Ethinyl Estradiol and Norelgestromin

Pronunciation

(ETH in il es tra DYE ole & nor el JES troe min)

U.S. Brand Names

Ortho Evra™

Synonyms

Norelgestromin and Ethinyl Estradiol; Ortho-Evra

Canadian Brand Names

Evra™

Use

Prevention of pregnancy

Pregnancy Risk Factor

Pregnancy Implications

Pregnancy should be ruled out prior to treatment and discontinued if pregnancy occurs. In general, the use of combination hormonal contraceptives when inadvertently taken early in pregnancy have not been associated with teratogenic effects. Due to increased risk of thromboembolism postpartum, combination hormonal contraceptives should not be started earlier than 4-6 weeks following delivery.

Lactation

Enters breast milk/not recommended (AAP rates "compatible")

Contraindications

Hypersensitivity to ethinyl estradiol, norelgestromin, or any component of the formulation; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); cerebral vascular disease, coronary artery disease, valvular heart disease with complications, severe hypertension; diabetes mellitus with vascular involvement; severe headache with focal neurological symptoms; known or suspected breast carcinoma, endometrial cancer, estrogen-dependent neoplasms, undiagnosed abnormal genital bleeding; hepatic dysfunction or tumor, cholestatic jaundice of pregnancy, jaundice with prior combination hormonal contraceptive use; major surgery with prolonged immobilization; heavy smoking (

15 cigarettes/day) in patients >35 years of age; pregnancy

Warnings/Precautions

Combination hormonal contraceptives do not protect against HIV infection or other sexually-transmitted diseases. The risk of cardiovascular side effects increases in women who smoke cigarettes, especially those who are >35 years of age; women who use combination hormonal contraceptives should be strongly advised not to smoke. Combination hormonal contraceptives may lead to increased risk of myocardial infarction, use with caution in patients with risk factors for coronary artery disease. May increase the risk of thromboembolism. Combination hormonal contraceptives may have a dose-related risk of vascular disease, hypertension, and gallbladder disease. Women with hypertension should be encouraged to use a nonhormonal form of contraception. The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer, however, studies are not consistent. Combination hormonal contraceptives may cause glucose intolerance. Retinal thrombosis has been reported (rarely). Use with caution in patients with renal disease, conditions that may be aggravated by fluid retention, depression, or history of migraine. Not for use prior to menarche.

The combination hormonal contraceptive patch may have adverse effects similar to those associated with oral contraceptive products. The topical patch may be less effective in patients weighing 90 kg (198 lb) and an increased incidence of pregnancy has been reported in this population; consider another form of contraception. Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.

Adverse Reactions

The following reactions have been reported with the contraceptive patch. Adverse reactions associated with oral combination hormonal contraceptive agents are also likely to appear with the topical contraceptive patch (frequency difficult to anticipate). Refer to individual oral contraceptive monographs for additional information.

9% to 22%: Abdominal pain, application site reaction, breast symptoms, headache, menstrual cramps, nausea, upper respiratory infection

Overdosage/Toxicology

Overdosage is unlikely due to the design of the patch. Toxicity from oral combination hormonal contraceptives is unlikely following single exposures of excessive doses. May cause withdrawal bleeding in females. If overdose is suspected, patch should be removed and treatment should be symptomatic and supportive.

Drug Interactions

Ethinyl estradiol: Substrate of CYP2C8/9 (minor), 3A4 (major), 3A5-7 (minor); Inhibits CYP1A2 (weak), 2B6 (weak), 2C19 (weak), 3A4 (weak)

Norelgestromin: Substrate of CYP3A4 (minor)

Interactions seen with oral contraceptive agents are likely to occur with the contraceptive patch; reported interactions include:

Acetaminophen: May increase plasma concentration of synthetic estrogens, possibly by inhibiting conjugation. Combination hormonal contraceptives may also decrease the plasma concentration of acetaminophen.

Acitretin: Interferes with the contraceptive effect of microdosed progestin-containing "minipill" preparations. The effect on other progestational contraceptives (eg, implants, injectables) is unknown.

Aminoglutethimide: May increase CYP metabolism of progestins leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Antibiotics (ampicillin, tetracycline): Pregnancy has been reported following concomitant use, however, pharmacokinetic studies have not shown consistent effects with these antibiotics on plasma concentrations of synthetic steroids. Use of a nonhormonal contraceptive product is recommended.

Anticoagulants: Combination hormonal contraceptives may increase or decrease the effects of coumarin derivatives. Combination hormonal contraceptives may also increase risk of thromboembolic disorders

Anticonvulsants (carbamazepine, felbamate, phenobarbital, phenytoin, topiramate): Increase the metabolism of ethinyl estradiol and/or some progestins, leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Ascorbic acid: Doses of ascorbic acid (vitamin C) 1 g/day have been reported to increase plasma concentration of synthetic estrogens by ~47%, possibly by inhibiting conjugation; clinical implications are unclear.

Atorvastatin: Atorvastatin increases the AUC for norethindrone and ethinyl estradiol.

Benzodiazepines: Combination hormonal contraceptives may decrease the clearance of some benzodiazepines (alprazolam, chlordiazepoxide, diazepam) and increase the clearance of others (lorazepam, oxazepam, temazepam)

Clofibric acid: Combination hormonal contraceptives may increase the clearance of clofibric acid.

Cyclosporine: Combination hormonal contraceptives may inhibit the metabolism of cyclosporine, leading to increased plasma concentrations; monitor cyclosporine levels

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ethinyl estradiol. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Griseofulvin: Griseofulvin may induce the metabolism of combination hormonal contraceptives causing menstrual changes; pregnancies have been reported. Use of barrier form of contraception is suggested while on griseofulvin therapy.

Morphine: Combination hormonal contraceptives may increase the clearance of morphine.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine may decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. No data for delavirdine; incomplete data for efavirenz

Prednisolone: Ethinyl estradiol may inhibit the metabolism of prednisolone, leading to increased plasma concentrations.

Protease inhibitors: Amprenavir, lopinavir, nelfinavir, and ritonavir have been shown to decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. Indinavir has been shown to increase plasma levels of combination hormonal contraceptives. No data for saquinavir.

Rifampin: Rifampin increases the metabolism of ethinyl estradiol and some progestins (norethindrone) resulting in decreased contraceptive effectiveness and increased menstrual irregularities. Use of a nonhormonal contraceptive product is recommended.

Salicylic acid: Combination hormonal contraceptives may increase the clearance of salicylic acid.

Selegiline: Combination hormonal contraceptives may increase the serum concentration of selegiline.

Theophylline: Ethinyl estradiol may inhibit the metabolism of theophylline, leading to increased plasma concentrations.

Tricyclic antidepressants (amitriptyline, imipramine, nortriptyline): Metabolism may be inhibited by combination hormonal contraceptives, increasing plasma levels of antidepressant; use caution.

Troglitazone: Troglitazone decreases the serum concentrations of ethinyl estradiol and norethindrone by ~30%, leading to possible reduction in contraceptive effectiveness.

Ethanol/Nutrition/Herb Interactions

Food: CNS effects of caffeine may be enhanced if combination hormonal contraceptives are used concurrently with caffeine. Grapefruit juice increases ethinyl estradiol concentrations and would be expected to increase progesterone serum levels as well; clinical implications are unclear.

Herb/Nutraceutical: St John's wort may decrease the effectiveness of combination hormonal contraceptives by inducing hepatic enzymes. Avoid dong quai and black cohosh (have estrogen activity). Avoid saw palmetto, red clover, ginseng.

Stability

Store at controlled room temperature of 25°C (77°F). Do not refrigerate or freeze.

Mechanism of Action

Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility.

Pharmacodynamics/Kinetics

Ortho Evra™:

Absorption: Topical: Equivalent when applied to abdomen, buttock, upper outer arm, and upper torso

Ethinyl estradiol and norelgestromin: Rapid; reaches plateau by ~48 hours

Protein binding: Norelgestromin: >97% to albumin

Metabolism: Topical:

Ethinyl estradiol: First-pass effect avoided

Norelgestromin: Hepatic to norgestrel and others; first-pass effect avoided

Half-life elimination: Topical:

Ethinyl estradiol: 17 hours

Norelgestromin: 28 hours

Excretion: Norelgestromin: Urine and feces

Dosage

Topical: Adults: Female:

Contraception: Apply one patch each week for 3 weeks (21 total days); followed by one week that is patch-free. Each patch should be applied on the same day each week ("patch change day") and only one patch should be worn at a time. No more than 7 days should pass during the patch-free interval.

Schedule 1 (Sunday starter): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, apply one patch that very same day. With a Sunday start, an additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration. Each patch change will then occur on Sunday.

Schedule 2 (Day 1 starter): Dose starts on first day of menstrual cycle, applying one patch during the first 24 hours of menstrual cycle. No back-up method of contraception is needed as long as the patch is applied on the first day of cycle. Each patch change will then occur on that same day of the week.

Additional dosing considerations:

No bleeding during patch-free week/missed menstrual period: If patch has been applied as directed, continue treatment on usual "patch change day". If used correctly, no bleeding during patch-free week does not necessarily indicate pregnancy. However, if no withdrawal bleeding occurs for 2 consecutive cycles, pregnancy should be ruled out. If patch has not been applied as directed, and one menstrual period is missed, pregnancy should be ruled out prior to continuing treatment.

If a patch becomes partially or completely detached for <24 hours: Try to reapply to same place, or replace with a new patch immediately. Do not reapply if patch is no longer sticky, if it is sticking to itself or another surface, or if it has material sticking to it.

If a patch becomes partially or completely detached for >24 hours (or time period is unknown): Apply a new patch and use this day of the week as the new "patch change day" from this point on. An additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration.

Switching from oral contraceptives: Apply first patch on the first day of withdrawal bleeding. If there is no bleeding within 5 days of taking the last active tablet, pregnancy must first be ruled out. If patch is applied later than the first day of bleeding, an additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration

Use after childbirth: Therapy should not be started <4 weeks after childbirth. Pregnancy should be ruled out prior to treatment if menstrual periods have not restarted. An additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration.

Use after abortion or miscarriage: Therapy may be started immediately if abortion/miscarriage occur within the first trimester. If therapy is not started within 5 days, follow instructions for first time use. If abortion/miscarriage occur during the second trimester, therapy should not be started for at least 4 weeks. Follow directions for use after childbirth.

Dosage adjustment in renal impairment: Specific guidelines not available; use with caution

Dosage adjustment in hepatic impairment: Contraindicated in patients with hepatic impairment

Administration

New patches should be applied on the same day each week. Apply to clean, dry, intact, healthy skin on the buttock, abdomen, upper arm, or upper torso. Avoid areas that will be rubbed by tight clothing. Do not apply to the breasts or to skin that is red, irritated, or cut. Do not apply make-up, creams, lotions, powders, or other topical products to the skin where the patch will be placed. Remove the patch and the plastic liner from the foil pouch, being careful not to remove the clear liner when removing the patch. Apply patch by first peeling back half of the clear protective liner. Avoid touching surface of patch. Apply patch to skin and remove the rest of the liner. Press patch down firmly onto skin using palm of the hand; apply pressure for 10 seconds. When changing the patch each week, the new patch may be applied in the same anatomic area but should be applied to a new spot in that area. Do not use supplemental adhesives or wraps to hold patch into place.

Forgetting to apply the patch at the start of cycle (week 1/day 1): Apply first patch as soon as remembering, using this day of the week as the new "patch change day" from this point on. An additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration.

Forgetting to change patch in the middle of the cycle (week 2/day 8 or week 3/day 15): If <48 hours from normal "patch change day," apply new patch immediately. No back-up contraception is needed. If >48 hours from normal "patch change day," apply a new patch and use this day of the week as the new "patch change day" from this point on. An additional method of contraception (nonhormonal) should be used until after the first 7 days of consecutive administration.

Forgetting to remove patch at end of cycle (week 4/day 22): Take off as soon as remembering, start new cycle on usual "patch change day."

Changing the "patch change day": The "patch change day" can be changed to an earlier day in the week by first completing the current cycle. Then, during the "patch-free interval", select an earlier day to start the new cycle. Do not allow >7 consecutive patch-free days.

Skin irritation: If patch is in an uncomfortable location, it can be removed and a new patch applied to a different location until the next "patch change day."

Monitoring Parameters

Blood pressure, breast exam, Pap smear, and pregnancy; lipid profiles in patients being treated for hyperlipidemias

Breakthrough bleeding/spotting: Continue use as directed. If bleeding/spotting occur for several cycles, a cause other than the contraceptive patch should be investigated.

Patient Education

Topical contraceptive patches do not protect against HIV or other sexually-transmitted diseases. Use exactly as directed by prescriber (also see package insert), always applying patch on same day of each week. You are at risk of becoming pregnant if doses are missed. Detailed and complete information on dosing and missed doses can be found in the package insert. Be aware that some medications may reduce the effectiveness of contraceptives; an alternate form of contraception may be needed. Check all medicines (prescription and OTC), herbal, and alternative products with prescriber. It is important that you check your blood pressure monthly (on same day each month) and that you have an annual physical assessment, Pap smear, and vision assessment while taking this medication. Avoid smoking while taking this medication; smoking increases risk of adverse effects, including thromboembolic events and heart attacks. You may experience loss of appetite (small, frequent meals will help); or constipation (increased exercise, fluids, fruit, fiber, or stool softeners may help). If you have diabetes, use accurate serum glucose testing to identify any changes in glucose tolerance; notify prescriber of significant changes so antidiabetic medication can be adjusted if necessary. Report immediately pain or muscle soreness; warmth, swelling, pain, or redness in calves; shortness of breath; sudden loss of vision; unresolved leg/foot swelling; change in menstrual pattern (unusual bleeding, amenorrhea, breakthrough spotting); breast tenderness that does not go away; acute abdominal cramping; signs of vaginal infection (drainage, pain, itching); CNS changes (blurred vision, confusion, acute anxiety, or unresolved depression); or significant weight gain (>5 lb/week). Notify prescriber of changes in contact lens tolerance. Pregnancy/breast-feeding precautions: This medication should not be used during pregnancy. If you suspect you may become pregnant, contact prescriber immediately. Breast-feeding is not recommended.

New patches should be applied on the same day each week. Apply to clean, dry, intact and healthy skin on the buttock, abdomen, upper arm or upper torso. Avoid areas that will be rubbed by tight clothing. Do not apply to the breasts or to skin that is red, irritated, or cut. Do not apply make-up, creams, lotions, powders, or other topical products to the skin where the patch will be placed. Remove the patch and the plastic liner from the foil pouch, being careful not to remove the clear liner when removing the patch. Apply patch by first peeling back half of the clear protective liner. Avoid touching surface of patch. Apply patch to skin and remove the rest of the liner. Press patch down firmly onto skin using palm of the hand; apply pressure for 10 seconds. When changing the patch each week, the new patch may be applied in the same anatomic area but should be applied to a new spot in that area. Do not use supplemental adhesives or wraps to hold patch into place.

Disposing of patch: Because the used patch contains some active hormones, fold it in half so that it sticks to itself before throwing it away.

Additional Information

Patches are available in boxes of 3 patches and also in single-patch cartons, intended for use as a replacement patch in case a patch is lost or destroyed.

Dental Health: Effects on Dental Treatment

When prescribing antibiotics, patient must be warned to use additional methods of birth control if on oral contraceptives.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause depression, dizziness, nervousness, or emotional lability

Mental Health: Effects on Psychiatric Treatment

May cause flu-like symptoms, take this into consideration if also concerned about SSRI discontinuation syndrome. Carbamazepine and topiramate may increase the metabolism of estradiol, leading to a decrease in serum concentrations. Estrogens may inhibit the metabolism of some benzodiazepines (alprazolam, chlordiazepoxide, diazepam), TCAs, and selegiline. Estrogens may increase the clearance of lorazepam, oxazepam, and temazepam. Associated with an increased risk of developing dementia in postmenopausal women

65 years of age when treated with conjugated estrogen and medroxyprogesterone acetate.

Dosage Forms

Patch, transdermal: Ethinyl estradiol 0.75 mg and norelgestromin 6 mg [releases ethinyl estradiol 20 mcg and norelgestromin 150 mcg per day] (1s, 3s)

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Panel on Clinical Practices for Treatment of HIV Infection," August 13, 2001. Available at: http://www.aidsinfo.nih.gov. Accessed September 5, 2001.

Hendeles S, Galand N, Schwers J, "Metabolism of Orally-Administered D-norgestrel in Women,"Acta Endocrinol (Copenh), 1972, 71(3):557-68.

Orme ML, Back DJ, and Breckenridge AM, "Clinical Pharmacokinetics of Oral Contraceptive Steroids,"Clin Pharmacokinet, 1983, 8(2):95-136.

International Brand Names

Evra™ (CA)