Gravibinon

Estradiol Valerate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Patient information
• Gravibinon (Estradiol Valerate) reviews

INDICATIONS AND USAGE

Gravibinon (Estradiol Valerate) (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).

CONTRAINDICATIONS

Gravibinon (Estradiol Valerate) 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.DELESTROGEN should not be used in patients with known hypersensitivity to its ingredients.
• 8.Known or suspected pregnancy. There is no indication for Gravibinon (Estradiol Valerate) 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 ).

WARNINGS

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. 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

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 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.

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.

PRECAUTIONS

A. GENERAL

1. Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

2. Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4. Impaired liver function and past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T₄ and T₃ serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid retention

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7. Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. 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 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.

9. Exacerbation of endometriosis

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

10. Exacerbation of other conditions

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

11. Hypercoagulability

Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies report no such increase.

12. Uterine bleeding and mastodynia

Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Gravibinon.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

• 1.Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• 2.Increased thyroid-binding globulin levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T₄ levels (by column or by radioimmunoassay) or T₃ levels by radioimmunoassay. T₃ resin uptake is decreased, reflecting the elevated TBG. Free T₄ and free T₃ concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
• 3.Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• 4.Increased plasma HDL and HDL₂ cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
• 5.Impaired glucose tolerance.
• 6.Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS ).

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

Gravibinon should not be used during pregnancy. (See CONTRAINDICATIONS ).

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Gravibinon (Estradiol Valerate) is administered to a nursing woman.

H. Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete.

I. Geriatric Use

Clinical studies of Gravibinon (Estradiol Valerate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of the women that were older than 70. (See WARNINGS, Dementia ).

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

ADVERSE REACTIONS

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 Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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 Gravibinon (Estradiol Valerate) (estradiol valerate injection, USP) 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.

Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) 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.
  

  
  

HOW SUPPLIED

Gravibinon ^® (estradiol valerate injection, USP)

Multiple Dose Vials

• 10 mg/mL (5 mL): NDC 42023-110-01
• 20 mg/mL (5 mL): NDC 42023-111-01
• 40 mg/mL (5 mL): NDC 42023-112-01

STORAGE

Store between 20° to 25°C (68° to 77°F).

Keep out of reach of children.

PATIENT INFORMATION

Gravibinon (Estradiol Valerate)^®

(estradiol valerate injection, USP)

Read this PATIENT INFORMATION before you start taking Gravibinon (Estradiol Valerate) and read what you get each time you refill Gravibinon (Estradiol Valerate). 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 THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Gravibinon (Estradiol Valerate) (AN ESTROGEN HORMONE)?

• -Estrogens increase the chances of getting cancer of the uterus.
  

  Report any unusual vaginal bleeding right away while you are taking estrogens. 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.

• -Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
  

  Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Gravibinon (Estradiol Valerate).

What is Gravibinon (Estradiol Valerate)?

Gravibinon (Estradiol Valerate) is a medicine that contains estrogen hormones.

What is Gravibinon (Estradiol Valerate) used for?

Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate).

• -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 Gravibinon (Estradiol Valerate) to control these problems. If you use Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate)?

Do not start taking Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate).
• -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 Gravibinon (Estradiol Valerate) or any of its ingredients. See the end of this leaflet for a list of ingredients in Gravibinon (Estradiol Valerate).
• -think you may be pregnant.

Tell your healthcare provider:

• -if you are breastfeeding. The hormone in Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) works. Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate)?

Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) (estradiol valerate injection, USP) 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.

Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate).

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/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/Sharps/default.htm

How should I dispose of expired or unused Gravibinon (Estradiol Valerate)?

• 1.Do not flush unused Gravibinon (Estradiol Valerate) 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/buyingusingmedicinesafely/ensuringsafeuseofmedicine/safedisposalofmedicines/ucm186187.htm

How to Dispose of Unused Medicines http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/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 Gravibinon (Estradiol Valerate). For more information, ask your healthcare provider or pharmacist.

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

Talk with your healthcare provider regularly about whether you should continue taking Gravibinon (Estradiol Valerate). 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 Gravibinon (Estradiol Valerate). 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 Gravibinon (Estradiol Valerate)

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

Keep Gravibinon (Estradiol Valerate) out of the reach of children.

This leaflet provides a summary of the most important information about Gravibinon (Estradiol Valerate). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate)?

Gravibinon (Estradiol Valerate) 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 Gravibinon (Estradiol Valerate) in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg Gravibinon (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg Gravibinon (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil.

How should I store Gravibinon (Estradiol Valerate)?

Store Gravibinon (Estradiol Valerate) at room temperature between 20° to 25°C (68° to 77°F).

Manufactured by:

Par Pharmaceutical, Inc.

Chestnut Ridge, NY 10977

Revised: 08/17

OS110J-1-90-03

3001078H

NDC 42023-110-01

Gravibinon (Estradiol Valerate)^®

(estradiol valerate

injection, USP)

50 mg/5 mL

(10 mg/mL)

For Intramuscular Use Only

5 mL Multiple Dose Vial

NDC 42023-111-01

Gravibinon (Estradiol Valerate) ^®

(estradiol valerate

injection, USP)

100 mg/5 mL

(20 mg/mL)

For Intramuscular Use Only

• 5 mL Multiple Dose Vial

NDC 42023-112-01

Gravibinon (Estradiol Valerate)^®

(estradiol valerate

injection, USP)

200 mg/5 mL

(40 mg/mL)

For Intramuscular Use Only

• 5 mL Multiple Dose Vial

Hydroxyprogesterone Caproate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Gravibinon (Hydroxyprogesterone Caproate) reviews

1 INDICATIONS AND USAGE

Gravibinon (Hydroxyprogesterone Caproate) is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Gravibinon (Hydroxyprogesterone Caproate) is based on improvement in the proportion of women who delivered < 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity.

Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of Gravibinon (Hydroxyprogesterone Caproate) has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Gravibinon (Hydroxyprogesterone Caproate) is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.

Limitation of use: Gravibinon (Hydroxyprogesterone Caproate) is not intended for use in women with multiple gestations or other risk factors for preterm birth. (1)

2 DOSAGE AND ADMINISTRATION

• Administer intramuscularly at a dose of 250 mg once weekly
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first (2.1)

2.1 Dosing

• Administer intramuscularly at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first

2.2 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Gravibinon (Hydroxyprogesterone Caproate) is a clear, yellow solution. Do not store for long periods of time at low temperatures as this may cause the solution to appear cloudy due to crystallization. The solution must be clear at the time of use, replace vial if visible particles are present. Do not refrigerate.

Instructions for administration:

• Clean the vial top with an alcohol swab before use.
• Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
• Change the needle to a 21 gauge 1½ inch needle.
• After preparing the skin, inject in the upper outer quadrant of the gluteus maximus. The solution is viscous and oily. Slow injection (over one minute or longer) is recommended.
• Applying pressure to the injection site may minimize bruising and swelling.

If the 5 mL multidose vial is used, discard any unused product 5 weeks after first use.

3 DOSAGE FORMS AND STRENGTHS

Gravibinon (Hydroxyprogesterone Caproate) (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection. Each 1 mL single dose vial contains 250 mg Gravibinon (Hydroxyprogesterone Caproate). Each 5 mL multidose vial contains 1250 mg Gravibinon (Hydroxyprogesterone Caproate).

1 mL single dose vial contains 250 mg of Gravibinon (Hydroxyprogesterone Caproate).

5 mL multidose vial (250 mg/mL) contains 1250 mg Gravibinon (Hydroxyprogesterone Caproate). (3)

4 CONTRAINDICATIONS

Do not use Gravibinon (Hydroxyprogesterone Caproate) in women with any of the following conditions:

• Current or history of thrombosis or thromboembolic disorders
• Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
• Cholestatic jaundice of pregnancy
• Liver tumors, benign or malignant, or active liver disease
• Uncontrolled hypertension

• Current or history of thrombosis or thromboembolic disorders (4)
• Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions (4)
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy (4)
• Cholestatic jaundice of pregnancy (4)
• Liver tumors, benign or malignant, or active liver disease (4)
• Uncontrolled hypertension (4)

5 WARNINGS AND PRECAUTIONS

• Thromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs
• Allergic reactions: Consider discontinuing if allergic reactions occur (5.2)
• Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving Gravibinon (Hydroxyprogesterone Caproate) (5.3)
• Fluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4)
• Depression: Monitor women with a history of clinical depression; discontinue Gravibinon (Hydroxyprogesterone Caproate) if depression recurs (5.5)

5.1 Thromboembolic Disorders

Discontinue Gravibinon (Hydroxyprogesterone Caproate) if an arterial or deep venous thrombotic or thromboembolic event occurs.

5.2 Allergic Reactions

Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Gravibinon or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.

5.3 Decrease in Glucose Tolerance

A decrease in glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this decrease is not known. Carefully monitor prediabetic and diabetic women while they are receiving Gravibinon (Hydroxyprogesterone Caproate).

5.4 Fluid Retention

Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect.

5.5 Depression

Monitor women who have a history of clinical depression and discontinue Gravibinon (Hydroxyprogesterone Caproate) if clinical depression recurs.

5.6 Jaundice

Carefully monitor women who develop jaundice while receiving Gravibinon and consider whether the benefit of use warrants continuation.

5.7 Hypertension

Carefully monitor women who develop hypertension while receiving Gravibinon (Hydroxyprogesterone Caproate) and consider whether the benefit of use warrants continuation.

6 ADVERSE REACTIONS

For the most serious adverse reactions to the use of progestins, see Warnings and Precautions.

Most common adverse reactions reported in ≥ 2% of subjects and at a higher rate in the Gravibinon (Hydroxyprogesterone Caproate) group than in the control group are injection site reactions (pain [35%], swelling [17%], pruritus [6%], nodule [5%]), urticaria (12%), pruritus (8%), nausea (6%), and diarrhea (2%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AMAG Pharmaceuticals at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm delivery based on obstetrical history, 310 received 250 mg of Gravibinon (Hydroxyprogesterone Caproate) and 153 received a vehicle formulation containing no drug by a weekly intramuscular injection beginning at 16 to 20 weeks of gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first.¹

Certain pregnancy-related fetal and maternal complications or events were numerically increased in the Makena-treated subjects as compared to control subjects, including miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2).

Common Adverse Reactions:

The most common adverse reaction was injection site pain, which was reported after at least one injection by 34.8% of the Gravibinon (Hydroxyprogesterone Caproate) group and 32.7% of the control group. Table 3 lists adverse reactions that occurred in ≥ 2% of subjects and at a higher rate in the Gravibinon (Hydroxyprogesterone Caproate) group than in the control group.

In the clinical trial, 2.2% of subjects receiving Gravibinon (Hydroxyprogesterone Caproate) were reported as discontinuing therapy due to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each).

Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as serious adverse reactions in Makena-treated subjects.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Gravibinon (Hydroxyprogesterone Caproate). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Body as a whole: Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushes
• Digestive disorders: Vomiting
• Infections: Urinary tract infection
• Nervous system disorders: Headache, dizziness
• Pregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranes
• Reproductive system and breast disorders: Cervical dilation, shortened cervix
• Respiratory disorders: Dyspnea, chest discomfort
• Skin: Rash

7 DRUG INTERACTIONS

In vitro drug-drug interaction studies were conducted with Gravibinon (Hydroxyprogesterone Caproate). No in vivo drug-drug interaction studies were conducted with Gravibinon (Hydroxyprogesterone Caproate).

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Controlled studies show no increase in congenital anomalies, including genital abnormalities in male or female infants, from exposure during pregnancy to Gravibinon. (8.1)

8.1 Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies of Gravibinon (Hydroxyprogesterone Caproate) use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Gravibinon (Hydroxyprogesterone Caproate) at weekly doses of 250 mg by intramuscular injection in their second and third trimesters¹, as well as long-term (2-5 years) follow-up safety data on 194 of their infants ², did not demonstrate any teratogenic risks to infants from in utero exposure to Gravibinon (Hydroxyprogesterone Caproate).

Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Gravibinon (Hydroxyprogesterone Caproate).

Gravibinon (Hydroxyprogesterone Caproate) administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either species.

8.2 Labor and Delivery

Gravibinon is not intended for use to stop active preterm labor. The effect of Gravibinon (Hydroxyprogesterone Caproate) in active labor is unknown.

8.3 Nursing Mothers

Discontinue Gravibinon (Hydroxyprogesterone Caproate) at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant.

8.4 Pediatric Use

Gravibinon is not indicated for use in children. Safety and effectiveness in pediatric patients less than 16 years of age have not been established. A small number of women under age 18 years were studied; safety and efficacy are expected to be the same in women aged 16 years and above as for users 18 years and older.

8.5 Geriatric Use

Gravibinon (Hydroxyprogesterone Caproate) is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.

8.6 Renal Impairment

No studies have been conducted to examine the pharmacokinetics of Gravibinon in patients with renal impairment.

8.7 Hepatic Impairment

No studies have been conducted to examine the pharmacokinetics of Gravibinon (Hydroxyprogesterone Caproate) in patients with hepatic impairment. Gravibinon (Hydroxyprogesterone Caproate) is extensively metabolized and hepatic impairment may reduce the elimination of Gravibinon (Hydroxyprogesterone Caproate).

10 OVERDOSAGE

There have been no reports of adverse events associated with overdosage of Gravibinon (Hydroxyprogesterone Caproate) in clinical trials. In the case of overdosage, the patient should be treated symptomatically.

11 DESCRIPTION

The active pharmaceutical ingredient in Gravibinon (Hydroxyprogesterone Caproate) is Gravibinon (Hydroxyprogesterone Caproate).

The chemical name for Gravibinon (Hydroxyprogesterone Caproate) is pregn-4-ene-3,20-dione, 17[(1-oxohexyl)oxy]. It has an empirical formula of C₂₇H₄₀O₄ and a molecular weight of 428.60. Gravibinon (Hydroxyprogesterone Caproate) exists as white to practically white crystals or powder with a melting point of 120°-124°C.

The structural formula is:

Gravibinon (Hydroxyprogesterone Caproate) is a clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each 1 mL single dose vial contains Gravibinon (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v). Each 5 mL multidose vial contains Gravibinon (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Chemical Structure for Gravibinon (Hydroxyprogesterone Caproate)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gravibinon is a synthetic progestin. The mechanism by which Gravibinon (Hydroxyprogesterone Caproate) reduces the risk of recurrent preterm birth is not known.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Gravibinon (Hydroxyprogesterone Caproate).

12.3 Pharmacokinetics

Absorption: Female patients with a singleton pregnancy received intramuscular doses of 250 mg Gravibinon for the reduction of preterm birth starting between 16 weeks 0 days and 20 weeks 6 days. All patients had blood drawn daily for 7 days to evaluate pharmacokinetics.

For all three groups, peak concentration (C_max) and area under the curve (AUC_{(1-7 days)}) of the mono-hydroxylated metabolites were approximately 3-8-fold lower than the respective parameters for the parent drug, Gravibinon (Hydroxyprogesterone Caproate). While di-hydroxylated and tri-hydroxylated metabolites were also detected in human plasma to a lesser extent, no meaningful quantitative results could be derived due to the absence of reference standards for these multiple hydroxylated metabolites. The relative activity and significance of these metabolites are not known.

The elimination half-life of Gravibinon (Hydroxyprogesterone Caproate), as evaluated from 4 patients in the study who reached full-term in their pregnancies, was 16.4 (±3.6) days. The elimination half-life of the mono-hydroxylated metabolites was 19.7 (±6.2) days.

Distribution: Gravibinon (Hydroxyprogesterone Caproate) binds extensively to plasma proteins including albumin and corticosteroid binding globulins.

Metabolism: In vitro studies have shown that Gravibinon (Hydroxyprogesterone Caproate) can be metabolized by human hepatocytes, both by phase I and phase II reactions. Gravibinon (Hydroxyprogesterone Caproate) undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of Gravibinon (Hydroxyprogesterone Caproate) is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of Gravibinon (Hydroxyprogesterone Caproate).

Excretion: Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.

Specific Populations

Renal Impairment: The effect of renal impairment on the pharmacokinetics of Gravibinon (Hydroxyprogesterone Caproate) has not been evaluated.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Gravibinon (Hydroxyprogesterone Caproate) has not been evaluated.

Drug Interactions

Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that Gravibinon (Hydroxyprogesterone Caproate) increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, Gravibinon (Hydroxyprogesterone Caproate) did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that Gravibinon (Hydroxyprogesterone Caproate) has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.

In vitro data indicated that therapeutic concentration of Gravibinon (Hydroxyprogesterone Caproate) is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Gravibinon (Hydroxyprogesterone Caproate) has not been adequately evaluated for carcinogenicity.

No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational study in rats. Gravibinon (Hydroxyprogesterone Caproate) administered intramuscularly, at gestational exposures up to 5 times the recommended human dose, had no adverse effects on the parental (F₀) dams, their developing offspring (F₁), or the latter offspring's ability to produce a viable, normal second (F₂) generation.

14 CLINICAL STUDIES

14.1 Clinical Trial to Evaluate Reduction of Risk of Preterm Birth

In a multicenter, randomized, double-blind, vehicle -controlled clinical trial, the safety and effectiveness of Gravibinon (Hydroxyprogesterone Caproate) for the reduction of the risk of spontaneous preterm birth was studied in women with a singleton pregnancy (age 16 to 43 years) who had a documented history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes).¹ At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disorder).

A total of 463 pregnant women were randomized to receive either Gravibinon (Hydroxyprogesterone Caproate) (N=310) or vehicle (N=153) at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the Makena-treated women were similar to those in the control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6% Asian. The mean body mass index was 26.9 kg/m².

The proportions of women in each treatment arm who delivered at < 37 (the primary study endpoint), < 35, and < 32 weeks of gestation are displayed in Table 5.

Compared to controls, treatment with Gravibinon (Hydroxyprogesterone Caproate) reduced the proportion of women who delivered preterm at < 37 weeks. The proportions of women delivering at < 35 and < 32 weeks also were lower among women treated with Gravibinon (Hydroxyprogesterone Caproate). The upper bounds of the confidence intervals for the treatment difference at < 35 and < 32 weeks were close to zero. Inclusion of zero in a confidence interval would indicate the treatment difference is not statistically significant. Compared to the other gestational ages evaluated, the number of preterm births at < 32 weeks was limited.

After adjusting for time in the study, 7.5% of Makena-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.

Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age

The rates of fetal losses and neonatal deaths in each treatment arm are displayed in Table 6. Due to the higher rate of miscarriages and stillbirths in the Gravibinon (Hydroxyprogesterone Caproate) arm, there was no overall survival difference demonstrated in this clinical trial.

A composite neonatal morbidity/mortality index evaluated adverse outcomes in livebirths. It was based on the number of neonates who died or experienced respiratory distress syndrome, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced 1 or more events was numerically lower in the Gravibinon (Hydroxyprogesterone Caproate) arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and thedifference between arms was not statistically significant.

Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age

14.2 Infant Follow-Up Safety Study

Infants born to women enrolled in this study, and who survived to be discharged from the nursery, were eligible for participation in a follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of Makena-treated women and 84 children of control subjects. The primary endpoint was the score on the Ages & Stages Questionnaire (ASQ), which evaluates communication, gross motor, fine motor, problem solving, and personal/social parameters. The proportion of children whose scores met the screening threshold for developmental delay in each developmental domain was similar for each treatment group.²

15 REFERENCES

¹Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.

²Northen A, Norman G, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate. Obstet & Gynecol. 2007;110:865-872.

16 HOW SUPPLIED/STORAGE AND HANDLING

Gravibinon (Hydroxyprogesterone Caproate) (NDC 64011-247-02) is supplied as 1 mL of a sterile solution in a single dose glass vial.

Each 1 mL vial contains Gravibinon (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v).

Single unit carton: Contains one 1 mL single dose vial of Gravibinon (Hydroxyprogesterone Caproate) containing 250 mg of Gravibinon (Hydroxyprogesterone Caproate).

Gravibinon (Hydroxyprogesterone Caproate) (NDC 64011-243-01) is supplied as 5 mL of a sterile solution in a multidose glass vial.

Each 5 mL vial contains Gravibinon (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Single unit carton: Contains one 5 mL multidose vial of Gravibinon (Hydroxyprogesterone Caproate) (250 mg/mL) containing 1250 mg of Gravibinon (Hydroxyprogesterone Caproate).

Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F). Do not refrigerate. Use multidose vials within 5 weeks after first use.

Caution: Protect vial from light. Store vial in its box. Store upright.

17 PATIENT COUNSELING INFORMATION

Counsel patients that Gravibinon (Hydroxyprogesterone Caproate) injections may cause pain, soreness, swelling, itching or bruising. Inform the patient to contact her physician if she notices increased discomfort over time, oozing of blood or fluid, or inflammatory reactions at the injection site .

Distributed by:

AMAG Pharmaceuticals, Inc.

Waltham, MA 02451

08/2017

Patient Information

Gravibinon (Hydroxyprogesterone Caproate) (mah-KEE-na)

(hydroxyprogesterone caproate injection) 250 mg/mL

Read this Patient Information Leaflet before you receive Gravibinon (Hydroxyprogesterone Caproate). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Gravibinon (Hydroxyprogesterone Caproate)?

Gravibinon (Hydroxyprogesterone Caproate) is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in the past. Gravibinon (Hydroxyprogesterone Caproate) is used in these women to help lower the risk of having a preterm baby again.

Gravibinon (Hydroxyprogesterone Caproate) is for women who:

• Are pregnant with one baby
• Have had a preterm delivery of one baby in the past

How well does Gravibinon (Hydroxyprogesterone Caproate) work?

Gravibinon (Hydroxyprogesterone Caproate) was studied in women who were at risk for having a preterm baby because they had previously given birth to a preterm baby. In the main study, about 37 of 100 women who received Gravibinon (Hydroxyprogesterone Caproate) gave birth preterm (before 37 weeks of pregnancy), compared to about 55 of 100 women who did not receive Gravibinon (Hydroxyprogesterone Caproate). Another study of Gravibinon (Hydroxyprogesterone Caproate) is going on to see whether Gravibinon (Hydroxyprogesterone Caproate) reduces the number of babies who have serious problems shortly after birth or who die.

It is not known whether Gravibinon (Hydroxyprogesterone Caproate) is safe and effective in women who have other risk factors for preterm birth.

It is not known whether Gravibinon (Hydroxyprogesterone Caproate) is safe and effective in women less than 16 years old.

Gravibinon (Hydroxyprogesterone Caproate) is not intended for use to stop active preterm labor.

Who should not receive Gravibinon (Hydroxyprogesterone Caproate)?

Gravibinon (Hydroxyprogesterone Caproate) should not be used if you:

• Have now or have had a history of blood clots or other blood clotting problems
• Have now or have had a history of breast cancer or other hormone-sensitive cancers
• Have unusual vaginal bleeding not related to your current pregnancy
• Have yellowing of your skin due to liver problems during your pregnancy
• Have liver problems, including liver tumors
• Have uncontrolled high blood pressure

What should I tell my healthcare provider before receiving Gravibinon (Hydroxyprogesterone Caproate)?

Before you receive Gravibinon (Hydroxyprogesterone Caproate), tell your healthcare provider if you have:

• An allergy to Gravibinon (Hydroxyprogesterone Caproate), castor oil, or any of the other ingredients in Gravibinon (Hydroxyprogesterone Caproate). See the end of this patient leaflet for a complete list of the ingredients in Gravibinon (Hydroxyprogesterone Caproate).
• Diabetes or prediabetes
• Epilepsy
• Migraine headaches
• Asthma
• Heart problems
• Kidney problems
• Depression
• High blood pressure

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

Gravibinon (Hydroxyprogesterone Caproate) may affect the way other medicines work, and other medicines may affect how Gravibinon (Hydroxyprogesterone Caproate) works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medication.

How should I receive Gravibinon (Hydroxyprogesterone Caproate)?

• Do not give yourself Gravibinon (Hydroxyprogesterone Caproate) injections. A healthcare professional will give you the Gravibinon (Hydroxyprogesterone Caproate) injection into your hip area (upper outer area of the buttocks) once a week (every 7 days).
• You will start receiving Gravibinon (Hydroxyprogesterone Caproate) injections anytime from 16 weeks and 0 days of your pregnancy up to 20 weeks and 6 days of your pregnancy.
• You will continue to receive Gravibinon (Hydroxyprogesterone Caproate) injections once weekly until week 37 of your pregnancy or when your baby is delivered, whichever happens first.

Gravibinon (Hydroxyprogesterone Caproate) comes in ready-to-use vials. There are either 1 or 5 doses of medicine in each vial. Your healthcare professional should give you only one dose (1 mL) of Gravibinon (Hydroxyprogesterone Caproate) as prescribed each week.

Gravibinon (Hydroxyprogesterone Caproate) supplied in multidose 5 mL vials should be used within 5 weeks after the first use.

It is very important that you do not miss a dose of Gravibinon (Hydroxyprogesterone Caproate) and that you continue to receive the medicine once a week. If you miss a dose, talk to your healthcare provider for specific directions on how to get back on schedule.

What are the possible side effects of Gravibinon (Hydroxyprogesterone Caproate)?

Gravibinon (Hydroxyprogesterone Caproate) may cause serious side effects, including:

• Blood clots. Symptoms of a blood clot may include:
  • Leg swelling
  • Redness in your leg
  • A spot on your leg that is warm to touch
  • Leg pain that worsens when you bend your foot
• Allergic reactions. Symptoms of an allergic reaction may include:
  • Hives
  • Itching
  • Swelling of the face
  
  

  Call your healthcare provider right away if you get any of the symptoms above.
  

• Depression
• Yellowing of your skin and the whites of your eyes

The most common side effects of Gravibinon (Hydroxyprogesterone Caproate) include:

• Pain, swelling, itching, bruising or a hard bump at the injection site
• Hives
• Itching
• Nausea
• Diarrhea

Call your healthcare provider if you have the following at your injection site:

• Increased pain over time
• Oozing of blood or fluid
• Swelling

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Gravibinon (Hydroxyprogesterone Caproate). For more information, ask your healthcare provider or pharmacist.

In a clinical study, certain complications or events associated with pregnancy occurred more often in women who received Gravibinon (Hydroxyprogesterone Caproate) compared to women who did not receive Gravibinon (Hydroxyprogesterone Caproate), including:

• Miscarriage (pregnancy loss before 20 weeks of pregnancy)
• Stillbirth (fetal death occurring during or after the 20th week of pregnancy)
• Hospital admission for preterm labor
• Preeclampsia (high blood pressure and too much protein in your urine)
• Gestational hypertension (high blood pressure caused by pregnancy)
• Gestational diabetes
• Oligohydramnios (low amniotic fluid levels)

Call your healthcare provider for medical advice about side effects or pregnancy complications. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Gravibinon (Hydroxyprogesterone Caproate)?

• Store Gravibinon (Hydroxyprogesterone Caproate) at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F)
• Do Not Refrigerate
• Store Gravibinon (Hydroxyprogesterone Caproate) in the original box to protect it from light
• Store the Gravibinon (Hydroxyprogesterone Caproate) box upright
• Gravibinon (Hydroxyprogesterone Caproate) 5 mL multidose vials should be used within 5 weeks after the first use
• Keep Gravibinon (Hydroxyprogesterone Caproate) out of the reach of children

General information about the safe and effective use of Gravibinon (Hydroxyprogesterone Caproate).

Medicines are sometimes prescribed for purposes other than those mentioned in the Patient Information Leaflets. Do not take Gravibinon (Hydroxyprogesterone Caproate) for conditions for which it was not prescribed. Do not give Gravibinon (Hydroxyprogesterone Caproate) to other people, even if they have the same condition you have. It may harm them.

This leaflet summarizes the most important information about Gravibinon (Hydroxyprogesterone Caproate). If you would like more information, talk with your healthcare provider. You can ask for information about Gravibinon (Hydroxyprogesterone Caproate) that is written for healthcare professionals.

For more information, go to www.makena.com or call AMAG Pharmaceuticals Customer Service at the toll free number 1-877-411-2510.

To refill a prescription or to check on prescription status, call the Gravibinon (Hydroxyprogesterone Caproate) Care Connection at the toll free number 1-800-847-3418.

What are the ingredients in Gravibinon (Hydroxyprogesterone Caproate)?

Active ingredient: Gravibinon (Hydroxyprogesterone Caproate)

Inactive ingredients: castor oil and benzyl benzoate. 5 mL multidose vials also contain benzyl alcohol (a preservative).

Makena®

Gravibinon (Hydroxyprogesterone Caproate) injection

1250 mg/5 mL

(250 mg/mL)

Makena®

Gravibinon (Hydroxyprogesterone Caproate) injection

250 mg/mL

1 mL vial