Special Alerts:

Lower Dose femhrt® Approved - January, 2005

The Food and Drug Administration (FDA) has approved a new, lower dosage form of femhrt® for the treatment of moderate-to-severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. It is expected to be available in the second quarter of 2005.

Pronunciation:

(ETH in il es tra DYE ole & nor eth IN drone)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Cardiovascular-related considerations: Use caution with cardiovascular disease or dysfunction. Combination estrogen/progestin therapy has been associated with an increased risk of cardiovascular disease, which may be dose related. May increase the risks of hypertension, myocardial infarction (MI), stroke, pulmonary emboli (PE), and deep vein thrombosis; incidence of these effects was shown to be significantly increased in postmenopausal women using conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (MPA). Nonfatal MI, PE, and thrombophlebitis have also been reported in males taking high doses of CEE (eg, for prostate cancer). An increased risk of MI has been noted with use of combination hormonal contraceptives, primarily in women with underlying risk factors. The risk of cardiovascular events 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. Women with hypertension should be encouraged to use another form of contraception. Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism. Estrogens with or without progestin should not be used to prevent coronary heart disease in postmenopausal women. Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to surgeries associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Estrogens may cause retinal vascular thrombosis. Discontinue pending examination in cases of sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

Cancer-related considerations: Estrogens may increase the risk of breast cancer. The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer, however studies are not consistent. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA; a smaller increase in risk was seen with estrogen therapy alone in observational studies. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy in post-menopausal women. Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women. Estrogen use may lead to severe hypercalcemia in post-menopausal patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes or renal dysfunction. Use with caution in patients with a history of severe hypocalcemia, SLE, hepatic hemangiomas, porphyria, endometriosis, and gallbladder disease. Use caution with history of cholestatic jaundice associated with past estrogen use or pregnancy.

Combination hormonal contraceptives do not protect against HIV infection or other sexually-transmitted diseases. The minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. New patients should be started on products containing <50 mcg of estrogen per tablet. When used for acne, use only in females 15 years, who also desire combination hormonal contraceptive therapy, are unresponsive to topical treatments, and have no contraindications to combination hormonal contraceptive use; treatment must continue for at least 6 months. Not for use prior to menarche.

The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women 65 years of age taking CEE in combination with MPA. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments. When used solely for prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered.

Adverse Reactions:

Cardiovascular: Arterial thromboembolism, cerebral hemorrhage, cerebral thrombosis, edema, hypertension, mesenteric thrombosis, MI

Central nervous system: Depression, dizziness, headache, migraine, nervousness, premenstrual syndrome, stroke

Dermatologic: Acne, erythema multiforme, erythema nodosum, hirsutism, loss of scalp hair, melasma (may persist), rash (allergic)

Endocrine & metabolic: Amenorrhea, breakthrough bleeding, breast enlargement, breast secretion, breast tenderness, carbohydrate intolerance, lactation decreased (postpartum), glucose tolerance decreased, libido changes, menstrual flow changes, sex hormone-binding globulins (SHBG) increased, spotting, temporary infertility (following discontinuation), thyroid-binding globulin increased, triglycerides increased

Gastrointestinal: Abdominal cramps, appetite changes, bloating, cholestasis, colitis, gallbladder disease, jaundice, nausea, vomiting, weight gain/loss

Genitourinary: Cervical erosion changes, cervical secretion changes, cystitis-like syndrome, vaginal candidiasis, vaginitis

Hematologic: Antithrombin III decreased, folate levels decreased, hemolytic uremic syndrome, norepinephrine induced platelet aggregability increased, porphyria, prothrombin increased; factors VII, VIII, IX, and X increased

Hepatic: Benign liver tumors, Budd-Chiari syndrome, cholestatic jaundice, hepatic adenomas

Local: Thrombophlebitis

Ocular: Cataracts, change in corneal curvature (steepening), contact lens intolerance, optic neuritis, retinal thrombosis

Renal: Impaired renal function

Respiratory: Pulmonary thromboembolism

Miscellaneous: Hemorrhagic eruption

Overdosage/Toxicology:

Drug Interactions:

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

Norethindrone: Substrate of CYP3A4 (major); Induces CYP2C19 (weak)

As reported with oral contraceptive agents; specific drug interaction studies have not been performed with femhrt®.

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.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ethinyl estradiol and norethindrone. 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.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Routine use increases estrogen level and risk of breast cancer; avoid ethanol. Ethanol may also increase the risk of osteoporosis.

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. Norethindrone absorption is increased by 27% following administration with food.

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:

Estrostep®: Protect from light.

Mechanism of Action:

In postmenopausal women, exogenous estrogen is used to replace decreased endogenous production. The addition of progestin reduces the incidence of endometrial hyperplasia and risk of endometrial cancer in women with an intact uterus.

Pharmacodynamics/Kinetics:

Norethindrone: See individual monograph.

Ethinyl estradiol:

Absorption: Rapid

Bioavailability: 43% to 55%

Distribution: Vd: 2-4 L/kg

Protein binding: >95% to albumin

Metabolism: Hepatic via oxidation and conjugation in GI tract; hydroxylated via CYP3A4 to metabolites; first-pass effect; enterohepatic recirculation; reversibly converted to estrone and estriol

Half-life elimination: 19-24 hours

Excretion: Urine (as estradiol, estrone, and estriol); feces

Dosage:

Adolescents 15 years and Adults: Female: Acne: Estrostep®: Refer to dosing for contraception

Adults: Female:

Moderate-to-severe vasomotor symptoms associated with menopause: Initial: femhrt® 0.5/2.5: 1 tablet daily; patient should be re-evaluated at 3- to 6-month intervals to determine if treatment is still necessary; patient should be maintained at the lowest effective dose

Prevention of osteoporosis: Initial: femhrt® 0.5/2.5: 1 tablet daily; patient should be maintained on the lowest effective dose

Contraception:

Schedule 1 (Sunday starter): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. With a Sunday start, an additional method of contraception should be used until after the first 7 days of consecutive administration.

For 21-tablet package: Dosage is 1 tablet daily for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken.

For 28-tablet package: Dosage is 1 tablet daily without interruption.

Schedule 2 (Day 1 starter): Dose starts on first day of menstrual cycle taking 1 tablet daily.

For 21-tablet package: Dosage is 1 tablet daily for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken.

For 28-tablet package: Dosage is 1 tablet daily without interruption.

If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.

Missed doses monophasic formulations (refer to package insert for complete information):

One dose missed: Take as soon as remembered or take 2 tablets next day Two consecutive doses missed in the first 2 weeks: Take 2 tablets as soon as remembered or 2 tablets next 2 days. An additional method of contraception should be used for 7 days after missed dose.

Two consecutive doses missed in week 3 or three consecutive doses missed at any time: An additional method of contraception must be used for 7 days after a missed dose.

Schedule 1 (Sunday starter): Continue dose of 1 tablet daily until Sunday, then discard the rest of the pack, and a new pack should be started that same day.

Schedule 2 (Day 1 starter): Current pack should be discarded, and a new pack should be started that same day.

Missed doses biphasic/triphasic formulations (refer to package insert for complete information):

One dose missed: Take as soon as remembered or take 2 tablets next day.

Two consecutive doses missed in week 1 or week 2 of the pack: Take 2 tablets as soon as remembered and 2 tablets the next day. Resume taking 1 tablet daily until the pack is empty. An additional method of contraception should be used for 7 days after a missed dose.

Two consecutive doses missed in week 3 of the pack: An additional method of contraception must be used for 7 days after a missed dose.

Schedule 1 (Sunday Starter): Take 1 tablet every day until Sunday. Discard the remaining pack and start a new pack of pills on the same day.

Schedule 2 (Day 1 starter): Discard the remaining pack and start a new pack the same day.

Three or more consecutive doses missed: An additional method of contraception must be used for 7 days after a missed dose.

Schedule 1 (Sunday Starter): Take 1 tablet every day until Sunday; on Sunday, discard the pack and start a new pack.

Schedule 2 (Day 1 Starter): Discard the remaining pack and begin new pack of tablets starting on the same day.

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

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

Administration:

Monitoring Parameters:

Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals

Prevention of osteoporosis: Bone density measurement

Test Interactions:

Dietary Considerations:

Patient Education:

Additional Information:

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

Tablet: femhrt®:

1/5: Ethinyl estradiol 5 mcg and norethindrone acetate 1 mg [white tablets]

0.5/2.5: Ethinyl estradiol 2.5 mcg and norethindrone acetate 0.5 mg [white tablets]

Tablet, monophasic formulations:

Brevicon®: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [21 blue tablets and 7 orange inactive tablets] (28s)

Junel™ 21 1/20: Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg [yellow tablets] (21s)

Junel™ 21 1.5/30: Ethinyl estradiol 0.03 mg and norethindrone acetate 1.5 mg [pink tablets] (21s)

Junel™ Fe 1/20: Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg [21 yellow tablets] and ferrous fumarate 75 mg [7 brown tablets] (28s)

Junel™ Fe 1.5/30: Ethinyl estradiol 0.03 mg and norethindrone acetate 1.5 mg [21 pink tablets] and ferrous fumarate 75 mg [7 brown tablets] (28s)

Loestrin® 21 1/20, Microgestin™ 1/20: Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg [white tablets] (21s)

Loestrin® 21 1.5/30, Microgestin™ 1.5/30: Ethinyl estradiol 0.03 mg and norethindrone acetate 1.5 mg [green tablets] (21s)

Loestrin® Fe 1/20, Microgestin™ Fe 1/20: Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg [21 white tablets] and ferrous fumarate 75 mg [7 brown tablets] (28s)

Loestrin® Fe 1.5/30, Microgestin™ Fe 1.5/30: Ethinyl estradiol 0.03 mg and norethindrone acetate 1.5 mg [21 green tablets] and ferrous fumarate 75 mg [7 brown tablets] (28s)

Modicon® 28: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [21 white tablets and 7 green inactive tablets] (28s)

Necon® 0.5/35-28: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [21 light yellow tablets and 7 white inactive tablets] (28s)

Necon® 1/35-28: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [21 dark yellow tablets and 7 white inactive tablets] (28s)

Norinyl® 1+35: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [21 yellow-green tablets and 7 orange inactive tablets] (28s)

Nortrel™ 0.5/35 mg:

Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [light yellow tablets] (21s)

Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [21 light yellow tablets and 7 white inactive tablets] (28s)

Nortrel™ 1/35 mg:

Ethinyl estradiol 0.035 mg and norethindrone 1 mg [yellow tablets] (21s)

Ethinyl estradiol 0.035 mg and norethindrone 1 mg [21 yellow tablets and 7 white inactive tablets] (28s)

Ortho-Novum® 1/35 28: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [21 peach tablets and 7 green inactive tablets] (28s)

Ovcon® 35 21-day: Ethinyl estradiol 0.035 mg and norethindrone 0.4 mg [peach tablets] (21s)

Ovcon® 35 28-day: Ethinyl estradiol 0.035 mg and norethindrone 0.4 mg [21 peach tablets and 7 green inactive tablets] (28s)

Ovcon® 50: Ethinyl estradiol 0.05 mg and norethindrone 1 mg [21 yellow tablets and 7 green inactive tablets] (28s)

Tablet, biphasic formulations:

Necon® 10/11-28:

Day 1-10: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [10 light yellow tablets]

Day 11-21: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [11 dark yellow tablets]

Day 22-28: 7 white inactive tablets (28s)

Ortho-Novum® 10/11-28:

Day 1-10: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [10 white tablets]

Day 11-21: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [11 peach tablets]

Day 22-28: 7 green inactive tablets (28s)

Tablet, triphasic formulations:

Aranelle™:

Day 1-7: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [7 light yellow tablets]

Day 8-16: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [9 white tablets]

Day 17-21: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [5 light yellow tablets]

Day 22-28: 7 peach inactive tablets (28s)

Estrostep® Fe:

Day 1-5: Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg [5 white triangular tablets]

Day 6-12: Ethinyl estradiol 0.03 mg and norethindrone acetate 1 mg [7 white square tablets]

Day 13-21: Ethinyl estradiol 0.035 mg and norethindrone acetate 1 mg [9 white round tablets]

Day 22-28: Ferrous fumarate 75 mg [7 brown tablets] (28s)

Necon® 7/7/7, Ortho-Novum® 7/7/7 28:

Day 1-7: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [7 white tablets]

Day 8-14: Ethinyl estradiol 0.035 mg and norethindrone 0.75 mg [7 light peach tablets]

Day 15-21: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [7 peach tablets]

Day 22-28: 7 green inactive tablets (28s)

Nortrel™ 7/7/7 28:

Day 1-7: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [7 light yellow tablets]

Day 8-14: Ethinyl estradiol 0.035 mg and norethindrone 0.75 mg [7 blue tablets]

Day 15-21: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [7 peach tablets]

Day 22-28: 7 white inactive tablets (28s)

Ortho-Novum® 7/7/7 28:

Day 1-7: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [7 white tablets]

Day 8-14: Ethinyl estradiol 0.035 mg and norethindrone 0.75 mg [7 light peach tablets]

Day 15-21: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [7 peach tablets]

Day 22-28: 7 green inactive tablets (28s)

Tri-Norinyl® 28:

Day 1-7: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [7 blue tablets]

Day 8-16: Ethinyl estradiol 0.035 mg and norethindrone 1 mg [9 yellow-green tablets]

Day 17-21: Ethinyl estradiol 0.035 mg and norethindrone 0.5 mg [5 blue tablets]

Day 22-28: 7 orange inactive tablets (28s)

International Brand Names: