Gynodiol

Before taking estradiol, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to estradiol or to any of its ingredients
• have or have ever had asthma
• have seizures
• have migraine headaches
• have endometriosis (a condition in which the type of tissue that lines the uterus [womb] grows in other areas of the body)
• have uterine fibroids (growths in the uterus that are not cancer)
• have or have had yellowing of the skin or eyes, especially during pregnancy or while you were using an estrogen product
• have very high or very low levels of calcium in your blood
• have porphyria (condition in which abnormal substances build up in the blood and cause problems with the skin or nervous system) or gallbladder, thyroid, pancreas, liver or kidney disease
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication

Topical:

The recommended starting dose of estradiol transdermal patches for the treatment of menopause symptoms or hypoestrogenism is 0.025 mg daily applied to the skin once weekly.

The recommended starting dose of estradiol transdermal spray for the treatment of menopause symptoms is 1.53 mg daily applied to the skin of the forearm once daily.

The recommended starting dose of estradiol transdermal gel for the treatment of menopause symptoms is 0.25 g daily applied to the skin of the upper thigh once daily.

The recommended starting dose of estradiol vaginal cream for the treatment of menopause symptoms is 2 to 4 g daily applied to the skin of the upper thigh once daily.

The recommended starting dose of estradiol vaginal insert for the treatment of menopause symptoms is 0.05 or 0.10 mg daily inserted into the vagina every 3 months.

Oral:

The recommended dose range of estradiol oral tablets for the treatment of menopause symptoms is 1 to 2 mg daily by mouth.

Injectable:

The recommended dose range of estradiol cypionate intramuscular injection for the treatment of menopause symptoms is 1 to 5 mg injected every 3 to 4 weeks.

The recommended dose range of estradiol valerate intramuscular injection for the treatment of menopause symptoms is 10 to 20 mg injected every 4 weeks.

In the U.S.

• Alora
• Cenestin
• Climara
• Divigel
• Elestrin
• Emcyt
• Enjuvia
• Esclim
• Estinyl
• EstroGel
• Evamist
• Femtrace
• Gynodiol
• Menest
• Menostar
• Minivelle
• Ogen .625
• Ogen 1.25
• Ogen 2.5
• Premarin
• Vivelle
• Vivelle-Dot

In Canada

• Estraderm
• Estradot Transdermal
• Estradot Transdermal Therapeutic System
• Estradot Transdermal Therapeutic System
• Estrogel
• Oesclim
• Rhoxal-Estradiol Derm 50
• Rhoxal-Estradiol Derm 75
• Roxal-Estradiol Derm 100
• Vivelle 100 Mcg
• Vivelle 25 Mcg

Available Dosage Forms:

• Tablet
• Cream
• Patch, Extended Release
• Gel/Jelly
• Spray
• Emulsion
• Tablet, Enteric Coated
• Capsule

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of this medicine before puberty is not recommended. Growth of bones can be stopped early. Girls and boys may develop growth of breasts. Girls may have vaginal changes, including vaginal bleeding.

This medicine may be used to start puberty in teenagers with some types of delayed puberty.

Geriatric

Elderly people are especially sensitive to the effects of estrogens. This may increase the chance of side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

Pregnancy

Estrogens are not recommended for use during pregnancy or right after giving birth. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause.

Certain estrogens have been shown to cause serious birth defects in humans and animals. Some daughters of women who took diethylstilbestrol (DES) during pregnancy have developed reproductive (genital) tract problems and, rarely, cancer of the vagina or cervix (opening to the uterus) when they reached childbearing age. Some sons of women who took DES during pregnancy have developed urinary-genital tract problems.

Breast Feeding

Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and their possible effect on the baby is not known.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Conivaptan
• Dabrafenib
• Darunavir
• Dasabuvir
• Dexamethasone
• Donepezil
• Eliglustat
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Netupitant
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Pixantrone
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

For all patients

• Asthma or
• Calcium, too much or too little in blood or
• Diabetes or
• Epilepsy or seizures or
• Heart problems or
• Kidney problems or
• Liver tumors, benign or
• Lupus erythematosus, systemic or
• Migraine headaches—Estrogens may worsen these conditions.

• Blood clotting problems, or history of during previous estrogen therapy—Estrogens usually are not used until blood clotting problems stop; using estrogens is not a problem for most patients without a history of blood clotting problems due to estrogen use.

• Breast cancer or
• Bone cancer or
• Cancer of the uterus or
• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.

• Bulging eyes or
• Double vision or
• Migraine headache or
• Vision changes, sudden onset including or
• Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems, especially while taking estrogen or oral contraceptives (“birth control pills”).

• Changes in genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen condition. The reason for the bleeding should be determined before estrogens are used.

• Endometriosis or
• Gallbladder disease or gallstones, or history of or
• High cholesterol or triglycerides, or history of or
• Liver disease, or history of or
• Pancreatitis (inflammation of pancreas) or
• Porphyria—Estrogens may worsen these conditions. Although estrogens can improve blood cholesterol, they can worsen blood triglycerides for some people.

• Hypothyroid (too little thyroid hormone)—Dose of thyroid medicine may need to be increased.

For males treated for breast or prostate cancer:

• Blood clots or
• Heart or circulation disease or
• Stroke—Males with these medical problems may be more likely to have clotting problems while taking estrogens; the high doses of estrogens used to treat male breast or prostate cancer have been shown to increase the chances of heart attack, phlebitis (inflamed veins) caused by a blood clot, or blood clots in the lungs.

• It is used to put off soft, brittle bones (osteoporosis) in women after change of life.
• It is used to prevent or lower the signs of the change of life (menopause).
• It is used to add estrogen to the body when the ovaries have been taken out or do not work the right way.
• Rarely, it is used to treat breast or prostate cancers.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to estradiol or any other part of Gynodiol (estradiol oral tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
• If you have had any of these health problems: Bleeding disorder, blood clots, a higher risk of having a blood clot, breast cancer, liver problems or liver tumor, heart attack, stroke, or a tumor where estrogen makes it grow.
• If you have eyesight problems like loss of eyesight from blood vessel problems in the eye.
• If you have thickening of the endometrium (lining of the uterus).
• If you have unexplained vaginal bleeding.
• If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.

This is not a list of all drugs or health problems that interact with Gynodiol.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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 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.
• Chest pain or pressure.
• Shortness of breath.
• Coughing up blood.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Very bad dizziness or passing out.
• 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.
• Back pain.
• Bulging eyes.
• Change in how contact lenses feel in the eyes.
• Loss of eyesight.
• Change in eyesight.
• 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.
• Fever.
• Not able to pass urine or change in how much urine is passed.
• Pain when passing urine.
• Swelling.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Applies to estradiol: vaginal cream, vaginal insert extended release, vaginal tablet

Other dosage forms:

• transdermal emulsion, transdermal gel/jelly, transdermal patch extended release, transdermal spray

Along with its needed effects, estradiol (the active ingredient contained in Gynodiol) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking estradiol:

• Vaginal yeast infection

• Change in vaginal discharge
• clear or bloody discharge from the nipple
• decrease in the amount of urine
• dimpling of the breast skin
• fast heartbeat
• fever
• hives, itching, or rash
• hoarseness
• inverted nipple
• irritation
• joint pain, stiffness, or swelling
• lump in the breast or under the arm
• noisy, rattling breathing
• pain or feeling of pressure in the pelvis
• pain, redness, or swelling in the arm or leg
• persistent crusting or scaling of the nipple
• redness of the skin
• redness or swelling of the breast
• sore on the skin of the breast that does not heal
• swelling of the eyelids, face, fingers, lips, hands, feet, or lower legs
• tightness in the chest
• troubled breathing at rest
• troubled breathing or swallowing
• vaginal bleeding

Get emergency help immediately if any of the following symptoms of overdose occur while taking estradiol:

• Abdominal or stomach pain
• dizziness
• drowsiness
• nausea or vomiting
• tenderness of the breasts
• unusual tiredness or weakness

Some side effects of estradiol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• headache
• itching or pain of the vagina or genital area
• thick, white vaginal discharge with mild or no odor
• weight gain

• Body aches or pain
• chills
• cough
• diarrhea
• ear congestion
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat

• Feeling sad or empty
• headache, severe and throbbing
• irritability
• lack of appetite
• tiredness
• trouble concentrating
• trouble sleeping
• welts

Applies to estradiol: compounding powder, intramuscular solution, oral tablet, transdermal emulsion, transdermal film extended release, transdermal gel, transdermal spray, vaginal ring

Gastrointestinal

Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]

Gastrointestinal side effects have included nausea, abdominal cramps, bloating and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy. Cholestatic jaundice, pancreatitis, and enlargement of hepatic hemangiomas have been reported. Postmarketing experience with the vaginal ring has included a few cases of bowel obstruction and vaginal ring use. Postmarketing side effects with Vivelle-Dot include nausea, vomiting, abdominal cramps, bloating, cholelithiasis and diarrhea.[Ref]

Oncologic

Oncologic side effects have included reports of an increased risk of endometrial carcinoma in patients with an intact uterus and less persuasively, with an increased risk of breast cancer.[Ref]

A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

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 5 yrs and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5 yrs, 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 5 yrs and 2.63, CI, 1.18 to 5.89 for > 5 yrs). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5 yrs was RR = 1.38, CI, 1.03 to 1.85.[Ref]

Cardiovascular

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]

Cardiovascular side effects have included studies suggesting that unopposed estrogen therapy decreased the risk of coronary heart disease by as much as 35%. Combination therapy with a progestin may have also decreased 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. Postmarketing side effects with Vivelle-Dot include deep vein thrombosis, pulmonary embolism and thrombophlebitis.[Ref]

Metabolic

Metabolic side effects have included reports of generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels have occurred. Estrogen therapy may have led to increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects.

Metabolic adverse effects such as hypercalcemia have occurred in patients with breast cancer and bone metastases.[Ref]

Endocrine

Endocrine side effects have included increased levels of thyroxin-binding globulin which led to increased total thyroid serum levels and a decreased in resin uptake of T3. Free thyroid hormone levels remained unchanged. Other endocrine effects have included decreased fasting plasma glucose.[Ref]

General

General side effects have included fluid retention and mastodynia. Alterations in libido have occurred. Postmarketing experience with the vaginal ring has included a few cases of toxic shock syndrome. Postmarketing side effects with Vivelle-Dot include decrease in weight, reduced carbohydrate tolerance and edema.[Ref]

Hepatic

Hepatic side effects have included reports of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas, and well-differentiated hepatocellular carcinomas. Aggravation of porphyria has been reported. Postmarketing side effects with Vivelle-Dot include abnormal liver function tests.[Ref]

Many of the reports of hepatic tumors have occurred in women taking long-term oral contraceptives. However, some tumors have been reported in women taking isolated estrogen therapy.[Ref]

Hematologic

Hematologic side effects have included hypercoagulability and an increase in venous thromboembolism.[Ref]

The clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.[Ref]

Ocular

Ocular side effects have included alterations in corneal curvature and contact lens discomfort. Retinal vascular thrombosis has been reported. Postmarketing side effects with Vivelle-Dot include intolerance to contact lenses.[Ref]

Hypersensitivity

Hypersensitivity side effects have included reports of reactions including anaphylaxis. Some reports have implicated the dyes contained in some conjugated estrogen formulations. Urticaria and angioedema have also been reported.[Ref]

Postmarketing reports concerning a transdermal product (Climara) have included a few cases in which there were a combination of the symptoms of generalized hives or rash with swelling of the throat or eyelid edema.[Ref]

Other

Other side effects have included reports of a possible increase in the risk of "fibrocystic breast disease" by as much as twofold. Postmarketing side effects with Vivelle-Dot include breast enlargement and pain, nipple discharge, fibrocystic breast changes and breast cancer.[Ref]

Psychiatric

Psychiatric side effects have included case reports of rapid mood cycling in patients with severe depression. Postmarketing side effects with Vivelle-Dot include nervousness, affect liability and irritability.[Ref]

Nervous system

Nervous system side effects have included dementia, dizziness, mental depression, headache, nervousness, irritability exacerbation of epilepsy and new onset or exacerbation of migraine headaches. A case of chorea has been reported in association with estrogen therapy.[Ref]

Dermatologic

Dermatologic side effects have included chloasma or melasma, which did not always resolve following discontinuation of estrogen therapy. Scalp hair loss, hirsutism, erythema nodosum, and hemorrhagic eruptions have occurred. Postmarketing side effects with Vivelle-Dot include erythema multiforme, pruritus, purpura and rash.[Ref]

Genitourinary

Genitourinary side effects have included abnormal uterine bleeding and dysmenorrhea. In some cases, this was bleeding related to endometrial carcinoma. In addition, estrogens have increased the size of preexisting uterine leiomyomata. Postmarketing experience with the vaginal ring has included a few cases of ring adherence to the vaginal wall, making removal difficult. Postmarketing side effects with Vivelle-Dot include vaginal hemorrhage, abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer and endometrial hyperplasia.[Ref]

Musculoskeletal

Musculoskeletal side effects have included arthralgias. Postmarketing side effects with Vivelle-Dot include leg cramps.[Ref]

Some side effects of Gynodiol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.