrual period should start during this patch-free week.

Every new patch should be applied on the same day of the week. This day will be your 'Patch Change Day.' For example, if you apply your first patch on a Monday, all of your patches should be applied on a Monday. You should wear only one patch at a time.

On the day after week four ends, you should begin a new four week cycle by applying a new patch.

HOW TO START USING YOUR ORTHO EVRA PATCH FOR THE FIRST TIME

You have two options for starting the patch. Choose which option is right for you:

• First Day Start–Apply your first patch during the first 24 hours of your menstrual period.
• Sunday Start–Wait until the first Sunday after your menstrual period begins. With this option, a non-hormonal backup method of birth control, such as a condom or diaphragm and spermicide, is needed for the first 7 days of the first cycle only. If your period starts on a Sunday, the first patch should be applied that day, and no backup contraception is needed.
• When Switching From the Pill or Vaginal Contraceptive Ring to the Patch-If you are switching from the pill or vaginal contraceptive ring to Ortho Evra, complete your current pill cycle or vaginal ring cycle and apply the first Ortho Evra patch on the day you would normally start your next pill or insert your next vaginal ring. If you do not get your period within a week after taking the last active pill or removing the last vaginal ring, you may still start the norelgestromin/ethinyl estradiol patch. Check with your healthcare professional to be sure that you are not pregnant. If the patch is applied more than a week after taking the last active pill or removal of the last vaginal ring, a non-hormonal method of birth control should be used at the same time as the patch for the first 7 days of patch use.

CHOOSE A PLACE ON YOUR BODY TO PUT THE PATCH

• The patch may be placed on your upper outer arm, abdomen, buttock or back in a place where it won't be rubbed by tight clothing. For example, do not place it under the waistband of clothing.
• Do not put the patch on your breasts, on cut or irritated skin, or on the same location as the previous patch.

Before you apply the patch:

• Make sure your skin is clean and dry.
• Do not use lotions, creams, oils, powders, or make-up at the patch site. It may cause the patch to fail to stick properly or to become loose.

HOW TO APPLY THE PATCH

Tear open the pouch at the top edge. Peel open the foil pouch that contains the patch and its clear plastic cover. Gently remove the patch and its plastic cover together from the pouch, being careful not to separate the patch from the clear plastic cover. Using a fingernail, peel away half of the clear plastic. Avoid touching the sticky surface with your fingers. Apply the sticky side of the patch on the skin you have cleaned and dried. Remove the other half of the clear plastic and attach the entire patch to your skin. 

• Press firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch adheres to your skin.
• Run your fingers over the entire surface area to smooth out any "wrinkles" around the outer edges of the patch.

• Check your patch every day to make sure all edges are sticking correctly.

Never cut, damage or alter the patch in any way.

When to change patch:

• The patch works for seven days (one week). Apply a new patch on the same day each week (your Patch Change Day) for 3 weeks in a row. Make sure you have removed your old patch prior to applying the new patch.
• During week 4, DO NOT wear a patch. Make sure you removed your old patch. (Your period should begin during this week).
• Following week 4, repeat the cycle of three weekly applications followed by a patch-free week.

The patch must stick securely to your skin to work properly. Do not try to reapply a patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it.

If a patch edge lifts up:

• Press down firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch adheres to your skin. Run your fingers over the entire surface area to smooth out any "wrinkles" around the edges of the patch.
• If your patch does not stick completely, remove it and apply a replacement patch. (Ask your healthcare professional for a replacement patch prescription so you always have an extra patch available).
• Do not tape or wrap the patch to your skin or reapply a patch that is partially adhered to clothing.

If your patch has been off or partially off:

• For less than 1 Day, try to reapply it. If the patch does not adhere completely, apply a new patch immediately. (No backup contraception is needed and your Patch Change Day will stay the same).
• For more than 1 Day or if you are not sure for how long, you may become pregnant. To reduce this risk, apply a new patch and start a new 4-week cycle. You will now have a new Patch Change Day and MUST USE NON-HORMONAL BACKUP CONTRACEPTION (such as a condom or diaphragm and spermicide) for the first week of your new cycle.

Each beige Ortho Evra patch contains 6.00 mg norelgestromin and 0.75 mg ethinyl estradiol.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Body aches or pain
• chills
• cough
• difficulty with breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Anxiety
• changes in skin color
• chest pain or discomfort
• confusion
• dark urine
• diarrhea
• dizziness
• eye pain
• fainting
• inability to speak
• itching
• lack or loss of appetite
• light-colored stools
• lightheadedness
• nausea
• numbness in the hands
• pain in the abdomen or stomach
• pain in the chest, groin, or legs, especially the calves
• pain or discomfort in the arms, jaw, back, or neck
• pain, tenderness, or swelling of the foot or leg
• pounding in the ears
• rash
• seizures
• slow or fast heartbeat
• slurred speech
• sudden headache
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg on one side of the body
• sudden, unexplained shortness of breath
• sweating
• swelling, pain, or tenderness in the upper abdominal or stomach area
• temporary blindness
• unpleasant breath odor
• vision changes
• vomiting of blood
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

• Unusual vaginal bleeding in women
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Burning, itching, or redness of the skin
• menstrual cramps
• pain, soreness, swelling, or discharge from the breast or breasts
• swelling or soreness at the patch site

• Abdominal or stomach cramps or bloating
• absent, missed, or irregular menstrual periods
• bloody vaginal discharge
• brown, blotchy spots on exposed skin
• change in amount of vaginal discharge
• change in menstrual flow
• decreased amount of breast milk
• discouragement
• dry mouth
• feeling sad or empty
• increase or decrease in weight
• increased hunger or thirst
• increased urination
• irritability
• itching of the vagina or outside of the genitals
• light vaginal bleeding between periods and after sexual intercourse
• loss of interest or pleasure
• pain during sexual intercourse
• stopping of menstrual bleeding
• swelling
• thick, white curd-like vaginal discharge without odor or with mild odor
• trouble concentrating
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Put patch on once a week for 3 weeks. Put it on the same day each week. Do not use patch on the 4th week.
• Put patch on clean, dry, healthy skin on the buttock, belly, upper arm, or back.
• Do not put on the breast.
• Do not put the patch on the waistline.
• Move the site with each patch.
• Do not put on skin that is irritated or damaged. Do not put on an area with skin folds or skin that will be rubbed by tight clothes.
• Do not use patches that are cut or do not look right.
• Do not use adhesives or wraps to hold the patch in place.
• Do not put on skin where you have just used creams, oils, lotions, powder, or other skin products. The patch may not stick as well.
• Avoid sunlight on treated area.
• Do not skip doses, even if you do not have sex very often.
• Do not put on more than 1 patch at a time.
• If you miss 2 periods in a row, take a pregnancy test before starting a new cycle.
• If Ortho Evra (ethinyl estradiol and norelgestromin) has not been used the right way and 1 monthly period is missed, take a pregnancy test.
• Put the same patch on the same place if it falls off and has been off for less than 24 hours.
• Put on a new patch if the patch being used is no longer sticky or if it is sticking to itself or some other surface.
• If a patch has been off for more than 1 day, you may not be protected from pregnancy. Put a new patch on to start a new 4 week cycle. Use another type of birth control like a condom during the first week of the new cycle.

What do I do if I miss a dose?

• If a dose is missed, check the package insert or call the doctor to find out what to do. If using this medicine to prevent pregnancy, another form of birth control may need to be used for some time to prevent pregnancy.

Ortho Evra is a transdermal system with a contact surface area of 20 cm2. It contains 6 mg NGMN and 0.75 mg EE, and its delivery rate is approximately 150 mcg of NGMN and 35 mcg of EE per day. 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 the Cmax is lower than those produced by an oral contraceptive containing NGM 250 mcg / EE 35 mcg. [see Boxed Warning and Clinical Pharmacology (12.3)].

Ortho Evra is a thin, matrix-type transdermal system 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, NGMN and EE. 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".

The structural formulas of the components are:

Molecular weight, NGMN: 327.47

Molecular weight, EE: 296.41

Chemical name for NGMN: 18, 19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,3-oxime,(17α)

Chemical name for EE: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17-diol,(17α)

Mechanism of Action

NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of Ortho Evra. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products.

Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Pharmacodynamics

One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.

Pharmacokinetics

Absorption

The systemic delivery rate of NGMN and EE from Ortho Evra is approximately 150 mcg of NGMN and 35 mcg of EE per day based on a comparative analysis with intravenous (IV) data. Following a single application of Ortho Evra, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady state is reached within 2 weeks of application. In one of the clinical studies, Css concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE.

Absorption of NGMN and EE following application of Ortho Evra to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.

The mean (%CV) PK parameters Css and AUC0–168 for NGMN and EE following a single buttock application of Ortho Evra are summarized in Table 5.

In multiple dose studies, AUC0–168 for NGMN and EE was found to increase over time (Table 5). In a three-cycle study, these PK parameters reached steady state conditions during Cycle 3 (Figures 3 and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days.

Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Ortho Evra on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)

Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Ortho Evra on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)

The absorption of NGMN and EE following application of Ortho Evra was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN, there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.

Results from a study of consecutive Ortho Evra wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations.

Metabolism

Since Ortho Evra is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Distribution

NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see Table 5).

Elimination

Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways.

Transdermal versus Oral Contraceptives

The Ortho Evra transdermal patch delivers EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis. Figures 5 and 6 present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg / EE 35 mcg) compared to the 7-day transdermal Ortho Evra patch (containing NGMN 6 mg / EE 0.75 mg) during Cycle 2 in 32 healthy female volunteers.

Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once­Daily Administration of an Oral Contraceptive for 2 Cycles or Application of Ortho Evra for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15–21, Ortho Evra: Cycle 2, Week 3]

Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of Ortho Evra for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15–21, Ortho Evra: Cycle 2, Week 3]

Table 6 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.

In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with Ortho Evra for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0–168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from Ortho Evra was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.

In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for Ortho Evra users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for Ortho Evra and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.

Drug Interactions

In a PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for 3 days prior to and 7 days during wear of Ortho Evra did not significantly affect the PK of NGMN or EE.

Use in Specific Populations

Effects of Age, Body Weight, Body Surface Area and Race

The effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of Ortho Evra. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only a small fraction (10–25%) of the overall variability in the PK of NGMN and EE following application of Ortho Evra may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.

Use Ortho Evra patches exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not use more skin patches or wear them for longer than recommended by your doctor. You will apply your first patch on the first day of your period or on the first Sunday after your period begins (follow your doctor's instructions).

Place the Ortho Evra patch on your skin and press it into place firmly for 10 seconds. Make sure the edges stick well. You will wear the patch for a full week.

Apply the Ortho Evra patch to clean, dry skin on any of these areas: the outside of your upper arm, your stomach, your buttocks, or your upper back. Do not apply the patch to skin that is broken or irritated, or to a skin area that may be rubbed by tight clothing (such as a waistband).

Remove the patch and apply a new one on the same day each week for three weeks in a row. At the end of the third week, remove the patch and do not apply a new one for 7 full days. Your period should start during this time Do not allow more than 7 days to pass before starting your next 3-week patch cycle..

Check your Ortho Evra patch every day to make sure it is sticking well. If a patch comes loose or falls off, throw it away and apply a new one. You may need to use back-up birth control, such as condoms or a spermicide, if a patch has been off for more than 24 hours. Follow your doctor's instructions.

You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using Ortho Evra for a short time. Any doctor or surgeon who treats you should know that you are using this medicine.

While using Ortho Evra, you will need to visit your doctor regularly.

After removing a skin patch fold it in half, sticky side in, and throw it away in a place where children and pets cannot get to it. Do not flush a used patch down the toilet.

Store the skin patches at room temperature away from moisture and heat. Do not freeze or refrigerate. Keep each patch in its foil pouch until you are ready to apply it.

Get emergency medical help if you have any signs of an allergic reaction to Ortho Evra skin patches: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Ortho Evra and call your doctor at once if you have:

• signs of a stroke - sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with balance, sudden vision loss;

• signs of a blood clot in the lung - chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• signs of a blood clot in your leg - pain, swelling, warmth, or redness in one or both legs;

• heart attack symptoms - chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• a change in the pattern or severity of migraine headaches;

• swelling in your hands, ankles, or feet;

• a breast lump; or

• symptoms of depression - sleep problems, weakness, tired feeling, mood changes.

Common Ortho Evra side effects may include:

• nausea, stomach pain;

• breast tenderness or swelling;

• headache, anxiety, mood changes;

• skin irritation, redness, itching, or swelling where the patch was worn;

• menstrual cramps; or

• irregular vaginal bleeding or spotting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.