Note: This document contains side effect information about estradiol topical. Some dosage forms listed on this page may not apply to the brand name Vagifem.

Applies to estradiol topical: vaginal cream, vaginal insert, vaginal tablet. Other dosage forms:

• vaginal ring

Serious side effects of Vagifem

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 gallbladder problems like pain in the upper right belly area, right shoulder area, or between the shoulder blades; change in stools; dark urine or yellow skin or eyes; or fever with chills.
• 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.
• Signs of low thyroid levels like constipation; not able to handle cold; memory problems; mood changes; or a burning, numbness, or tingling feeling that is not normal.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Pelvic pain or pressure.
• Vaginal irritation.
• Vaginal itching or discharge.
• Vaginal bleeding that is not normal.
• A lump in the breast, breast pain or soreness, or nipple discharge.
• Depression or other mood changes.
• Memory problems or loss.
• Eyesight changes or loss, bulging eyes, or change in how contact lenses feel.
• This drug may cause you to swell or keep fluid in your body. Tell your doctor if you have swelling, weight gain, or trouble breathing.
• 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.

Other side effects of Vagifem

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:

• Headache.
• Hair loss.
• Tender breasts.
• Upset stomach or throwing up.
• Stomach pain or cramps.
• Bloating.
• Back pain.
• Diarrhea.

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 1-800-332-1088. You may also report side effects at https://www.fda.gov/medwatch.

For Healthcare Professionals

Applies to estradiol topical: transdermal film extended release, vaginal cream, vaginal insert, vaginal ring, vaginal tablet.

General

The most commonly reported side effects were headache, upper respiratory tract infection, moniliasis, genital pruritus, vulvovaginal mycotic infection, and diarrhea.^[Ref]

Cardiovascular

Common (1% to 10%): Hot flushes

Frequency not reported: Deep and superficial venous thrombosis, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure, congestive heart disease

Postmarketing reports: Palpitations, ventricular extrasystoles, chest discomfort, increased heart rate^[Ref]

Oncologic

Frequency not reported: Breast cancer, endometrial cancer, ovarian cancer^[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity, anaphylactoid/anaphylactic reactions^[Ref]

Immunologic

Very common (10% or more): Infection (12%)

Common (1% to 10%): Allergy

Postmarketing reports: Toxic shock syndrome (fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body)^[Ref]

Genitourinary

Very common (10% or more): Endometrial disorder (15%)

Common (1% to 10%): Urinary tract infection, leukorrhea, vaginitis, vaginal discomfort/pain, vaginal hemorrhage, asymptomatic genital bacterial growth, genital moniliasis, vulvovaginal mycotic infection, vulvovaginal pruritus, bladder discomfort

Frequency not reported: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, dysmenorrhea, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion, changes in cervical ectropion, application site reactions of vulvovaginal discomfort including burning and irritation, genital pruritus, endometrial hyperplasia

Postmarketing reports: Ring adherence to the vaginal wall, genital edema, vulval disorder, micturition frequency, urethral disorder, endometrial hyperplasia, vaginal erosion, vaginal ulceration, ovarian cyst^[Ref]

Metabolic

Frequency not reported: Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, hypocalcemia, increased triglycerides

Postmarketing reports: Fluid retention^[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain, nausea, diarrhea, lower abdominal pain, abdominal discomfort, anorectal discomfort, dyspepsia

Frequency not reported: Vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis

Postmarketing reports: Bowel obstruction, enlarged abdomen, bloating, flatulence^[Ref]

Endocrine

Very common (10% or more): Breast pain (10%)

Frequency not reported: Increased thyroid-binding globulin (TBG) levels, breast (tenderness, enlargement), nipple discharge, galactorrhea, fibrocystic breast changes

Postmarketing reports: Estrogen increase, gynecomastia^[Ref]

Hepatic

Frequency not reported: Enlargement of hepatic hemangiomas^[Ref]

Ocular

Frequency not reported: Retinal vascular thrombosis, intolerance to contact lenses, steepening of corneal curvature

Postmarketing reports: Abnormal vision, retinal vein occlusion, blindness^[Ref]

Other

Common (1% to 10%): Flu-like symptoms, peripheral edema

Frequency not reported: Edema

Postmarketing reports: Asthenia, fatigue, feeling abnormal, malaise^[Ref]

Psychiatric

Common (1% to 10%): Insomnia

Uncommon (0.1% to 1%): Anxiety

Frequency not reported: Changes in libido, nervousness, mood disturbances, irritability

Postmarketing reports: Depression, insomnia^[Ref]

Nervous system

Very common (10% or more): Headache (13%)

Frequency not reported: Migraine, dizziness, chorea, exacerbation of epilepsy, dementia

Postmarketing reports: Tremor^[Ref]

Dermatologic

Common (1% to 10%): Hyperhidrosis

Frequency not reported: Chloasma or melasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, pruritus, rash, urticaria, angioedema, vascular purpura

Postmarketing reports: Pruritus ani, erythematous rash, urticaria^[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinusitis, pharyngitis

Frequency not reported: Pulmonary embolism (venous thromboembolism or VTE), exacerbation of asthma^[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthritis, arthralgia, skeletal pain

Frequency not reported: Leg cramps

Postmarketing reports: Arthropathy (including arthrosis), muscle spasms, extremity pain^[Ref]

Local

Frequency not reported: Local abrasion

Postmarketing reports: Application site rash^[Ref]