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Estrogens / Progestins , Oral

(Combination Products)

Pronunciation: ES-troe-jenz proe-JES-tinz
Class: Estrogen and progestin combined

Trade Names

- Tablets estradiol 0.5 mg/norethindrone 0.1 mg
- Tablets estradiol 1 mg/norethindrone 0.5 mg

- Tablets estradiol 1 mg/drospirenone 0.5 mg

- Tablets ethinyl estradiol 2.5 mcg/norethindrone 0.5 mg
- Tablets ethinyl estradiol 5 mcg/norethindrone 1 mg

- Tablets estradiol 1 mg/norethindrone 0.5 mg

- Tablets estradiol 1 mg and estradiol 1 mg/norgestimate 0.09 mg

- Tablets conjugated estrogens 0.625 mg and conjugated estrogens 0.625 mg/medroxyprogesterone 5 mg

- Tablets conjugated estrogens 0.3 mg/medroxyprogesterone 1.5 mg
- Tablets conjugated estrogens 0.45 mg/medroxyprogesterone 1.5 mg
- Tablets conjugated estrogens 0.625 mg/medroxyprogesterone 2.5 mg
- Tablets conjugated estrogens 0.625 mg/medroxyprogesterone 5 mg


Estrogens act to reduce elevated levels of the gonadotropins, luteinizing hormone, and follicle-stimulating hormone found in postmenopausal women. Progestins enhance cellular differentiation and generally oppose the action of estrogens.

Indications and Usage

Moderate to severe vasomotor symptoms associated with menopause; moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause (except Femhrt and Activella 0.5 mg/0.1 mg); prevention of postmenopausal osteoporosis (except Angeliq ).


Active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or recent (eg, within past year) arterial thromboembolic disease (eg, MI, stroke); adrenal insufficiency ( Angeliq only); hypersensitivity to any component of the product; known or suspected estrogen-dependent neoplasia; known or suspected pregnancy; known, suspected, or a history of cancer of the breast; liver dysfunction or disease; renal insufficiency ( Angeliq only); undiagnosed abnormal genital bleeding.

Dosage and Administration

Activella , Angeliq , Femhrt , Mimvey , Prempro

PO 1 tablet daily.


PO One estradiol 1 mg tablet (peach) daily for 3 days, followed by one estradiol 1 mg/norgestimate 0.09 mg tablet (white) daily for 3 days. Repeat regimen continuously without interruption.


PO One conjugated estrogen 0.625 mg tablet (maroon) daily on days 1 to 14 followed by one conjugated estrogen 0.625 mg/medroxyprogesterone 5 mg tablet (light blue) daily on days 15 to 28.


Store between 68° and 77°F.

Drug Interactions


Acitretin may interfere with the pharmacologic effects of progestins.

ACE inhibitors (eg, captopril), angiotensin blockers (eg, losartan), NSAIDs (eg, ibuprofen), potassium-sparing diuretics (eg, spironolactone)

In estrogen/progestin combinations containing drospirenone, serum potassium concentrations may be elevated, increasing the risk of hyperkalemia. Patients with underlying impaired renal function may be at a higher risk for hyperkalemia. Monitor serum potassium concentrations.


Estrogen/progestin plasma concentrations and pharmacologic effects may be decreased by aprepitant, reducing the efficacy.

Beta-blockers (eg, metoprolol, propranolol)

The pharmacologic effects of beta-blockers may be increased. Monitor patient response; adjust the beta-blocker dose as needed.

Corticosteroids (eg, prednisolone)

Corticosteroid plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Monitor for signs of corticosteroid toxicity (cushingoid facies, fluid retention, weight gain); reduce the corticosteroid dose if necessary.


Cyclosporine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity (eg, nephrotoxicity). Monitor serum cyclosporine concentrations as well as renal and liver function for evidence of cyclosporine toxicity. Adjust the cyclosporine dose as needed.

CYP3A4 inducers (eg, barbiturates [eg, phenobarbital], carbamazepine, efavirenz, modafinil, rifampin, rufinamide, St. John's wort)

Coadministration may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.

CYP3A4 inhibitors (eg, azole antifungals [eg, itraconazole, ketoconazole], grapefruit juice, macrolide antibiotics [eg, clarithromycin, erythromycin], protease inhibitors [eg, ritonavir])

Coadministration may increase plasma concentrations of estrogens, increasing the risk of adverse reactions. Monitor for estrogen-related adverse reactions.

Felbamate, griseofulvin, penicillins (eg, ampicillin), pioglitazone, tetracyclines

These agents may decrease the pharmacologic effects of estrogen/progestin combinations.

Hydantoins (eg, phenytoin)

Hydantoins may decrease the pharmacologic effects of estrogen/progestin combinations. In addition, hydantoin concentrations may be altered. Adjust the hydantoin dose as needed.


Lamotrigine plasma concentrations may be reduced, decreasing the pharmacologic effects. Adjust the lamotrigine dose as needed.


Nevirapine may decrease the pharmacologic effects of estrogen/progestin combinations. Coadministration is not recommended.

Selegiline, tacrine, tacrolimus, tizanidine

Estrogen/progestin combinations may elevate the plasma concentrations of these agents, increasing the pharmacologic effects and risk of adverse reactions. Monitor closely; adjust the dose of these agents as needed.

Theophyllines (eg, aminophylline)

Theophylline plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity (eg, nausea, vomiting, CV instability, seizures). Monitor theophylline concentrations and the patient for signs of theophylline toxicity; adjust the theophylline dose as needed.


Cl of estrogen from plasma is increased by topiramate at dosages greater than 200 mg/day. Cl of progestin does not appear to be affected.

Tranexamic acid

The risk of estrogen/progestin-related thrombotic events may be increased. Coadministration of tranexamic acid with an estrogen/progestin combination should be limited to patients with a strong medical need in whom the potential benefits outweigh the increased risk of a thrombotic event.

Valproic acid

Valproic acid plasma concentrations may be reduced, decreasing the pharmacologic effects and increasing the risk of seizures. Monitor patient and valproic acid concentrations; adjust the valproic acid dose as needed.

Laboratory Test Interactions

Impaired glucose tolerance.


Antithrombin III activity; levels of anti-factor Xa and antithrombin III; free hormone concentrations; LDL; response to metyrapone test; T3 resin uptake.


PTT, platelet aggregation time, and PT; platelet count; factors II, VII antigen, VIII antigen, VIII coagulation activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta thromboglobulin; levels of fibrinogen and fibrinogen activity; plasminogen antigen and activity; thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone (as measured by protein-bound iodine, T4 or T3); corticosteroid binding globulin; sex hormone–binding globulin; angiotensinogen/renin substrate, alpha-1 antitrypsin, ceruloplasmin; HDL, HDL2, and triglyceride levels.

Adverse Reactions


Deep and superficial venous thrombosis, increase in BP, MI, pulmonary embolism, stroke, thrombophlebitis.


Headache (37%); depression (11%); asthenia (10%); insomnia (7%); emotional lability, fatigue (6%); anxiety, dizziness, nervousness (5%); hypertonia (4%); chorea, exacerbation of epilepsy, growth potentiation of benign meningioma, irritability, migraine, mood disturbances, probable dementia.


Pruritus (10%); rash (6%); acne, chloasma or melasma (may persist when drug is discontinued), erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, itching, loss of scalp hair, seborrhea, urticaria.


Intolerance of contact lenses, retinal vascular thrombosis.


Abdominal pain (23%); nausea (11%); flatulence (9%); dyspepsia (8%); diarrhea, enlarged abdomen, nausea and/or vomiting (7%); gastroenteritis (6%); tooth disorder (5%); bloating, changes in appetite, cholestatic jaundice, enlargement of hepatic hemangiomas, gallbladder disease, ischemic colitis, pancreatitis.


Breast pain (38%); vaginal hemorrhage (26%); dysmenorrhea (13%); postmenopausal bleeding (11%); endometrial thickening (10%); leukorrhea, vaginal bleeding (9%); vaginal/genital moniliasis (8%); ovarian cyst, vaginitis (7%); UTI (6%); breast enlargement, cervix disorder, pelvic pain, uterine fibroid (5%); endometrial disorder (2%); abnormal uterine bleeding, abnormal withdrawal bleeding or flow, amenorrhea, breakthrough bleeding, breast cancer, breast tenderness, change in cervical secretion, changes in cervical ectropion, changes in libido, changes in vaginal bleeding pattern, cystitis-like syndrome, endometrial cancer, endometrial hyperplasia, fibrocystic breast changes, galactorrhea, increase in size of uterine leiomyomata, nipple discharge, ovarian cancer, spotting, vaginal candidiasis.


Anaphylactoid/anaphylactic reactions, hypersensitivity.


Weight increase (9%); peripheral edema (4%); edema, glucose intolerance, hypocalcemia, increased triglycerides, reduced carbohydrate tolerance, weight decrease.


Arthralgia (13%); leg cramps (7%); myalgia (5%).


Nasopharyngitis, upper respiratory tract infection (21%); sinusitis (15%); pharyngitis (13%); cough, rhinitis (8%); exacerbation of asthma.


Pain (20%); infection (18%); accidental injury (17%); back pain (16%); flu syndrome (13%); viral infection (9%); pain in extremity (8%); surgery (5%); aggravation of porphyria, angioedema.



Do not use estrogens and progestins for prevention of CV disease or dementia. The Women's Health Initiative study reported increased risks of MI, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5.6 y of treatment with oral conjugated estrogens combined with medroxyprogesterone. In addition, increased risk of developing probable dementia in postmenopausal women 65 y of age and older during 5.2 y of treatment with conjugated estrogens alone and during 4 y of treatment with oral conjugated estrogens plus medroxyprogesterone was reported. Because of these risks, prescribe estrogens with or without progestins at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.


Reevaluate patients as clinically appropriate (eg, 3 to 6 mo intervals) to determine if treatment is still necessary. Monitor BP at regular intervals; monitor blood glucose levels in patients with diabetes. For patients with hypothyroidism, monitor thyroid function. For patients taking Angeliq , consider checking potassium levels during the first treatment cycle in patients predisposed to hyperkalemia.


Category X . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins in oral contraceptives inadvertently during early pregnancy.


Secreted in breast milk. Estrogens decrease the quantity and quality of breast milk.


Not indicated for use in children.

Hepatic Function

Estrogens may be poorly metabolized in patients with liver impairment. Drospirenone Cl may be decreased. Use with caution in patients with history of cholestatic jaundice associated with past estrogen use or pregnancy.

Special Risk Patients

Use with caution in patients with asthma, diabetes mellitus, epilepsy, hepatic hemangiomas, migraine, porphyria, and systemic lupus erythematosus. Estrogens may exacerbate these conditions.

Elevated BP

Substantial increases in BP have been attributed to idiosyncratic reactions to estrogens.

Endometrial hyperplasia in women with intact uteri

Addition of a progestin for 10 or more days of a cycle of estrogen or daily with estrogen has lowered incidence of endometrial hyperplasia.


May be exacerbated.

Fluid retention

Carefully monitor patients with conditions that might be influenced by fluid retention (eg, cardiac or renal dysfunction) because estrogen/progestin therapy may cause fluid retention.

Gallbladder disease

The risk of gallbladder disease requiring surgery is increased 2- to 4-fold.


Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases.


Do not use Angeliq in patients with conditions that predispose them to hyperkalemia (eg, adrenal insufficiency, hepatic or renal impairment).


In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations in plasma triglycerides, leading to pancreatitis. Consider discontinuation if pancreatitis occurs.


Use with caution in patients with hypoparathyroidism as estrogen-induced hypocalcemia may occur.


Risk may be increased by Angeliq (drospirenone).


Estrogen use may lead to increased TBG levels. Monitor thyroid function in patients with hypothyroidism.

Malignant neoplasms

Unopposed estrogen therapy in women with a uterus has been reported to increase the risk of endometrial cancer, which is related to the dose and duration of estrogen therapy. Risk of breast cancer and ovarian cancer may also be increased.

Visual abnormalities

Retinal vascular thrombosis has been reported. Discontinue medication pending examination if sudden partial or complete vision loss, or a sudden onset of diplopia, migraine, or proptosis occurs.



Abdominal pain, breast tenderness, drowsiness/fatigue, nausea, vomiting, withdrawal bleeding in women.

Patient Information

  • Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their health care provider as soon as possible.
  • Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy, including CV disorders, malignant neoplasms, and probable dementia.
  • Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy, such as breast pain and tenderness, headache, nausea, and vomiting.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.