norelgestromin and ethinyl estradiol transdermal system
Ortho Evra

Available forms
Transdermal patch: Norelgestromin 6 mg and ethinyl estradiol 0.75 mg

Indications and dosages
 Prevention of pregnancy. Women: Apply 1 patch weekly for 3 weeks. Apply each new patch on the same day of the week. Week 4 is patch-free. On the day after week 4 ends, apply a new patch to start a new 4-week cycle. The patch-free interval between cycles should never be longer than 7 days.

Pharmacodynamics
Contraceptive action: Norelgestromin is the progestin most responsible for the progestational activity that follows application of drug. Combination hormonal contraceptives act by suppression of gonadotropins. The primary mechanism of this action is inhibition of ovulation. However, changes in cervical mucus increase the difficulty of sperm entry into the uterus and changes in the endometrium decrease the likelihood of implantation.

Pharmacokinetics
Absorption: After patch application, both components of drug rapidly appear in the serum, peak at about 48 hours, and are maintained at steady state while the patch is worn.
Distribution: Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are more than 97% protein-bound. Norelgestromin is bound to albumin and not to sex hormone-binding globulins (SHBG). Norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to albumin.
Metabolism: Norelgestromin and its metabolites are metabolized through the liver. Ethinyl estradiol is metabolized to various hydroxylated products.
Excretion: Upon removal of the patch, norelgestromin and ethinyl estradiol are eliminated in 28 hours and 17 hours, respectively. The metabolites of both are eliminated in urine and feces.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or its components and in those with history of deep vein thrombosis or related disorder, current or history of cerebrovascular or coronary artery disease, past or current known or suspected breast cancer, endometrial cancer or other known or suspected estrogen-dependent neoplasia, hepatic adenoma or carcinoma, or known or suspected pregnancy.
  Also contraindicated in patients experiencing major surgery with prolonged immobilization and in those with thrombophlebitis, thromboembolic disorders, valvular heart disease with complications, severe hypertension, diabetes with vascular involvement, headaches with focal neurologic symptoms, undiagnosed abnormal genital bleeding, cholestatic jaundice of pregnancy or jaundice with previous hormonal contraceptive use, or acute or chronic hepatocellular disease with abnormal liver function.
 Use cautiously in patients with risk factors for CV disease, with conditions that might be aggravated by fluid retention, or with a history of depression.

Interactions
Drug-drug. Acetaminophen, clofibric acid, morphine, salicylic acid, temazepam: Decreases plasma levels or increases clearance of these drugs. Monitor patient for lack of effect.
Ampicillin, barbiturates, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenylbutazone, phenytoin, rifampin, topiramate: May reduce contraceptive effectiveness, resulting in unintended pregnancy or breakthrough bleeding. Encourage backup method of contraception if used together.
Anti-HIV protease inhibitors: May affect safety and efficacy of contraceptives. Use cautiously together.
Ascorbic acid, atorvastatin, itraconazole, ketoconazole: Increases plasma hormone levels. Use together cautiously.
Cyclosporine, prednisolone, theophylline: Increases plasma levels of these drugs. Monitor patient for adverse effects.
Drug-herb. St John’s wort: May reduce effectiveness of contraceptive and cause breakthrough bleeding. Discourage use together.
Drug-lifestyle. Smoking: Increases risk of CV adverse effects; possible effects related to age and heavy smoking (15 or more cigarettes per day). Discourage smoking.

Adverse reactions
CNS: headache, emotional lability.
CV: thromboembolic events, MI, hypertension, edema, cerebral hemorrhage.
EENT: contact lens intolerance.
GI: nausea, abdominal pain, vomiting.
GU: menstrual cramps, changes in menstrual flow, vaginal candidiasis.
Hematologic: gallbladder disease.
Hepatic: hepatic adenomas, benign liver tumors.
Metabolic: weight changes.
Respiratory: upper respiratory tract infection.
Skin: application site reaction.
Other: breast tenderness, enlargement, or secretion.

Effects on lab test results
• May increase levels of factors VII, VIII, IX, and X; circulating total thyroid hormone; triglycerides; other binding proteins; sex homone-binding globulins; total circulating endogenous sex steroids; and corticoids. May decrease antithrombin III and folate levels.
• May increase PT. May decrease free T₃ resin uptake and glucose tolerance.

Special considerations
• Patients taking combination hormonal contraceptives may be at increased risk for thrombophlebitis, venous thrombosis with or without embolism, pulmonary embolism, MI, cerebral hemorrhage, cerebral thrombosis, hypertension, gallbladder disease, hepatic adenomas, benign liver tumors, mesenteric thrombosis, and retinal thrombosis.
• Increased risk of MI occurs primarily in smokers and women with hypertension, hypercholesterolemia, morbid obesity, or diabetes.
• Encourage women with a history of hypertension or renal disease to use a different method of contraception. If Ortho Evra is used, monitor blood pressure closely and discontinue use if hypertension occurs.
• Drug may be less effective in women weighing 198 lb (90 kg) or more.
• Cigarette smoking increases the risk of serious CV adverse effects. This risk increases with age and with heavy smoking (15 or more cigarettes per day).
• The risk of thromboembolic disease increases if therapy is used postpartum or postabortion.
• If patient starting the patch for the first time, she should wait until the day she begins her menstrual period. She will then choose a first-day start or a Sunday start.
• If patient chooses a first-day start, the patch should be applied during the first 24 hours of her menstrual period. If therapy starts after day 1 of the menstrual cycle, a nonhormonal backup method of contraception should be used for the first week of the first treatment cycle.
• If patient chooses a Sunday start, the patch should be applied on the first Sunday after her menstrual period starts. She must use backup method of contraception for the first week of her cycle. If patient’s menstrual period begins on a Sunday, she should apply the first patch on that day, and no backup method of contraception is needed.
• To switch patient from an oral contraceptive, begin treatment on the first day of withdrawal bleeding. If therapy starts later than the first day of withdrawal bleeding, a backup method of contraception should be used for the first week.
• Therapy should be started no sooner than 4 weeks after childbirth. If patient hasn’t had a menstrual period, rule out pregnancy. Patient should use a backup method of contraception for the first week.
• After abortion or miscarriage in the first trimester, the patch may be started immediately. If patch isn’t started within 5 days of a first-trimester abortion, follow directions for patient starting therapy for the first time.
• Therapy should be started no earlier than 4 weeks after a second-trimester abortion or miscarriage.
• If breakthrough bleeding occurs, stop treatment and evaluate cause if bleeding lasts longer than a few cycles.
• If no withdrawal bleeding occurs on patch-free week, resume treatment on the next scheduled patch-change day. Rule out pregnancy if withdrawal bleeding fails to occur for two consecutive cycles.
• If skin becomes irritated, the patch may be removed and a new patch applied at a different site until the next patch-change day.
• Discontinue use at least 4 weeks before and for 2 weeks after elective surgery of a type associated with increased risk of thromboembolism and during and after prolonged immobilization.
• Discontinue use if patient has recurrent, persistent, or severe headaches or if jaundice occurs.
• Discontinue use and evaluate patient if vision loss, proptosis, diplopia, papilledema, or retinal vascular lesions occur.
• Discontinue use if patient becomes severely depressed, and evaluate if the depression is drug-related.
• Monitor diabetic women and women with hyperlipidemia closely during use.
Pregnant patients
• Don’t use contraceptive patch in pregnant patients.
Breast-feeding patients
• Contraceptive patch hasn’t been evaluated in breast-feeding women; its effects aren’t known. Breast-feeding women should use alternative methods of contraception.
Pediatric patients
• Safety and efficacy of contraceptive patch haven’t been evaluated. Patch isn’t indicated before menarche.
Geriatric patients
• This product hasn’t been studied for this age group and isn’t indicated in patients older than age 65.

Patient education
• Emphasize the importance of having regular annual physical examinations to check for adverse effects or developing contraindications of the contraceptive patch.
• Tell patient that the contraceptive patch doesn’t protect against HIV and other sexually transmitted diseases.
• Advise patient to immediately apply a new patch once the used patch is removed, on the same day of the week every 7 days for 3 weeks. Week 4 is patch-free. Tell patient that bleeding is expected to occur during the patch-free week.
• Advise patient to start a new cycle, applying a new patch on the usual patch-change day, regardless of when the menstrual period starts or ends.
• Teach patient how to use the patch:
- Peel apart the foil pouch and open flat. Firmly grasp a corner of the patch and gently remove it from the foil pouch.
-Using a fingernail, lift one corner of the patch and peel the patch and the plastic liner from the foil liner. Don’t accidentally remove the clear liner as the patch is being removed.
- Peel away half of the clear protective liner. Don’t touch the sticky surface of the patch.
- Apply the sticky surface of the patch to the skin and remove the other half of the liner. Press down firmly on the patch with palm of hand for 10 seconds, making sure that the edges stick well.
• Tell patient to apply each patch to a new, clean, dry area of the skin on the buttocks, abdomen, upper outer arm, or upper torso to avoid irritation. Tell patient not to apply to the breasts or to skin that is red, irritated, or cut. Instruct patient to avoid creams, oils, powder, or makeup on or near the skin where the patch will be placed because the patch may loosen.
• Tell patient what to do if a patch is partially or completely detached:
- If patch is detached for less than 24 hours, try to reapply it to the same place or replace it with a new patch immediately. No backup method of contraception is needed.
- If patch is detached for 24 hours or longer, or if patient isn’t sure how long patch has been detached, she should stop the current cycle and start a new cycle immediately by applying a new patch. Backup method of contraception must be used for the first week of the new cycle because patient may not be protected from pregnancy.
- Patient shouldn’t attempt to reapply patch if it’s 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 patient can’t reapply a patch, she must apply a new patch immediately. She shouldn’t use adhesives or wraps to hold the patch in place.
• Tell patient what to do if she forgets to change her patch:
- At the start of the cycle: Tell patient to apply the first patch of the new cycle as soon as she remembers and to use backup method of contraception for the first week of the new cycle.
- In the middle of the patch cycle for 1 or 2 days: Advise patient to apply a new patch immediately. She should apply the next patch on the usual patch-change day. No backup method of contraception is needed.
- In the middle of the patch cycle for longer than 2 days: Tell patient to stop the current contraceptive cycle and start a new 4-week cycle immediately by applying a new patch. She should use a backup method of contraception for 1 week.
- At the end of a patch cycle: If patient forgets to take off her patch, tell her to remove it as soon as she remembers. Tell patient to start next cycle on the usual patch-change day, the day after day 28. No backup method of contraception is needed.
• If patient wants to change her patch-change day, tell her to complete her current cycle, and, during the patch-free week, apply a new patch on the desired day. There shouldn’t be more than 7 consecutive patch-free days.
• Tell patient what to do if she misses a menstrual period:
- If patient hasn’t adhered to the prescribed schedule, pregnancy should be ruled out at the time of the first missed period.
- If patient has adhered to the prescribed regimen and missed one period, she should continue using the patches. If she has adhered to the prescribed regimen and missed two consecutive periods, pregnancy should be ruled out.
• Tell patient to immediately discontinue use if pregnancy is confirmed.
• Tell patient who wears contact lenses to contact an ophthalmologist if visual changes or changes in lens tolerance develop.
• Tell patient to carefully fold the used patch in half so that it sticks to itself before discarding.
• Advise patient not to smoke while using patch.
• Stress that, if patient isn’t sure what to do about mistakes with patch use, she should use a backup method of contraception, such as a condom, spermicide, or diaphragm, when she has sexual intercourse. Advise her to call for further instructions.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use