Estradiol Valerate Injection, USP contains estradiol valerate, a long-acting estrogen in sterile oil solutions for intramuscular use. These solutions are clear, colorless to pale yellow. Formulations (per mL): 10 mg Estradiol Valerate, USP in a vehicle containing 5 mg Chlorobutanol, NF (chloral derivative/preservative) and 895 mg Sesame Oil, NF; 20 mg Estradiol Valerate, USP in a vehicle containing 224 mg Benzyl Benzoate, USP, 20 mg Benzyl Alcohol, NF (preservative), and 726 mg Castor Oil, USP; 40 mg Estradiol Valerate, USP in a vehicle containing 447 mg Benzyl Benzoate, USP, 20 mg Benzyl Alcohol, NF, and 533 mg Castor Oil, USP.

Estradiol Valerate, USP is designated chemically as estra-1,3,5(10)-triene-3, 17-diol(17β)-, 17-pentanoate. Graphic formula:

C23H32O3                        MW 356.50

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Estradiol Valerate Injection, USP is indicated in the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Estradiol Valerate Injection should not be used in women with any of the following conditions:

1.  Undiagnosed abnormal genital bleeding.

2.  Known, suspected, or history of cancer of the breast.

3.  Known or suspected estrogen-dependent neoplasia.

4.  Active deep vein thrombosis, pulmonary embolism or a history of these conditions.

5.  Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial   infarction).

6.  Liver dysfunction or disease.

7.  Estradiol Valerate Injection should not be used in patients with known hypersensitivity to its ingredients.

8.  Known or suspected pregnancy. There is no indication for Estradiol Valerate Injection in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

See BOXED WARNINGS.

The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.

1. Cardiovascular disorders

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

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

a. Coronary heart disease and stroke

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

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

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

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

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

b. Venous thromboembolism (VTE)

In the Women's Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

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

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

2. Malignant neoplasms

a. Endometrial cancer

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

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

b. Breast cancer

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

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

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

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

c. Ovarian cancer

The CE/MPa substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years.

A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis).  The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

3. Dementia

In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

It is unknown whether these findings apply to estrogen alone therapy.

4. Gallbladder disease

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

5. Hypercalcemia

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

6. Visual abnormalities

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

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.

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 practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

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

1. Genitourinary system

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

2. Breasts

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

3. Cardiovascular

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

4. Gastrointestinal

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

5. Skin

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

6. Eyes

Retinal vascular thrombosis; intolerance to contact lenses.

7. Central Nervous System

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

8. Miscellaneous

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

For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

Care should be taken to inject deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Estradiol Valerate Injection, may be administered with a small gauge needle (i.e., 20 Gauge × 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.

Estradiol Valerate Injection should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.

Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.

Patients should be started at the lowest dose for the indication. The lowest effective dose of Estradiol Valerate Injection has not been determined for any indication. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. See PRECAUTIONS concerning addition of a progestin.

1. For treatment of moderate to severe vasomotor symptoms, vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

The usual dosage is 10 to 20 mg Estradiol Valerate Injection every four weeks.

Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.

2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

The usual dosage is 10 to 20 mg Estradiol Valerate Injection every four weeks.

3. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.

The usual dosage is 30 mg or more administered every one or two weeks.

Estradiol Valerate Injection, USP

Multiple Dose Vials

Storage

Store between 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]

Keep out of reach of children.

Protect from light. Store vial in carton until used.

 Manufactured by:

 HIKMA FARMACÊUTICA (PORTUGAL) S.A.

 Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem, SNT, Portugal  

Distributed by: 

Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922

Revised: March 2022

PIN556-WES/3

Estradiol Valerate Injection, USP

Read this PATIENT INFORMATION before you start taking Estradiol Valerate Injection and read what you get each time you refill Estradiol Valerate Injection. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is Estradiol Valerate Injection?

Estradiol valerate is a medicine that contains estrogen hormones.

What is Estradiol Valerate Injection used for?

Estradiol Valerate Injection is used after menopause to:

• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause." When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feeling of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol Valerate Injection.
• treat moderate to severe dryness, itching, and burning in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol Valerate Injection to control these problems. If you use Estradiol Valerate Injection only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not take Estradiol Valerate Injection?

Do not start taking Estradiol Valerate Injection if you:

• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Estradiol Valerate Injection.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have or have had liver problems.
• are allergic to Estradiol Valerate Injection or any of its ingredients. See the end of this leaflet for a list of ingredients in Estradiol Valerate Injection.
• think you may be pregnant.

Tell your healthcare provider:

• if you are breastfeeding. The hormone in Estradiol Valerate Injection can pass into your milk.
• 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), migraine, endometriosis, lupus, 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 Estradiol Valerate Injection works. Estradiol Valerate Injection may also affect how your other medicines work.
• if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.

How should I take Estradiol Valerate Injection?

Estradiol Valerate Injection should be injected deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Estradiol Valerate Injection, may be administered with a small gauge needle (i.e., 20 Gauge x 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.

Estradiol Valerate Injection should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.

Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.

1. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.
2. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of Estradiol Valerate Injection has not been determined. 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 Estradiol Valerate Injection.

How should I dispose of used syringes and needles?

1. Do not re-use needles or syringes.
2. Do not throw the needles and syringes in household waste. These should be discarded into an appropriate container (such as a sharps container) immediately after use. Refer to state or local laws and regulations for appropriate container requirements.
3. Make sure the container is tightly capped.
4. Strategically place the container so as to minimize handling and keep out of the reach of children.
5. Label the container indicating the presence of used needles/sharps.
6. For disposal of containers containing used needles and syringes refer to the state or local  laws and regulations or as instructed by your healthcare provider or pharmacist.

7. Refer to your health care provider or pharmacist for guidance, and for additional information contact the Coalition for Safe Community Needle Disposal online at http://www.safeneedledisposal.org or refer to the FDA website Needles and Other Sharps at http://www.fda.gov/MedicalDevices/ProductsandMedical Procedures/HomeHealthandConsumer/ConsumerProducts/ Sharps/default.htm

How should I dispose of expired or unused Estradiol Valerate Injection?

1. Do not flush unused Estradiol Valerate Injection or pour down the sink or drain.
2. Refer to the state or local laws and regulations for the safest and proper disposal of injectable medications. Contact your city or county government’s household trash and recycling service to find out if a drug take-back program is available in your community. You can also refer to your health care provider or pharmacist for guidance.

3. For additional information refer to the following FDA websites:
   
   Disposal of Unused Medicines: What You Should Know http://www.fda.gov/drugs/resourcesforyou/consumers/buyng usingmedicinesafely/ensureingsafeuseofmedicine/safedisposal ofmedicines/ucm186187.htm
   
   How to Dispose of Unused Medicines http://www.fda.gov/ downloads/Drugs/ResourcesForYou/Consumers/BuyingUsing MedicineSafely/Understandingover-the-CounterMedicines/ ucm107163.pdf

What are the possible side effects of estrogens? Less common but serious side effects include:

• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer

These are some of the warning signs of serious side effects:

• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss

Other side effects include:

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus ("fibroids")
• Vaginal yeast infection

These are not all the possible side effects of Estradiol Valerate Injection. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of a serious side effect with Estradiol Valerate Injection?

Talk with your healthcare provider regularly about whether you should continue taking Estradiol Valerate Injection. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. See your healthcare provider right away if you get vaginal bleeding while taking Estradiol Valerate Injection . Have a 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 safe and effective use of Estradiol Valerate Injection

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

Keep Estradiol Valerate Injection out of the reach of children.

This leaflet provides a summary of the most important information about Estradiol Valerate Injection. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Estradiol Valerate Injection that is written for health professionals. You can get more information by calling the toll free number 1-800-828-9393.

What are the ingredients in Estradiol Valerate Injection?

Estradiol Valerate Injection is supplied in three 5 mL multiple dose vials; 10 mg/mL, 20 mg/mL, and 40 mg/mL strengths. The 10 mg/mL strength contains 10 mg Estradiol Valerate, USP in a solution of Chlorobutanol, NF and Sesame Oil, NF. The 20 mg/mL strength contains 20 mg Estradiol Valerate, USP in a solution of Benzyl Benzoate, USP, Benzyl Alcohol, NF and Castor Oil, USP. The 40 mg/mL strength contains 40 mg Estradiol Valerate, USP in a solution of Benzyl Benzoate, USP, Benzyl Alcohol, NF and Castor Oil, USP.

How should I store Estradiol Valerate Injection?

Store Estradiol Valerate Injection at room  temperature  between  20°  to  25°C  (68°  to  77°F). (See USP Controlled Room Temperature.)

Manufactured by:

Hikma Farmacêutica (Portugal) S.A.

Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem, SNT, Portugal

Distributed by:

Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922, USA

Revised: March 2022

PIN556-WES/3

NDC 0143-9289-01    Rx only

Estradiol Valerate

Injection, USP

50 mg per 5 mL

(10 mg/mL)

For Intramuscular use ONLY

5 mL Multiple Dose Vial     STERILE

NDC 0143-9289-01    Rx only

5 mL Multiple Dose Vial

Estradiol Valerate

Injection, USP

50 mg per 5 mL

(10 mg/mL)

STERILE

For Intramuscular use ONLY

NDC 0143-9290-01     Rx only

Estradiol Valerate

Injection, USP

100 mg per 5 mL

(20 mg/mL)

For Intramuscular use ONLY

5 mL Multiple Dose Vial    STERILE

NDC 0143-9290-01     Rx only

5 mL Multiple Dose Vial

Estradiol Valerate

Injection, USP

100 mg per 5 mL

(20 mg/mL)

STERILE

For Intramuscular use ONLY

NDC 0143-9291-01    Rx only

Estradiol Valerate

Injection, USP

200 mg per 5 mL

(40 mg/mL)

For Intramuscular use ONLY

5 mL Multiple Dose Vial    STERILE

NDC 0143-9291-01    Rx only

5 mL Multiple Dose Vial

Estradiol Valerate

Injection, USP

200 mg per 5 mL

(40 mg/mL)

STERILE

For Intramuscular use ONLY