estradiol/norethindrone [Transdermal]

Adult Dosing

Moderate-severe vasomotor symptoms/vulvovaginal atrophy associated with the menopause

Start [0.05 mg estradiol/0.14 mg NETA]/24 hrs TDP twice weekly during a 28-day cycle; if greater progestin dose is desired, apply [0.05 mg estradiol/0.25 mg NETA]/24 hrs TDP
Alt: Apply estradiol 0.05 mg/24 hr TDP x 2 qwk for the first 14 days of a 28-day cycle followed by [0.05 mg estradiol/0.14 mg NETA]/24 hr TDP x 2 qwk for the next 14 days of 28-day cycle; if greater progestin dose is desired, apply [0.05 mg estradiol/0.25 mg NETA]/24 hr TDP

Treatment of hypoestrogenism

Start [0.05 mg estradiol/0.14 mg NETA]/24 hrs TDP twice weekly during a 28-day cycle; if greater progestin dose is desired, apply [0.05 mg estradiol/0.25 mg NETA]/24 hrs TDP
Alt: Apply estradiol 0.05 mg/24 hr TDP x 2 qwk for the first 14 days of a 28-day cycle followed by [0.05 mg estradiol/0.14 mg NETA]/24 hr TDP x 2 qwk for the next 14 days of 28-day cycle; if greater progestin dose is desired, apply [0.05 mg estradiol/0.25 mg NETA]/24 hrs TDP

Notes:

Use lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman
Reevaluate patients periodically at 3- to 6-month intervals to determine if changes in hormone therapy or if continued hormone therapy is appropriate
To be applied on a smooth (fold-free), clean, dry area of the skin on the lower abdomen; rotate application sites

Pediatric Dosing

Not indicated for use in pediatric patients

[Outline]

Adult Dosing
Pediatric Dosing

Indications ⬆ ⬇

Indicated in women with an intact uterus for

Treatment of moderate to severe vasomotor symptoms associated with menopause
Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause
Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure

Contraindications ⬆ ⬇

Hypersensitivity to any of the ingredients of the product
Undiagnosed abnormal vaginal bleeding
Known, suspected, or history of breast cancer
Known or suspected estrogen- or progestin-dependent neoplasia
Active or history of deep vein thrombosis or pulmonary embolism
Active or recent arterial thromboembolic disease (e.g., stroke, MI) within the past 12 months
Liver dysfunction/disease
Known or suspected pregnancy
Hysterectomy

Black Box Warnings ⬆ ⬇

Do not use estrogens and progestins for the prevention of cardiovascular disease or dementia. As per the study conducted by the Women’s Health Initiative (WHI), oral conjugated equine estrogens of 0.625 mg combined with medroxyprogesterone acetate 2.5 mg increased the risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women 50 to 79 years of age during 5 years of treatment relative to placebo
According to the Women's Health Initiative Memory Study (WHIMS), oral conjugated estrogens in combination with medroxyprogesterone acetate increase the risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment. It is not known whether this finding applies to younger postmenopausal women
Other doses of estrogen and progestin combinations and dosage forms are not studied. In the absence of comparable data, these risks should be assumed to be similar. Use lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman

Dosing Adjustment ⬆ ⬇

Renal Dose Adjustment

Renal impairment: Caution advised; dose adjustments not defined

Hepatic Dose Adjustment

Hepatic impairment: Contraindicated

Warnings/Precautions ⬆ ⬇

Increased risk of cardiovascular events including MI, DVT, stroke, and also venous thrombosis and pulmonary embolism has been associated with estrogen and estrogen/progestin therapy. Discontinue therapy immediately if any of these events occur or be suspected [US Black Box warning]
If feasible, discontinue estrogens at least 4-6 weeks before surgery of the type associated with an increased risk of thromboembolism or during prolonged immobilization
Estrogen plus progestin therapy in postmenopausal women may increase the risk of breast cancer. Increase in abnormal mammograms requiring further evaluation has been reported with estrogen/progestin therapy. Perform yearly breast examinations by a physician and monthly breast self-examinations; perform regular mammography examinations based on patient age, risk factors, and prior mammogram results
Unopposed estrogen use in women with intact uteri may increase the risk of endometrial cancer; prolonged use further increases this risk. Closely monitor all women receiving estrogen plus progestin therapy; consider adequate diagnostic measures, such as endometrial sampling, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding
Estrogen and estrogen/progestin therapy has been reported to increase the risk of probable dementia in postmenopausal women 65 years of age and older [US Black Box warning]
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery has been reported in postmenopausal women receiving estrogens
Estrogen therapy may cause severe hypercalcemia in patients with breast cancer and bone metastases. Discontinue therapy if hypercalcemia occurs and institute appropriate measures to reduce serum calcium level
Retinal vascular thrombosis may occur in patients receiving estrogens. Discontinue the drug pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. Permanently discontinue therapy if examination reveals papilledema or retinal vascular lesions
Addition of progestin to estrogen therapy has been reported to lower the incidence of endometrial hyperplasia than would be induced by estrogen-alone treatment. However, there is a possible increased risk of breast cancer associated with the use of progestins with estrogens compared to estrogen-alone regimens
Estrogen use may cause elevations in blood pressure; monitor BP regularly during therapy
Estrogen therapy may elevate plasma triglycerides in patients with preexisting hypertriglyceridemia, leading to pancreatitis and other complications
Administer estrogen therapy cautiously in patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy; discontinue therapy in case of recurrence
Estrogen administration causes increased thyroid-binding globulin (TBG) levels. Patients on thyroid hormone replacement therapy, also receiving estrogens, may require increased doses of their thyroid replacement therapy. Monitor thyroid functions regularly in such patients to maintain free thyroid hormone levels in an acceptable range
Estrogens may cause some degree of fluid retention; use cautiously in patients with cardiac or renal dysfunction
Use of estrogen-alone therapy for 10 or more years may increase the risk of ovarian cancer
Endometriosis may be exacerbated in women treated post-hysterectomy with estrogen alone therapy; consider adding progestin to estrogen therapy for patients known to have residual endometriosis post-hysterectomy

Cautions: Use cautiously in

Renal impairment
Cardiovascular diseases
Cardiac disease risk
Smoking
Hypertension
Hypothyroidism
Asthma
Diabetes mellitus
Chorea
Epilepsy
Migraine
Porphyria
Systemic lupus erythematosus
Hepatic hemangiomas
Severe hypocalcemia
Gallbladder disease
Obesity
Patients >65 yrs

Pregnancy/Breast Feeding ⬆ ⬇

Pregnancy Category:X

Breastfeeding: Limited data regarding the use of estradiol during breastfeeding indicate that the amount transferred into breastmilk is influenced by the route of administration and dosage form. Transdermal maternal doses of up to 100 mcg daily produce low levels in milk and are not expected to cause any adverse effects in breastfed infants. Progestin-only contraceptives such as norethindrone are considered the hormonal contraceptives of choice during lactation as it does not adversely affect the composition of milk, the growth and development of the infant or the milk supply. The advantages of using progestin-only contraceptive products generally outweigh the theoretical or proven risks before 4 weeks postpartum. However, it is advisable to give it no sooner than 3 days postpartum when lactation is established. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 14 June 2011). Although estradiol is found to be compatible with breastfeeding, withdrawal bleeding may occur after the drug is withdrawn based upon data from AAP Policy Guidelines (available at http://aappolicy.aappublications.org/cgi/content/full/pediatrics;108/3/776) last accessed 14 June 2011)As per manufacturer's data, estrogen administration to nursing mothers interferes with lactation. Detectable amounts of estrogens and progestins are secreted in breast milk; exercise caution while administering to a nursing woman.

Adverse Reactions ⬆ ⬇

CNS: Headache, insomnia, nervousness, dementia, migraine, chorea exacerbation, seizure exacerbation
PSYCHIATRY: Depression, mood changes
CV: Deep and superficial venous thrombosis, pulmonary embolism, thromboembolism, thrombophlebitis, myocardial infarction, stroke, hypertension, increased triglycerides
GI: Abdominal pain, abdominal bloating, diarrhea, dyspepsia, flatulence, nausea, vomiting, constipation, cholestatic jaundice, gallbladder disease, pancreatitis, ischemic colitis, enlargement of hepatic hemangiomas
GU: Breast pain, dysmenorrhea, leukorrhea, cervical secretion changes, menstrual disorder, vulvovaginal candidiasis, vaginitis, breast enlargement, menorrhagia, vaginal hemorrhage/spotting, breast cancer, ovarian cancer, endometrial cancer, endometrial hyperplasia, uterine fibroid enlargement, libido changes
RESP: Pharyngitis, respiratory disorder, rhinitis, sinusitis, bronchitis, exacerbation of asthma
DERM: Application site reaction, acne, rash, SLE exacerbation, erythema multiforme, erythema nodosum, hair loss, hirsutism, melasma
EENT: Retinal thrombosis, contact lens intolerance, vision changes
METABOLIC: Severe hypercalcemia (metastatic breast cancer), fluid retention, weight changes, peripheral edema
MUSC: Arthralgia, back pain
HYPERSENSITIVITY: Anaphylaxis/anaphylactoid reactions
MISC: Accidental injury, asthenia, flu syndrome, pain, porphyria aggravation

Clinical Pharmacology ⬆ ⬇

Estradiol

Estrogen; binds to nuclear receptors in estrogen-responsive tissues, enhancing DNA, RNA, and protein synthesis. In androgen-dependent prostate cancer, competes for androgen receptor sites, inhibiting androgen activity. Also, decreases pituitary release of follicle-stimulating hormone and luteinizing hormone
Metabolized by liver; CYP450: 3A4 (minor extent) substrate. Also, undergoes enterohepatic recirculation
Excreted in urine along with glucuronide and sulfate conjugates
Half-life: 2-3 hrs

Norethindrone

Progestin; acts by suppression of pituitary gonadotropins, inhibits ovulation, and induces changes in the cervical mucus thereby increasing the difficulty of sperm entry into the uterine cavity and the endometrium, reducing likelihood of implantation
Metabolized primarily in the liver; transdermal administration markedly reduces metabolism
Excretion: Feces, urine
Half-life: 6-8 hrs

Brands and Availability ⬆ ⬇

US Trade Name(s)

Combipatch

US Availability

Combipatch (estradiol/norethindrone)

[0.05 mg/0.14 mg]/24 hrs
[0.05 mg/0.25 mg]/24 hrs

Canadian Trade Name(s)

Estalis 140/50
Estalis 250/50

Canadian Availability

Estalis 140/50 (norethindrone/estradiol)

TDP: [0.14 mg/0.05 mg]/24 hrs

Estalis 250/50 (norethindrone/estradiol)

TDP: [0.25 mg/0.05 mg]/24 hrs

UK Trade Name(s)

Evorel Conti
Evorel Sequi

UK Availability

Evorel Conti (estradiol/norethisterone)

TDP: [0.05 mg/0.17 mg]/24 hrs

Evorel Sequi (estradiol; estradiol/norethisterone)

TDP: 0.05 mg/24 hrs (Evorel); [0.05 mg/0.17 mg]/24 hrs (Evorel Conti)

Australian Trade Name(s)

Estalis Continuous 50/140
Estalis Continuous 50/250
Estalis Sequi 50/140
Estalis Sequi 50/250
Estracombi

Australian Availability

Estalis Continuous 50/140

TDP: [0.05 mg/0.14 mg]/24 hrs

Estalis Continuous 50/250

TDP: [0.05 mg/0.25 mg]/24 hrs

Estalis Sequi 50/140 (estradiol; estradiol/norethindrone)

TDP: 0.05 mg/24 hrs; [0.05 mg/0.14 mg]/24 hrs

Estalis Sequi 50/250 (estradiol; estradiol/norethindrone)

TDP: 0.05 mg/24 hr; [0.05 mg/0.25 mg]/24 hrs

Estracombi (estradiol; estradiol/norethindrone)

TDP: 0.05 mg/24 hrs (Estraderm); [0.05 mg/0.25 mg]/24 hrs (Estragest 50/250)

[Outline]

section name header

Use and Dosing ⬇