Depo-estradiol

Overdose

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

Contraindications

Estrogens should not be used in individuals with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.
2. Known or suspected cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.
5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
6. Liver dysfunction or disease.
7. DEPO-Estradiol (estradiol cypionate injection) should not be used in patients with known hypersensitivity to its ingredients.
8. Known or suspected pregnancy. There is no indication for DEPO-Estradiol (estradiol cypionate injection) in pregnancy.

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

Undesirable effects

See Boxed Warnings, WARNINGS and PRECAUTIONS.

The following additional adverse reactions have been reported with estrogens and/or progestin therapy.

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.

Tenderness, enlargement pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.

Chloasma or melasma that may persist when drug is discontinued. Erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.

Retinal vascular thrombosis; steepening of corneal curvature; intolerance to contact lenses.

Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.

Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido; arthralgias; leg cramps; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides.

Chlorobutanol anhydrous (chloral derivative) added as a preservative may be habit forming.

Depo-Estradiol price

Therapeutic indications

DEPO-Estradiol (estradiol cypionate injection) Injection is indicated in the treatment of:

1. Moderate to severe vasomotor symptoms associated with the menopause.
2. Hypoestrogenism due to hypogonadism.

Name of the medicinal product

Fertility, pregnancy and lactation

DEPO-Estradiol should not be used during pregnancy. See CONTRAINDICATIONS and Boxed Warnings.

Qualitative and quantitative composition

DEPO-Estradiol (estradiol cypionate injection) Injection is available in the following concentration containing per mL:

5 mg estradiol cypionate; also 5.4 mg chlorobutanol anhydrous (chloral deriv.) added as preservative; in 913 mg cottonseed oil— in 5 mL vials, NDC 0009-0271-01.

WARNING: Chlorobutanol may be habit forming.

Store at controlled room temperature 20° to 25° C (68° to 77° F).

REFERENCES

1. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167–1170, 1975.

2. Smith DC, Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164–1167, 1975.

3. Mack TM, Pike MC, Henderson BE, et al: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294:1262–1267, 1976.

4. Weiss NS, Szekely DR, Austin DF: Increasing incidence of endometrial cancer in the United States. N Engl J Med 294:1259–1262, 1976.

5. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881, 1971.

6. Greenwald P, Barlow JJ, Nasca PC, Burnett WS: Vaginal cancer after maternal treatment with synthetic estrogens. N Engl J Med 285:390–392, 1971.

7. Lanier AP, Noller KL, Decker DG, Elveback LR, Kurland LT: Cancer and stilbestrol. A follow-up of 1,719 persons exposed to estrogens in utero and born 1943–1959. Mayo Clin Proc 48:793–799, 1973.

8. Herbst AL, Kurman RJ, Scully RE: Vaginal and cervical abnormalities after exposure to stilbestrol in utero. Obstet Gynecol 40:287–298, 1972.

9. Herbst AL, Robboy SJ, Macdonald GJ, Scully RE: The effects of local progesterone on stilbestrol-associated vaginal adenosis. Am J Obstet Gynecol 118:607–615, 1974.

10. Herbst AL, Poskanzer DC, Robboy SJ, Friedlander L, Scully RE: Prenatal exposure to stilbestrol. A prospective comparison of exposed female offspring with unexposed control. N Engl J Med 292:334–339, 1975.

11. Stafl A, Mattingly RF, Foley DV, Fetherston WC: Clinical diagnosis of vaginal adenosis. Obstet Gynecol 43:118–128, 1974.

12. Sherman AL, Goldrath M, Berlin A, et al: Cervical-vaginal adenosis after in utero exposure to synthetic estrogens. Obstet Gynecol 44:531545, 1974.

13. Gall, Kirman B, Stern J: Hormonal pregnancy tests and congenital malformation. Nature 216:83, 1967.

14. Levy EP, Cohen A, Fraser FC: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973.

15. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941–942, 1973.

16. Janerich DT, Piper JM, Glebatis DM: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697–700, 1974.

17. Boston Collaborative Drug Surveillance Program: Surgically confirmed gall bladder disease, venous thromboembolism, and breast tumors in relation to post-menopausal estrogen therapy. N Engl J Med 290:15–19, 1974.

18. Hoover R, Gray LA, Cole P, MacMahon B: Menopausal estrogens and breast cancer. N Engl J Med 295:401–405, 1976.

19. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gall bladder disease, and breast tumors. Lancet 1:1399–1404, 1973.

20. Daniel DG, Campbell H, Turnbull AC: Puerperal thromboembolism and suppression of lactation. Lancet 2:287–289, 1967.

21. The Veterans Administration Cooperative Urological Research Group: Carcinoma of the prostate: Treatment comparisons. J Urol 98:516522, 1967.

22. Bailar JC: Thromboembolism and estrogen therapy. Lancet 2:560, 1967.

23. Blackard CE, Doe RP, Mellinger GT, Byar DP: Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer 26:249–256, 1970.

24. Royal College of General Practitioners: Oral contraception and thromboembolic disease. J R Coll Gen Pract 13:267–279, 1967.

25. Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of childbearing age. Br Med J 2:193–199, 1968.

26. Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 2:651–657, 1969.

27. Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiologic case-control study. Am J Epidemiol 90:365–380, 1969.

28. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 288:871–878, 1973.

29. Collaborative Group for the Study of Stroke in Young Women: Oral contraceptives and stroke in young women: Associated risk factors. JAMA 231:718–722, 1975.

30. Mann JI, Inman WHW: Oral contraceptives and death from myocardial infarction. Br Med J 2:245–248, 1975.

31. Mann JI, Vessey MP, Thorogood M, Doll R: Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 2:241–245, 1975.

32. Inman WHW, Vessey MP, Westerholm B, Engelund A: Thromboembolic disease and the steroidal content of oral contraceptives. Br Med J 2:203–209, 1970.

33. Stolley PD, Tonascia JA, Tockman MS, et al: Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol 102:197–208, 1975.

34. Vessey MP, Doll R, Fairbairn AS, Glober G: Postoperative thromboembolism and the use of oral contraceptives. Br Med J 3:123–126, 1970.

35. Greene GR, Sartwell PE: Oral contraceptive use in patients with thromboembolism following surgery, trauma or infection. Am J Public Health 62:680–685, 1972.

36. Rosenberg L, Armstrong B, Phil D, Jick H: Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 294:1256–1259, 1976.

37. Coronary Drug Project Research Group: The Coronary Drug Project: Initial findings leading to modifications of its research protocol. JAMA 214:1303–1313, 1970.

38. Baum J, Holtz F, Bookstein JJ, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926–929, 1973.

39. Mays ET, Christopherson WM, Mahr MM, Williams HC: Hepatic changes in young women ingesting contraceptive steroids. Hepatic hemorrhage and primary hepatic tumors. JAMA 235:730–732, 1976.

40. Edmondson HA, Henderson B, Benton B: Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med 294:470–472, 1976.

41. Pfeffer RI, VanDenNoort S: Estrogen use and stroke risk in post-menopausal women. Am J Epidemiol 103:445–456, 1976.

Distributed by: Pharmacia & Upjohn Company, Division of Pfizer Inc, NY, NY 10017. Revised October 2006.

Special warnings and precautions for use

See Boxed Warnings

Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

In the Women's Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

In the Women's Health Initiative (WHI) study, in women receiving CE compared to placebo, the risk of VTE (including both DVT and PE) was increased 33% (28 vs. 21 per 10,000 person-years) although only the increased rate of DVT reached statistical significance (p = 0.03). (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA treatment substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving treatment with CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users was about 2-to-12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15-to-24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen-alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01–1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n= 2,229) and 21 women in the placebo group (0.9%, n= 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogen has been reported.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, require careful observation when estrogens are prescribed.

Estrogens should be used with caution in individuals with severe hypocalcemia.

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 20 versus 12 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe DEPO-Estradiol (estradiol cypionate injection).

Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See Boxed Warnings, WARNINGS and PRECAUTIONS.)

DEPO-Estradiol should not be used during pregnancy. See CONTRAINDICATIONS and Boxed Warnings.

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when DEPO-Estradiol (estradiol cypionate injection) is administered to a nursing woman.

In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n= 3,729) were 65 to 74 while 18% (n= 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

Dosage (Posology) and method of administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.

DEPO-Estradiol (estradiol cypionate injection) INJECTION IS FOR INTRAMUSCULAR USE ONLY.

When estrogen is prescribed for a woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary. (See Boxed Warnings and WARNINGS.) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

1. Short-term cyclic use for treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.
   Attempts to discontinue or taper medication should be made at 3- to 6-month intervals. The usual dosage range is 1 to 5 mg injected every 3 to 4 weeks.
2. For treatment of female hypoestrogenism due to hypogonadism 1.5 to 2 mg injected at monthly intervals.

Interaction with other medicinal products and other forms of interaction

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Estrogen drug products administered by non oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.