How long does it take for premarin to work?

Premarin

SIDE EFFECTS

The following serious adverse reactions are discussed elsewhere in labeling:

  • Cardiovascular Disorders
  • Malignant Neoplasms

Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.

Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.

Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary system

Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.

Breasts

Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.

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

Gastrointestinal

Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.

Skin

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

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central nervous system

Headache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

Miscellaneous

Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.

Read the entire FDA prescribing information for Premarin (Conjugated Estrogens)

Premarin Side Effects

1. 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

2. Collins P, Beale CM, Rosano GMC “Oestrogen as a calcium channel blocker.” Eur Heart J 17 ( Suppl (1996): 27-31

3. Grady D, Wenger NK, Herrington D, et al. “Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the heart and estrogen replacement study.” Ann Intern Med 132 (2000): 689-96

4. Kamali P, Muller T, Lang U, Clapp JF “Cardiovascular responses of perimenopausal women to hormonal replacement therapy.” Am J Obstet Gynecol 182 (2000): 17-22

5. 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

6. Barrett-Connor E, Bush TL “Estrogen and coronary heart disease in women.” JAMA 265 (1991): 1861-7

7. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH “Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.” JAMA 287 (2002): 2668-76

8. 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

9. Wren BG, Routledge DA “Blood pressure changes: oestrogens in climacteric women.” Med J Aust 2 (1981): 528-31

10. Herrington DM, Reboussin DM, Brosniham KB, et al. “Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.” N Engl J Med 343 (2000): 522-9

14. “Product Information. Premarin (conjugated estrogens).” Wyeth-Ayerst Laboratories, Philadelphia, PA.

15. Jick H, Dinan B, Rothman KJ “Noncontraceptive estrogens and nonfatal myocardial infarction.” JAMA 239 (1978): 1407-8

16. Cerner Multum, Inc. “Australian Product Information.” O 0

17. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

18. Pripp U, Hall G, Csemiczky G, Eksborg S, Landgren BM, SchenckGustafsson K “A randomized trial on effects of hormone therapy on ambulatory blood pressure and lipoprotein levels in women with coronary artery disease.” J Hypertens 17 (1999): 1379-86

19. Miller J, Chan BK, Nelson HD “Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. preventive services task force.” Ann Intern Med 136 (2002): 680-90

20. Petitti DB “Hormone replacement therapy and heart disease prevention: experimentation trumps observation.” JAMA 280 (1998): 650-2

21. “Product Information. Enjuvia (conjugated estrogens).” Barr Pharmaceuticals Inc, Pomona, NY.

23. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E “Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.” JAMA 280 (1998): 605-13

24. Herrington DM “The HERS Trial results: paradigms lost?” Ann Intern Med 131 (1999): 463-6

25. Mendelsohn ME, Karas RH “The protective effects of estrogen on the cardiovascular system.” N Engl J Med 340 (1999): 1801-11

26. Sidney S, Petitti DB, Quesenberry CP “Myocardial infarction and the use of estrogen and estrogen-progestogen in postmenopausal women.” Ann Intern Med 127 (1997): 501-8

27. 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

28. 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

29. Belchetz PE “Hormonal treatment of postmenopausal women.” N Engl J Med 330 (1994): 1062-71

30. 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

31. McClennan BL “Ischemic colitis secondary to Premarin: report of a case.” Dis Colon Rectum 19 (1976): 618-20

32. Perusse R, Morency R “Oral pigmentation induced by Premarin.” Cutis 48 (1991): 61-4

33. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T “Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women.” Circulation 106 (2002): 1771-6

34. Gambacciani M, Ciaponi M, Cappagli B, Genazzani AR “Effects of low-dose continuous combined conjugated estrogens and medroxyprogesterone acetate on menopausal symptoms, body weight, bone density, and metabolism in postmenopausal women.” Am J Obstet Gynecol 185 (2001): 1180-5

35. OrrWalker BJ, Horne AM, Evans MC, Grey AB, Murray MAF, McNeil AR, Reid IR “Hormone replacement therapy causes a respiratory alkalosis in normal postmenopausal women.” J Clin Endocrinol Metab 84 (1999): 1997-2001

36. Civitelli R, Pilgram TK, Dotson M, et al. “Alveolar and Postcranial Bone Density in Postmenopausal Women Receiving Hormone/Estrogen Replacement Therapy: A Randomized, Double-blind, Placebo-Controlled Trial.” Arch Intern Med 162 (2002): 1409-15

37. Steiger MJ, Quinn NP “Hormone replacement therapy induced chorea.” BMJ 302 (1991): 762

38. Jick SS, Walker AM, Jick H “Conjugated estrogens and fibrocystic breast disease.” Am J Epidemiol 124 (1986): 746-51

39. Pastides H, Najjar MA, Kelsey JL “Estrogen replacement therapy and fibrocystic breast disease.” Am J Prev Med 3 (1987): 282-6

40. Oppenheim G “A case of rapid mood cycling with estrogen: implications for therapy.” J Clin Psychiatry 45 (1984): 34-5

41. 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

42. Conter RL, Longmire WP Jr “Recurrent hepatic hemangiomas. Possible association with estrogen therapy.” Ann Surg 207 (1988): 115-9

44. Caucino JA, Armenaka M, Rosenstreich DL “Anaphylaxis associated with a change in premarin dye formulation.” Ann Allergy 72 (1994): 33-5

45. 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

46. 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

47. Buring JE, Bain CJ, Ehrmann RL “Conjugated estrogen use and risk of endometrial cancer.” Am J Epidemiol 124 (1986): 434-41

48. 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

49. 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

50. Ziel HK, Finkle WD “Increased risk of endometrial carcinoma among users of conjugated estrogens.” N Engl J Med 293 (1975): 1167-70

51. 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

52. Woodruff JD, Pickar JH “Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone.” Am J Obstet Gynecol 170 (1994): 1213-23

53. Obrink A, Bunne G, Collen J, Tjernberg B “Endometrial cancer and exogenous estrogens.” Acta Obstet Gynecol Scand 58 (1979): 123

54. Shapiro S, Kelly JP, Rosenberg L, Kaufman DW, Helmrich SP, Rosenshein NB, Lewis JL Jr, Knapp RC, Stolley PD, Schottenfeld D “Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens.” N Engl J Med 313 (1985): 969-72

55. 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

56. 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

57. Gray LA Sr, Christopherson WM, Hoover RN “Estrogens and endometrial carcinoma.” Obstet Gynecol 49 (1977): 385-9

59. The Writing Group for the PEPI Trial “Effects of hormone replacement therapy on endometrial histology in postmenopausal women.” JAMA 275 (1996): 370-5

60. 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

62. 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

Premarin 0.625 mg Coated Tablets

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

1. Medical examination/Follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual women. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast Cancer’ below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

2. Conditions that need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Premarin, in particular:− Leiomyoma (uterine fibroids) or endometriosis− Risk factors for thromboembolic disorders (see below)− Risk factors for estrogen dependent tumours (e.g. first degree heredity for breast cancer)− Hypertension− Liver disorders (e.g. liver adenoma)− Diabetes mellitus with or without vascular involvement− Cholelithiasis− Migraine or (severe) headaches− Systemic lupus erythematosus (SLE)− A history of endometrial hyperplasia (see below)− Epilepsy− Asthma− Otosclerosis

3. Reasons for immediate withdrawal of therapy

Therapy should be discontinued if a contra-indication is discovered and in the following situations:− Jaundice or deterioration in liver function− Significant increase in blood pressure− New onset of migraine-type headache− Pregnancy

4. Endometrial Hyperplasia and Carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. For oral doses of conjugated equine estrogens >0.625 mg the endometrial safety of added progestogens has not been demonstrated. The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see ‘Breast Cancer’ below and section 4.8). Breakthrough bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.Unopposed estrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).

5. Breast Cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.The Women’s Health Initiative trial (WHI) found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

6. Ovarian Cancer

Ovarian cancer is much rarer than breast cancer.Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).

7. Venous thromboembolism

Hormone replacement therapy (HRT) is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >30kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.As in all postoperative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

8. Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

9. Ischaemic Stroke

Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).

Other Conditions

10. Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. 11. The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes. Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.12. A worsening of glucose tolerance may occur in patients taking estrogens and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy. 13. There is an increase in the risk of gallbladder disease in women receiving HRT (see Conditions that need supervision).14.Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.15.Estrogens should be used with caution in individuals with severe hypocalcaemia.16.HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.17. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema. 18. Laboratory monitoringEstrogen administration should be guided by clinical response rather than by hormone levels (e.g., estradiol, FSH). 19. This product contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

PREMARIN® (conjugated estrogens) vaginal cream Information for Patients

What is PREMARIN Vaginal Cream?

PREMARIN Vaginal Cream is a medicine that contains a mixture of estrogen hormones.

What is PREMARIN Vaginal Cream used for?

PREMARIN Vaginal Cream is used after menopause to:

  • Treat menopausal changes in and around the vagina
    You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN Vaginal Cream to control these problems.
  • Treat painful intercourse caused by menopausal changes of the vagina

Who should not use PREMARIN Vaginal Cream?

Do not start using PREMARIN Vaginal Cream if you:

  • Have unusual vaginal bleeding
  • Currently have or have had certain cancers
    Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use PREMARIN Vaginal Cream.
  • Had a stroke or heart attack
  • Currently have or have had blood clots
  • Currently have or have had liver problems
  • Have been diagnosed with a bleeding disorder
  • Are allergic to PREMARIN Vaginal Cream or any of its ingredients
    See the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.
  • Think you may be pregnant

Tell your healthcare provider:

  • If you have unusual vaginal bleeding
    Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
  • About all of your medical problems
    Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
  • About all the medicines you take
    This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN Vaginal Cream works. PREMARIN Vaginal Cream may also affect how your other medicines work.
  • If you are going to have surgery or will be on bedrest
    You may need to stop using PREMARIN Vaginal Cream.
  • If you are breast feeding
    The estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.

How should I use PREMARIN Vaginal Cream?

PREMARIN Vaginal Cream is a cream that you place in your vagina with the applicator provided with the cream.

  • Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you
  • Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with PREMARIN Vaginal Cream

• Step 1. Remove cap from tube. • Step 2. Screw nozzle end of applicator onto tube (Figure A).

Figure A

Step 3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator to measure the correct dose, as prescribed by your healthcare provider (Figure B).

Figure B

Step 4. Unscrew applicator from tube. Step 5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position (Figure C).

Figure C

Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water (Figure D).
DO NOT BOIL OR USE HOT WATER.

Figure D

What are the possible side effects of PREMARIN Vaginal Cream?

PREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated with oral estrogens should be taken into account.

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

  • Heart attack
  • Stroke
  • Blood clots
  • Dementia
  • Breast cancer
  • Cancer of the lining of the uterus (womb)
  • Cancer of the ovary
  • High blood pressure
  • High blood sugar
  • Gallbladder disease
  • Liver problems
  • Enlargement of benign tumors of the uterus (“fibroids”)
  • Severe allergic reaction

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

  • New breast lumps
  • Unusual vaginal bleeding
  • Changes in vision or speech
  • Sudden new severe headaches
  • Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
  • Swollen lips, tongue or face
  • Less serious, but common side effects include:
  • Headache
  • Breast pain
  • Irregular vaginal bleeding or spotting
  • Stomach or abdominal cramps, bloating
  • Nausea and vomiting
  • Hair loss
  • Fluid retention
  • Vaginal yeast infection
  • Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation, and itching

These are not all the possible side effects of PREMARIN Vaginal Cream. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of getting a serious side effect with PREMARIN Vaginal Cream?

  • Talk with your healthcare provider regularly about whether you should continue using PREMARIN Vaginal Cream
  • If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you
    The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using PREMARIN Vaginal Cream.
  • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else
    If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
  • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease
    Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about the safe and effective use of PREMARIN Vaginal Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed. Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms you have. It may harm them.

Keep PREMARIN Vaginal Cream out of the reach of children.

Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they come into contact with PREMARIN Vaginal Cream.

This leaflet provides a summary of the most important information about PREMARIN Vaginal Cream. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about PREMARIN Vaginal Cream that is written for health professionals.

What are the ingredients in PREMARIN Vaginal Cream?

PREMARIN Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components, including sodium sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. PREMARIN Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil.

PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated estrogens, USP.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0519-6.0
Rev 09/2018

Premarin Cream Online Prescription

  • Request Premarin cream online
  • Same day prescriptions available
  • Fast and private

Premarin – Summary

Premarin is a medication that contains conjugated estrogens and is used in the management of several women’s health issues. Women who need a Premarin prescription can use Push Health to connect with a medical provider who can prescribe Premarin, including Premarin cream, when appropriate and safe to do so.

How To Use Premarin Cream

Premarin, available in both cream and tablet form, is a medication that contains conjugated estrogens. Premarin vaginal cream is indicated for the treatment of atrophic vaginitis and some cases of dyspareunia related to vulvar and vaginal atrophy secondary to menopause. Generally speaking, estrogens help maintain the female reproductive system – a balance which changes after menopause. To use Premarin vaginal cream, the cap needs to be removed from the tube after which the applicator is screwed onto the tube. After that, the Premarin vaginal cream is squeezed into the barrel after which the applicator is inserted into the vagina and the plunger is depressed. The package insert that comes with Premarin vaginal cream should be utilized for exact instructions on the best way to administer Premarin cream prior to use.

Premarin Cream – Coupon and Dosage

Premarin cream is expensive, costing up to $370 for Premarin cream 0.625 mg / g (30 gram tube). Premarin coupons are available online at times from the manufacturer or various sources. Also, some insurance plans may cover some or all of the costs related to a Premarin vaginal cream prescription. In some regimens, Premarin is prescribed intravaginally in doses starting at 0.5 g daily for 21 days with a break for 7 days after that. The estrogens in Premarin vaginal cream are well absorbed. Premarin cream should generally be stored at 20° C to 25° C.

Can I Buy Premarin Cream Online?

One cannot just buy Premarin cream online in the United States as it is a prescription medication. As such, Premarin vaginal cream is not available over-the-counter (OTC), either. Instead, the first step to getting Premarin cream is getting a prescription from a medical provider. Push Health can connect people who might need a Premarin cream prescription with licensed medical providers who can prescribe Premarin when safe and appropriate to do so.

Premarin Cream – Side Effects

Side effects related to the use of Premarin cream include headache, back pain, flu-like syndrome, mood changes, infection and pharyngitis. Other side effects from Premarin vaginal cream use include elevated blood pressure, high triglyceride levels, fluid retention and hypothyroidism. Premarin use can increase the risk of cancer, dementia, stroke, deep vein thrombosis, pulmonary embolism, myocardial infarction in certain women. Premarin and alcohol should not be used together. People who have had a hypersensitivity or allergic reaction to Premarin or similar medications should not use it. A number of other contraindications to Premarin use exist and, prior to using Premarin, concerns and possible side effects should be discussed with a pharmacist and one’s medical provider.

More Premarin Cream Information

Last updated August 10, 2019. Given the evolving nature of medicine and science, this information might not be accurate and should not be construed as medical advice or diagnosis / treatment recommendations. Please consult a licensed medical provider if you have additional questions.

Generic Name: conjugated estrogens (oral) (KON joo gay ted ES troe jenz)
Brand Names: Enjuvia, Premarin

Medically reviewed by Sanjai Sinha, MD Last updated on Mar 1, 2019.

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What is Premarin?

Premarin tablets contain conjugated estrogens, a mixture of estrogen hormones. Estrogen is a female sex hormone produced by the ovaries. Estrogen is necessary for many processes in the body.

Premarin is used to treat menopause symptoms such as hot flashes and vaginal changes, and to prevent osteoporosis (bone loss) in menopausal women.

Premarin is also used to replace estrogen in women with ovarian failure or other conditions that cause a lack of natural estrogen in the body.

Do not use if you are pregnant.

Premarin may increase your risk of developing a condition that may lead to uterine cancer. Report any unusual vaginal bleeding right away.

Using this medicine can increase your risk of blood clots, stroke, or heart attack, or cancer of the breast, uterus, or ovaries. Estrogen should not be used to prevent heart disease, stroke, or dementia.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using Premarin.

Before taking this medicine

You should not use Premarin if you have:

  • unusual vaginal bleeding that has not been checked by a doctor;

  • liver disease;

  • a history of heart attack, stroke, or blood clot;

  • an increased risk of having blood clots due to a heart problem or a hereditary blood disorder; or

  • a history of hormone-related cancer, or cancer of the breast, uterus/cervix, or vagina.

Do not use Premarin if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

Using this medicine can increase your risk of blood clots, stroke, or heart attack. You are even more at risk if you have high blood pressure, diabetes, high cholesterol, if you are overweight, or if you smoke.

Estrogen should not be used to prevent heart disease, stroke, or dementia. This medicine may actually increase your risk of developing these conditions.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

  • a hysterectomy;

  • heart disease;

  • liver problems, or jaundice caused by pregnancy or taking hormones;

  • kidney disease;

  • gallbladder disease;

  • asthma;

  • epilepsy or other seizure disorder;

  • migraines;

  • lupus;

  • endometriosis or uterine fibroid tumors;

  • hereditary angioedema;

  • porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

  • a thyroid disorder; or

  • high levels of calcium in your blood.

Use of Premarin may increase your risk of cancer of the breast, uterus, or ovaries. Talk with your doctor about this risk.

Estrogen lowers the hormone needed to produce breast milk and can slow breast milk production. Tell your doctor if you are breast-feeding.

How should I take Premarin?

Take Premarin exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger amounts or for longer than recommended.

Premarin may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to take while you are using Premarin, to help lower this risk. Report any unusual vaginal bleeding right away.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Premarin is sometimes taken on a daily basis. For certain conditions, the medicine is given in a cycle, such as 3 weeks on followed by 1 week off. Follow your doctor’s instructions.

If you see what looks like part of a conjugated estrogen tablet in your stool, talk with your doctor.

Your doctor should check your progress on a regular basis to determine whether you should continue this treatment. Self-examine your breasts for lumps on a monthly basis, and have regular mammograms.

If you need major surgery or will be on long-term bed rest, you may need to stop using this medicine for a short time. Any doctor or surgeon who treats you should know that you are using Premarin.

Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Premarin?

Avoid smoking. It can greatly increase your risk of blood clots, stroke, or heart attack while using conjugated estrogens.

Grapefruit and grapefruit juice may interact with conjugated estrogens and lead to unwanted side effects. Avoid the use of grapefruit products.

Premarin side effects

Get emergency medical help if you have signs of an allergic reaction to Premarin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • heart attack symptoms – chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

  • signs of a stroke – sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

  • signs of a blood clot – sudden vision loss, stabbing chest pain, feeling short of breath, coughing up blood, pain or warmth in one or both legs;

  • swelling or tenderness in your stomach;

  • jaundice (yellowing of the skin or eyes);

  • memory problems, confusion, unusual behavior;

  • unusual vaginal bleeding, pelvic pain;

  • a lump in your breast; or

  • high levels of calcium in your blood – nausea, vomiting, constipation, increased thirst or urination, muscle weakness, bone pain, lack of energy.

Common Premarin side effects may include:

  • nausea, gas, stomach pain;

  • headache, back pain;

  • depression, sleep problems (insomnia);

  • breast pain; or

  • vaginal itching or discharge, changes in your menstrual periods, breakthrough bleeding.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Premarin?

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with conjugated estrogens. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Premarin only for the indication prescribed.

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

Copyright 1996-2020 Cerner Multum, Inc. Version: 13.02.

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Other brands: Cenestin, Enjuvia

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PREMARIN Tablets (conjugated estrogens)

Warnings And Precautions

Serious Warnings and Precautions

The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.

The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for 5.2 years compared to those receiving placebo.

The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE-alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.

Therefore, the following should be given serious consideration at the time of prescribing:

  • Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases.
  • Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication.
  • Estrogens with or without progestins should be prescribed for the shortest period possible for the approved indication.
  • The use of PREMARIN for the prevention of osteoporosis should be considered in light of other available therapies.

General

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms/conditions that are consistent with the indications (see INDICATIONS AND CLINICAL USE). In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risks.”

Combined Estrogen and Progestin Therapy:
There are additional and/or increased risks that may be associated with the use of combination estrogen-plus-progestin therapy compared with using estrogen-alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer.

Carcinogenesis and Mutagenesis

Breast cancer
Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer.

In the estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were:

  • 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).

The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean , 1.7 cm vs 1.5 cm , respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at year one and persisted in each year thereafter.

In the estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see CONTRAINDICATIONS).

There is a need for caution in prescribing estrogens for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).

Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.

It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.

Instructions for regular self-examination of the breasts should be included in this counselling.

Endometrial hyperplasia & endometrial carcinoma
Estrogen-only HRT increases the risk of endometrial hyperplasia/carcinoma if taken by women with intact uteri. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold or greater than in non-users and appears to be dependent on duration of treatment and on estrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24- fold for five years or more, and this risk has been shown to persist for at least 8 to15 years after ERT is discontinued.

Clinical surveillance of all women taking combined estrogen plus progestin HRT 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 postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Ovarian cancer
In some epidemiologic studies, the use of estrogen therapy has been associated with an increased risk of ovarian cancer over multiple years of use. Other epidemiologic studies have not found these associations.

Cardiovascular

Cardiovascular risk
ERT has been reported to increase the risk of stroke and deep venous thrombosis (DVT).

Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately.

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women’s Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women. The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.

Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.

Should a stroke occur or be suspected, PREMARIN should be discontinued immediately.

WHI trial findings
In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one- year period, there were:

  • 8 more cases of stroke (29 on combined HRT versus 21 on placebo)
  • 7 more cases of CHD (37 on combined HRT versus 30 on placebo).

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one-year period, there were/was:

  • 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)
  • no statistically significant difference in the rate of CHD.

HERS and HERS II findings
In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n=2763, average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with CEE plus 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 hormone-treated group than in the placebo group in year 1, but not during the subsequent years.

From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.

Blood pressure
Women using hormone replacement therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT may have to be discontinued.

Endocrine and Metabolism

Glucose and lipid metabolism
Women with familial hyperlipidemias need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.

A worsening of glucose tolerance and lipid metabolism has been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients, or those with a predisposition to diabetes, should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.

Caution should be exercised in patients with pre-existing hypertriglyceridemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population.

Heme metabolism
Women with porphyria need special surveillance.

Estrogens should be used with caution in individuals with pre-existing severe hypocalcemia.

Calcium and phosphorus metabolism
Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.

Estrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

If hypercalcemia occurs, use of the drug should be stopped and appropriate measures should be taken to reduce the serum calcium level.

Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients who require thyroid hormone replacement therapy and who are also taking estrogen may required increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels remain in an acceptable range (see Drug-Laboratory Test Interactions).

Other conditions
PREMARIN contains lactose. In patients with rare hereditary galactose intolerance, lactase deficiency or gIucose-galactose malabsorption, the severity of the condition should be taken into careful consideration before prescribing PREMARIN. The patient should be closely monitored.

Genitourinary

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

Uterine Leiomyomata
Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

Vaginal bleeding
Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Hematologic

Venous thromboembolism
Available epidemiological data indicate that use of estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined HRT over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism.

In the estrogen-alone arm of the WHI trial, among 10,000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index > 30 kg/m2) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, PREMARIN should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, PREMARIN should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Hepatic/Biliary/Pancreatic

Liver disorders
Patients who have previously had liver disorders such as liver adenoma should be closely supervised as this condition may recur or be aggravated during treatment with PREMARIN.

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

Hepatic hemangiomas
Particular caution is indicated in women with hepatic hemangiomas, as HRT may cause an exacerbation of this condition.

Jaundice
Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out. Estrogens may be poorly metabolized in patients with impaired liver function.

Liver function tests
Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see Monitoring and Laboratory Tests.

Immune

Systemic lupus erythematosus
Particular caution is indicated in women with systemic lupus erythematosus, as HRT may cause an exacerbation of this condition.

Angioedema
Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Anaphylactic Reaction and Angioedema
Cases of anaphylaxis, which developed within minutes to hours after taking PREMARIN and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.

Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred postmarketing in patients taking PREMARIN. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with PREMARIN should not receive PREMARIN again.

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Neurologic

Cerebrovascular insufficiency
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.

Ophthalmologic
If visual abnormalities develop: Discontinue PREMARIN 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, PREMARIN should be withdrawn. Retinal vascular thrombosis has been reported in patients receiving estrogens with or without progestins.

Dementia
Available epidemiological data indicate that the use of combined estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

The Women’s Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.

It is unknown whether these findings apply to younger postmenopausal women (see Special Populations, Geriatrics).

In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:

  • 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).

In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:

  • 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.

When data from the estrogen plus progestin arm of the WHIMS and the estrogen-alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10,000 women over a one- year period, there were:

  • 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone versus 23 on placebo).

Epilepsy
Particular caution is indicated in women with epilepsy, as HRT may cause an exacerbation of this condition.

Ear/Nose/Throat

Otosclerosis
Estrogens should be used with cautions in patients with otosclerosis.

Psychiatric

Depression
Patients who are taking progestogens and have a history of depression should be observed. If the depression occurs to a serious degree, the drug should be discontinued.

Renal

Fluid retention
Estrogens may cause fluid retention.

Therefore, particular caution is indicated in cardiac, renal dysfunction, or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.

Special Populations

Pregnant Women: PREMARIN is contraindicated during pregnancy (see CONTRAINDICATIONS). If pregnancy occurs during medication with PREMARIN treatment should be withdrawn immediately.

Nursing Women: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the drug. Where an assessment of the risk to benefit ratio suggests the use of this product in nursing women is unfavourable, formula feeding should be substituted for breast feeding.

Pediatrics (< 16 years of age): PREMARIN is not indicated for use in children. Safety and effectiveness in pediatric patients have not been established.

Large and repeated doses of estrogens over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogens are administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during administration of estrogens.

Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. (See INDICATIONS AND CLINICALUSE and DOSAGE AND ADMINISTRATION).

Geriatrics (> 65 years of age): There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMARIN to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN.

The Women’s Health Initiative Study
In the Women’s Health Initiative (WHI) estrogen-alone substudy (daily versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.

In the WHI estrogen plus progestin substudy (daily CE plus MPA versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women older than 65 years of age.

The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo.

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

Information for Patients

No studies on the effect of ability to drive or use machines have been performed.

Monitoring and Laboratory Tests

Before PREMARIN is administered, the patient should have a complete physical examination including blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with ERT/HRT therapy. The first follow-up examination should be done within three to six months of initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

Mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.

The importance of regular self-examination of the breasts should be discussed with the patient.

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