Estropipate Side Effects
For the Consumer
Applies to estropipate: oral tablet
What are some side effects that I need to call my doctor about right away?
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
- Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
- Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
- Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
- Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
- Very upset stomach or throwing up.
- Very bad belly pain.
- Dizziness or passing out.
- Change in eyesight.
- Loss of eyesight.
- Bulging eyes.
- Change in how contact lenses feel in the eyes.
- A lump in the breast, breast soreness, or nipple discharge.
- Breast pain.
- Vaginal itching or discharge.
- Vaginal bleeding that is not normal.
- Low mood (depression).
- Mood changes.
- Memory problems or loss.
- Shortness of breath, a big weight gain, or swelling in the arms or legs.
- Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
What are some other side effects of this drug?
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
- Hair loss.
- Upset stomach or throwing up.
- Stomach cramps.
- Tender breasts.
- Vaginal bleeding or spotting.
- Feeling nervous and excitable.
- Weight gain or loss.
- Joint pain.
- Lowered interest in sex.
- This drug may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.
For Healthcare Professionals
Applies to estropipate: oral tablet
Gastrointestinal effects are common and most often include nausea and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy.[Ref]
The increased risk of breast cancer due to use of estrogens is controversial. Several studies have suggested that long-term estrogen therapy may be associated with a slightly increased risk of breast cancer. Meta analysis of 51 studies (epidemiological data) supports a modest risk increase associated with long-term hormone replacement therapy (HRT).
One study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen therapy. In that study, women with more than nine years of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.
The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out.
The Case-Control Surveillance Study has reported that there is "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded."
Follow-up to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)
A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."
A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women who ever used HRT. No association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis (relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5yrs and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5yrs, p = 0.005). The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5yrs and 2.63, CI, 1.18 to 5.89 for > 5yrs). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5yrs was RR = 1.38, CI, 1.03 to 1.85.[Ref]
Use of unopposed estrogen therapy has been associated with an increased risk of endometrial cancer in patients with an intact uterus and less persuasively, with an increased risk of breast cancer.[Ref]
Studies suggest that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35%. Combination therapy with a progestin may also decrease coronary risk. However, the extent of risk reduction with combination therapy has not been determined. Data are available that suggest combination therapy does not reduce the overall rate of coronary heart disease in postmenopausal women with established coronary disease.[Ref]
The reported effects of estrogens on cardiovascular activity are variable. Alterations in lipid profiles in treated women are thought to be responsible for reducing cardiovascular risks. Data suggest estrogen use may increase blood pressure, particularly in patients receiving high doses, decrease blood pressure, or result in no change. In addition, noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Other studies have concluded that no increased risk of myocardial infarction exists.[Ref]
Metabolic effects include generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels occur. Estrogen therapy may lead to increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects.
Endocrine side effects with estrogen use may result in increased levels of thyroxin-binding globulin, leading to an increase in total thyroid serum levels and a decrease in resin uptake of T3. Free thyroid hormone levels remain unchanged. Other endocrine effects include decreased fasting plasma glucose.[Ref]
Estrogens may cause some degree of fluid retention and mastodynia. Alterations in libido have occurred.[Ref]
Rare cases of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas and well-differentiated hepatocellular carcinomas have been reported in association with estrogen therapy. Aggravation of porphyria has been reported.[Ref]
Hypercoagulability has been reported in women taking estrogens, although the clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.[Ref]
Psychiatric side effects associated with estrogen therapy include cases of rapid mood cycling in patients with severe depression.[Ref]
Nervous system side effects include migraine, dizziness, and mental depression.[Ref]
Estrogens may cause abnormal uterine bleeding (which must be carefully distinguished from bleeding related to endometrial carcinoma). In addition, estrogens may increase the size of preexisting uterine leiomyomata.
Several cases of pseudoincontinence (excessive vaginal discharge perceived by patients as urinary incontinence) have been reported in premenopausal who have undergone hysterectomy-oophorectomy and received post-operative estrogens.[Ref]
Ocular side effects of estrogen therapy include alterations in corneal curvature and contact lens discomfort.[Ref]
Dermatologic effects include chloasma or melasma, which may not resolve following discontinuation of estrogen therapy. Scalp hair loss, hirsutism, erythema nodosum, and hemorrhagic eruptions have occurred.[Ref]
1. Boston Collaborative Drug Surveilance Program "Surgically confirmed gallbladder disease, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy." N Engl J Med 290 (1974): 15-9
2. Lozman H, Barlow AL, Levitt DG "Piperazine estrone sulfate and conjugated estrogens equine in the treatment of the menopausal syndrome." South Med J 64 (1971): 1143-9
3. "Product Information. Ortho-Est (estropipate)." Ortho McNeil Pharmaceutical, Raritan, NJ.
4. Obrink A, Bunne G, Collen J, Tjernberg B "Endometrial cancer and exogenous estrogens." Acta Obstet Gynecol Scand 58 (1979): 123
5. Gray LA Sr, Christopherson WM, Hoover RN "Estrogens and endometrial carcinoma." Obstet Gynecol 49 (1977): 385-9
6. Kaufman DW, Palmer JR, de Mouzon J, Rosenberg L, Stolley PD, Warshauer ME, Zauber AG, Shapiro S "Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study." Am J Epidemiol 134 (1991): 1375-85
7. Colditz GA, Hankinson SE, Hunter DJ, et al. "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women." N Engl J Med 332 (1995): 1589-93
8. Gapstur SM, Morrow M, Sellers TA "Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa women's health study." JAMA 281 (1999): 2091-7
9. Antunes CM, Strolley PD, Rosenshein NB, Davies JL, Tonascia JA, Brown C, Burnett L, Rutledge A, Pokempner M, Garcia R "Endometrial cancer and estrogen use. Report of a large case-control study." N Engl J Med 300 (1979): 9-13
10. The Writing Group for the PEPI Trial "Effects of hormone replacement therapy on endometrial histology in postmenopausal women." JAMA 275 (1996): 370-5
11. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C "The risk of breast cancer after estrogen and estrogen-progestin replacement." N Engl J Med 321 (1989): 293-7
12. Thomas DB, Persing JP, Hutchinson WB "Exogenous estrogens and other risk factors for breast cancer in women with benign breast diseases." J Natl Cancer Inst 69 (1982): 1017-25
13. Persson I, Adami HO, Bergkvist L, Lindgren A, Pettersson B, Hoover R, Schairer C "Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study." BMJ 298 (1989): 147-51
14. Palmer JR, Rosenberg L, Clarke EA, Miller DR, Shapiro S "Breast cancer risk after estrogen replacement therapy: results from the Toronto Breast Cancer Study." Am J Epidemiol 134 (1991): 1386-95
15. Spengler RF, Clarke EA, Woolever CA, Newman AM, Osborn RW "Exogenous estrogens and endometrial cancer: a case-control study and assessment of potential biases." Am J Epidemiol 114 (1981): 497-506
16. Gordon J, Reagan JW, Finkle WD, Ziel HK "Estrogen and endometrial carcinoma. An independent pathology review supporting original risk estimate." N Engl J Med 297 (1977): 570-1
17. Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA "Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women." JAMA 274 (1995): 137-42
18. Grady D, Rubin SM, Petiti DB, et al. "Hormone therapy to prevent disease and prolong life in postmenopausal women." Ann Intern Med 117 (1992): 1016-36
19. Rosenberg L, Slone D, Shapiro S, Kaufman D, Stolley PD, Miettinen OS "Noncontraceptive estrogens and myocardial infarction in young women." JAMA 244 (1980): 339-42
20. Barrett-Connor E, Wingard DL, Criqui MH "Postmenopausal estrogen use and heart disease risk factors in the 1980s. Rancho Bernardo, Calif, revisited." JAMA 261 (1989): 1095-2100
21. Jick H, Dinan B, Rothman KJ "Noncontraceptive estrogens and nonfatal myocardial infarction." JAMA 239 (1978): 1407-8
22. Collins P, Beale CM, Rosano GMC "Oestrogen as a calcium channel blocker." Eur Heart J 17 ( Suppl (1996): 27-31
23. Devor M, Barrett-Connor E, Renvall M, Feigal D, Ramsdell J "Estrogen replacement therapy and the risk of venous thrombosis." Am J Med 92 (1992): 275-81
24. Schwartz J, Freeman R, Frishman W "Clinical pharmacology of estrogens: cardiovascular actions and cardioprotective benefits of replacement therapy in postmenopausal women." J Clin Pharmacol 35 (1995): 1-16
25. Isaacs AJ, Havard CW "Effect of piperazine oestrone sulphate on serum lipids and lipoproteins in menopausal women." Acta Endocrinol (Copenh) 85 (1977): 143-50
26. The Writing Group for the PEPI Trial "Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial." JAMA 273 (1995): 199-208
27. Bagdade JD, Subbaiah PV "Effects of estropipate treatment on plasma lipids and lipoprotein lipid composition in postmenopausal women." J Clin Endocrinol Metab 72 (1991): 283-6
28. Stampfer MJ, Colditz GA, Willett WC, et al. "Postmenopausal estrogen and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study." N Engl J Med 325 (1991): 756-62
29. Barrett-Connor E, Bush TL "Estrogen and coronary heart disease in women." JAMA 265 (1991): 1861-7
30. Crane MG, Harris JJ "Estrogens and hypertension: effect of discontinuing estrogens on blood pressure, exchangeable sodium, and the renin-aldosterone system." Am J Med Sci 276 (1978): 33-55
31. Wren BG, Routledge DA "Blood pressure changes: oestrogens in climacteric women." Med J Aust 2 (1981): 528-31
32. Lagrelius A, Johnson P, Lunell NO, Samsioe G "Treatment with oral estrone sulphate in the female climacteric. I. Influence on lipids." Acta Obstet Gynecol Scand 60 (1981): 27-31
33. Molitch ME, Oill P, Odell WD "Massive hyperlipemia during estrogen therapy." JAMA 227 (1974): 522-5
34. Conter RL, Longmire WP Jr "Recurrent hepatic hemangiomas. Possible association with estrogen therapy." Ann Surg 207 (1988): 115-9
35. Aldinger K, Ben-Menachem Y, Whalen G "Focal nodular hyperplasia of the liver associated with high-dosage estrogens." Arch Intern Med 137 (1977): 357-9
36. Poller L, Thomson JM, Coope J "A double-blind cross-over study of piperazine oestrone sulphate and placebo with coagulation studies." Br J Obstet Gynaecol 87 (1980): 718-25
37. Pastides H, Najjar MA, Kelsey JL "Estrogen replacement therapy and fibrocystic breast disease." Am J Prev Med 3 (1987): 282-6
38. Oppenheim G "A case of rapid mood cycling with estrogen: implications for therapy." J Clin Psychiatry 45 (1984): 34-5
39. Steiger MJ, Quinn NP "Hormone replacement therapy induced chorea." BMJ 302 (1991): 762
40. Julian TM "Pseudoincontinence secondary to unopposed estrogen replacement in the surgically castrate premenopausal female." Obstet Gynecol 70 (1987): 382-3
Some side effects may not be reported. You may report them to the FDA.
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