Androfemon

Estradiol Valerate:

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

INDICATIONS AND USAGE

Androfemon (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

Androfemon (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 Androfemon (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 Androfemon.

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

Androfemon 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 Androfemon (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 Androfemon (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 Androfemon (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.

Androfemon (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 Androfemon (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 Androfemon (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 Androfemon (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

Androfemon ^® (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

Androfemon (Estradiol Valerate)^®

(estradiol valerate injection, USP)

Read this PATIENT INFORMATION before you start taking Androfemon (Estradiol Valerate) and read what you get each time you refill Androfemon (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 Androfemon (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 Androfemon (Estradiol Valerate).

What is Androfemon (Estradiol Valerate)?

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

What is Androfemon (Estradiol Valerate) used for?

Androfemon (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 Androfemon (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 Androfemon (Estradiol Valerate) to control these problems. If you use Androfemon (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 Androfemon (Estradiol Valerate)?

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

Tell your healthcare provider:

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

Androfemon (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 Androfemon (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.

Androfemon (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 Androfemon (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 Androfemon (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 Androfemon (Estradiol Valerate)?

• 1.Do not flush unused Androfemon (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 Androfemon (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 Androfemon (Estradiol Valerate)?

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

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

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

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

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

How should I store Androfemon (Estradiol Valerate)?

Store Androfemon (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

Androfemon (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

Androfemon (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

Androfemon (Estradiol Valerate)^®

(estradiol valerate

injection, USP)

200 mg/5 mL

(40 mg/mL)

For Intramuscular Use Only

• 5 mL Multiple Dose Vial

Testosterone Enanthate:

• Warning: serious pulmonary oil microembolism (pome) reactions and anaphylaxis
• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Androfemon (Testosterone Enanthate) reviews

WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM REACTIONS AND ANAPHYLAXIS

• Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of Androfemon (Testosterone Enanthate) undecanoate injection. These reactions can occur after any injection of Androfemon (Testosterone Enanthate) undecanoate during the course of therapy, including after the first dose [see Warnings and Precautions (5.1)].
• Following each injection of Androfemon (Testosterone Enanthate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis .
• Because of the risks of serious POME reactions and anaphylaxis, Androfemon (Testosterone Enanthate) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Androfemon (Testosterone Enanthate) REMS Program [see Warnings and Precautions (5.2)].

WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS AND ANAPHYLAXIS

See full prescribing information for complete boxed warning

• Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of Androfemon (Testosterone Enanthate) undecanoate injection. These reactions can occur after any injection of Androfemon (Testosterone Enanthate) undecanoate during the course of therapy, including after the first dose (5.1).
• Following each injection of Androfemon (Testosterone Enanthate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1).
• Androfemon (Testosterone Enanthate) is available only through a restricted program called the Androfemon (Testosterone Enanthate) REMS Program (5.2).

RECENT MAJOR CHANGES

Warnings and Precautions (5.7) 10/2016

1 INDICATIONS AND USAGE

Androfemon (Testosterone Enanthate) is indicated for Androfemon (Testosterone Enanthate) replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Androfemon (Testosterone Enanthate).

• Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter"s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum Androfemon (Testosterone Enanthate) concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low Androfemon (Testosterone Enanthate) serum concentrations but have gonadotropins in the normal or low range.

Androfemon (Testosterone Enanthate) should only be used in patients who require Androfemon (Testosterone Enanthate) replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.

Limitations of use:

• Safety and efficacy of Androfemon (Testosterone Enanthate) in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Safety and efficacy of Androfemon (Testosterone Enanthate) in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )].

Androfemon (Testosterone Enanthate) (testosterone undecanoate) injection is an androgen indicated for Androfemon (Testosterone Enanthate) replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Androfemon (Testosterone Enanthate):

o Primary hypogonadism (congenital or acquired) (1)

o Hypogonadotropic hypogonadism (congenital or acquired) (1)

Androfemon (Testosterone Enanthate) should only be used in patients who require Androfemon (Testosterone Enanthate) replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis (1).

Limitations of use:

• Safety and efficacy of Androfemon (Testosterone Enanthate) in men with “age-related hypogonadism” have not been established (1).
• Safety and efficacy of Androfemon (Testosterone Enanthate) in males less than 18 years old have not been established (1, 8.4).

2 DOSAGE AND ADMINISTRATION

Prior to initiating Androfemon, confirm the diagnosis of hypogonadism by ensuring that serum Androfemon (Testosterone Enanthate) concentrations have been measured in the morning on at least two separate days and that these serum Androfemon (Testosterone Enanthate) concentrations are below the normal range.

• Prior to initiating Androfemon (Testosterone Enanthate), confirm the diagnosis of hypogonadism by ensuring that serum Androfemon (Testosterone Enanthate) has been measured in the morning on at least two separate days and that these concentrations are below the normal range (2).
• For intramuscular use only (2.1).
• 3 mL (750 mg) is to be injected intramuscularly at initiation, at 4 weeks, and every 10 weeks thereafter (2.1).
• Following each injection of Androfemon (Testosterone Enanthate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (2.3).
• Inject Androfemon (Testosterone Enanthate) deeply into the gluteal muscle following the usual precautions for intramuscular administration of oily solutions (2.3).

2.1 Dosage

Androfemon (Testosterone Enanthate) is for intramuscular use only. Dosage titration is not necessary.

Inject Androfemon (Testosterone Enanthate) deeply into the gluteal muscle following the usual precautions for intramuscular administration; care must be taken to avoid intravascular injection . Intravascular injection of Androfemon (Testosterone Enanthate) may lead to pulmonary oil microembolism .

The recommended dose of Aveed is 3 mL (750 mg) injected intramuscularly, followed by 3 mL (750 mg) injected after 4 weeks, then 3 mL (750 mg) injected every 10 weeks thereafter.

2.2 Preparation Instructions

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Carefully remove the gray plastic cap from the top of the vial by lifting it up from the edges with your fingers or by pushing the bottom edge of the cap upward using the top of your thumb. Remove only the gray plastic cap while leaving the aluminum metal ring and crimp seal around the gray rubber stopper in place. To facilitate the removal of medication from the vial, you can draw 3 mL of air into the syringe and inject it through the gray rubber stopper into the vial to create positive pressure within the vial chamber.

Withdraw 3 mL of Androfemon (Testosterone Enanthate) solution from the vial. Expel excess air bubbles from the syringe. Replace the syringe needle used to draw up the solution from the vial with a new intramuscular needle and inject. Discard any unused portion in the vial.

2.3 Administration Instructions

The site for injection for Androfemon (Testosterone Enanthate) is the gluteus medius muscle site located in the upper outer quadrant of the buttock. Care must be taken to avoid the needle hitting the superior gluteal arteries and sciatic nerve. Between consecutive injections, alternate the injection site between left and right buttock.

Figure 1: Identifying the injection site

Following antiseptic skin preparation, enter the muscle and maintain the syringe at a 90° angle with the needle in its deeply imbedded position. Grasp the barrel of the syringe firmly with one hand. With the other hand, pull back on the plunger and aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, immediately withdraw and discard the syringe and prepare another dose.

If no blood is aspirated, reinforce the current needle position to avoid any movement of the needle and slowly (over 60 to 90 seconds) depress the plunger carefully and at a constant rate, until all the medication has been delivered. Be sure to depress the plunger completely with sufficient controlled force. Withdraw the needle.

Immediately upon removal of the needle from the muscle, apply gentle pressure with a sterile pad to the injection site. If there is bleeding at the site of injection, apply a bandage.

Following each injection of Androfemon (Testosterone Enanthate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1).

Figure1

3 DOSAGE FORMS AND STRENGTHS

750 mg/3 mL (250 mg/mL) Androfemon (Testosterone Enanthate) undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap.

• 750 mg/3 mL (250 mg/mL) Androfemon (Testosterone Enanthate) undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap (3).

4 CONTRAINDICATIONS

Androfemon (Testosterone Enanthate) should not be used in any of the following patients:

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate .
• Women who are or may become pregnant, or who are breastfeeding. Androfemon (Testosterone Enanthate) can cause fetal harm when administered to a pregnant woman. Androfemon (Testosterone Enanthate) may cause serious adverse reactions in nursing infants. Exposure of a female fetus or nursing infant to androgens may result in varying degrees of virilization.
• Men with known hypersensitivity to Androfemon (Testosterone Enanthate) or any of its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate).

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate (4, 5.3).
• Pregnant or breastfeeding women. Testosterone may cause fetal harm (4, 8.1, 8.3).
• Known hypersensitivity to Androfemon (Testosterone Enanthate) or its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate) (4).

5 WARNINGS AND PRECAUTIONS

• Monitor patients with benign prostatic hyperplasia for worsening of signs and symptoms of BPH (5.3).
• Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using Androfemon (Testosterone Enanthate) products. Evaluate patients with signs or symptoms consistent with DVT or PE. (5.5)
• Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of Androfemon (Testosterone Enanthate) replacement therapy. (5.6)
• Exogenous administration of androgens may lead to azoospermia (5.9).
• Edema with or without congestive heart failure may be a complication in patients with preexisting cardiac, renal, or hepatic disease (5.11).
• Sleep apnea may occur in those with risk factors (5.13).
• Monitor prostatic specific antigen (PSA), hemoglobin, hematocrit, and lipid concentrations periodically (5.3, 5.4, 5.14).

5.1 Serious Pulmonary Oil Microembolism (POME) Reactions and Anaphylaxis

Serious POME reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate 1000 mg (4 mL). The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization. To minimize the risk of intravascular injection of Androfemon (Testosterone Enanthate), care should be taken to inject the preparation deeply into the gluteal muscle, being sure to follow the recommended procedure for intramuscular administration .

In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate.

Both serious POME reactions and anaphylaxis can occur after any injection of Androfemon (Testosterone Enanthate) undecanoate during the course of therapy, including after the first dose. Patients with suspected hypersensitivity reactions to Androfemon (Testosterone Enanthate) should not be re-treated with Androfemon (Testosterone Enanthate).

Following each injection of Androfemon (Testosterone Enanthate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions and anaphylaxis.

5.2 Androfemon Risk Evaluation and Mitigation Strategy (REMS) Program

Androfemon (Testosterone Enanthate) is available only through a restricted program called the Androfemon (Testosterone Enanthate) REMS Program because of the risk of serious POME and anaphylaxis.

Notable requirements of the Androfemon (Testosterone Enanthate) REMS Program include the following:

• Healthcare providers who prescribe Androfemon (Testosterone Enanthate) must be certified with the REMS Program before ordering or dispensing Androfemon (Testosterone Enanthate).
• Healthcare settings must be certified with the REMS Program and have healthcare providers who are certified before ordering or dispensing Androfemon (Testosterone Enanthate). Healthcare settings must have on-site access to equipment and personnel trained to manage serious POME and anaphylaxis.

Further information is available at www. AveedREMS.com or call 1-855-755-0494.

5.3 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer

Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.

Patients treated with androgens may be at an increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens .

5.4 Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require discontinuation of Androfemon.

Check hematocrit prior to initiating Androfemon (Testosterone Enanthate) treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting Androfemon (Testosterone Enanthate) treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events.

5.5 Venous Thromboembolism

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using Androfemon (Testosterone Enanthate) products, such as Androfemon (Testosterone Enanthate). Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with Androfemon (Testosterone Enanthate) and initiate appropriate workup and management.

5.6 Cardiovascular Risk

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of Androfemon replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of Androfemon (Testosterone Enanthate) compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of Androfemon (Testosterone Enanthate) replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Androfemon (Testosterone Enanthate).

5.7 Abuse of Androfemon (Testosterone Enanthate) and Monitoring of SerumTestosterone Concentrations

Androfemon (Testosterone Enanthate) has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions .

If Androfemon (Testosterone Enanthate) abuse is suspected, check serum Androfemon (Testosterone Enanthate) concentrations to ensure they are within therapeutic range. However, Androfemon (Testosterone Enanthate) levels may be in the normal or subnormal range in men abusing synthetic Androfemon (Testosterone Enanthate) derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of Androfemon (Testosterone Enanthate) and anabolic androgenic steroids. Conversely, consider the possibility of Androfemon (Testosterone Enanthate) and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

5.8 Use in Women

Due to lack of controlled evaluations in women and potential virilizing effects, Androfemon is not indicated for use in women.

5.9 Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including Androfemon (Testosterone Enanthate), spermatogenesis may be suppressed through feedback inhibition of pituitary follicle- stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

5.10 Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular Androfemon (Testosterone Enanthate) enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Androfemon (Testosterone Enanthate) is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue Androfemon (Testosterone Enanthate) while the cause is evaluated.

5.11 Edema

Androgens, including Androfemon (Testosterone Enanthate), may promote retention of sodium and water. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

5.12 Gynecomastia

Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism .

5.13 Sleep Apnea

The treatment of hypogonadal men with Androfemon (Testosterone Enanthate) products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.

5.14 Lipids

Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of Androfemon therapy.

5.15 Hypercalcemia

Androgens, including Androfemon (Testosterone Enanthate), should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

5.16 Decreased Thyroxine-binding Globulin

Androgens, including Androfemon (Testosterone Enanthate), may decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

6 ADVERSE REACTIONS

The most commonly reported adverse reactions are acne, injection site pain, prostatic specific antigen (PSA) increased, estradiol increased, hypogonadism, fatigue, irritability, hemoglobin increased, insomnia, and mood swings (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial Experience

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

Androfemon (Testosterone Enanthate) was evaluated in an 84-week clinical study using a dose regimen of 750 mg (3 mL) at initiation, at 4 weeks, and every 10 weeks thereafter in 153 hypogonadal men. The most commonly reported adverse reactions (>2%) were: acne (5.2%), injection site pain (4.6%), prostate specific antigen increased (4.6%), hypogonadism (2.6%) and estradiol increased (2.6%).

Table 1 presents adverse reactions reported by ≥1% of patients in the 84-week clinical study.

Table 1

Adverse Reactions Reported in at Least 1% of Patients in the 84-Week Clinical Study of Androfemon (Testosterone Enanthate)

* Prostate specific antigen increased defined as a serum PSA concentration >4 ng/mL.

In the 84-week clinical trial, 7 patients (4.6%) discontinued treatment because of adverse reactions. Adverse reactions leading to discontinuation included: hematocrit increased, estradiol increased, prostatic specific antigen increased, prostate cancer, mood swings, prostatic dysplasia, acne, and deep vein thrombosis.

During the 84-week clinical trial, the average serum PSA increased from 1.0 ± 0.8 ng/mL at baseline to 1.5 ± 1.3 ng/mL at the end of study. Fourteen patients (10.9%) in whom the baseline PSA was < 4 ng/mL had a post-baseline serum PSA of > 4 ng/mL during the 84-week treatment period.

A total of 725 hypogonadal men received intramuscular Androfemon (Testosterone Enanthate) undecanoate in a total of 7 controlled clinical trials. In these clinical trials, the dose and dose frequency of intramuscular Androfemon (Testosterone Enanthate) undecanoate varied from 750 mg to 1000 mg, and from every 9 weeks to every 14 weeks. Several of these clinical trials incorporated additional doses upon initiation of therapy (e.g., loading doses). In addition to those adverse reactions noted in Table 1, the following adverse events were reported by at least 3% of patients in these trials, irrespective of the investigator’s assessment of relationship to study medication: sinusitis, prostatitis, arthralgia, nasopharyngitis, upper respiratory tract infection, bronchitis, back pain, hypertension, diarrhea and headache.

Pulmonary Oil Microembolism (POME) and Anaphylaxis in Controlled Clinical Studies

Adverse events attributable to pulmonary oil microembolism and anaphylaxis were reported in a small number of patients in controlled clinical trials. In the 84-week clinical trial of Androfemon (Testosterone Enanthate), 1 patient experienced a mild coughing fit lasting 10 minutes after his third injection, which was retrospectively attributed to POME. In another clinical trial of intramuscular Androfemon (Testosterone Enanthate) undecanoate (1000 mg), a hypogonadal male patient experienced the urge to cough and respiratory distress at 1 minute after his tenth injection, which was also retrospectively attributed to POME.

During a review that involved adjudication of all cases meeting specific criteria, 9 POME events in 8 patients and 2 events of anaphylaxis among 3,556 patients treated with intramuscular Androfemon (Testosterone Enanthate) undecanoate in 18 clinical trials were judged to have occurred.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Androfemon (Testosterone Enanthate). Because the 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.

Pulmonary Oil Microembolism (POME) and Anaphylaxis

Serious pulmonary oil microembolism (POME) reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate 1000 mg (4 mL) in post-approval use outside the United States. The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization.

In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate in post-approval use outside of the United States.

Both serious POME reactions and anaphylaxis have been reported to occur after any injection of Androfemon (Testosterone Enanthate) undecanoate during the course of therapy, including after the first dose.

Other Events

The following treatment emergent adverse events or adverse reactions have been identified during post-marketing clinical trials and during post-approval use of intramuscular Androfemon (Testosterone Enanthate) undecanoate. In most cases, the dose being used was 1000 mg.

Blood and Lymphatic System Disorders: polycythemia, thrombocytopenia

Cardiac Disorders: angina pectoris, cardiac arrest, cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, tachycardia

Ear and Labyrinth Disorders: sudden hearing loss, tinnitus

Endocrine Disorders: hyperparathyroidism, hypoglycemia

Gastrointestinal Disorders: abdominal pain upper, diarrhea, vomiting

General Disorders and Administrative Site Conditions: chest pain, edema peripheral, injection site discomfort, injection site hematoma, injection site irritation, injection site pain, injection site reaction, malaise, paresthesia, procedural pain

Immune System Disorders: anaphylactic reaction, anaphylactic shock, asthma, dermatitis allergic, hypersensitivity, leukocytoclastic vasculitis

Infections and Infestations: injection site abscess, prostate infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood glucose increased, blood pressure increased, blood prolactin increased, blood Androfemon (Testosterone Enanthate) decreased, blood Androfemon (Testosterone Enanthate) increased, blood triglycerides increased, gamma-glutamyltransferase increased, hematocrit increased, intraocular pressure increased, liver function test abnormal, prostate examination abnormal, prostatic specific antigen increased, transaminases increased

Metabolism and Nutrition Disorders: diabetes mellitus, fluid retention, hyperlipidemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders: musculoskeletal chest pain, musculoskeletal pain, myalgia, osteopenia, osteoporosis, systemic lupus erythematosus

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): prostate cancer, prostatic intraepithelial neoplasia

Nervous System Disorders: stroke, cerebrovascular insufficiency, reversible ischemic neurological deficiency, transient ischemic attack

Psychiatric Disorders: aggression, anxiety, depression, insomnia, irritability, Korsakoff’s psychosis non-alcoholic, male orgasmic disorder, nervousness, restlessness, sleep disorder

Renal and Urinary Disorders: calculus urinary, dysuria, hematuria, nephrolithiasis, pollakiuria, renal colic, renal pain, urinary tract disorder

Reproductive System and Breast Disorders: azoospermia, benign prostatic hyperplasia, breast induration, breast pain, erectile dysfunction, gynecomastia, libido decreased, libido increased, prostate induration, prostatitis, spermatocele, testicular pain

Respiratory, Thoracic and Mediastinal Disorders: asthma, chronic obstructive pulmonary disease, cough, dysphonia, dyspnea, hyperventilation, obstructive airway disorder, pharyngeal edema, pharyngolaryngeal pain, pulmonary microemboli, pulmonary embolism, respiratory distress, rhinitis, sleep apnea syndrome, snoring

Skin and Subcutaneous Tissue Disorders: acne, alopecia, angioedema, angioneurotic edema, dermatitis allergic, erythema, hyperhidrosis, pruritus, rash

Vascular Disorders: cerebral infarction, cerebrovascular accident, circulatory collapse, deep venous thrombosis, hot flush, hypertension, syncope, thromboembolism, thrombosis, venous insufficiency.

7 DRUG INTERACTIONS

• Androgens may decrease blood glucose, and therefore may decrease insulin requirements in diabetic patients .
• Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of international normalized ratio (INR) and prothrombin time is recommended in patients taking warfarin (7.2).
• Use of Androfemon (Testosterone Enanthate) with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease (7.3).

7.1 Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in the dose of anti-diabetic medication.

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use of Androfemon (Testosterone Enanthate) with corticosteroids may result in increased fluid retention and requires careful monitoring, particularly in patients with cardiac, renal or hepatic disease.

8 USE IN SPECIFIC POPULATIONS

Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer.

8.1 Pregnancy

Pregnancy Category X: Aveed is contraindicated in pregnant women or in women who may become pregnant. Androfemon (Testosterone Enanthate) is teratogenic and may cause fetal harm. Exposure of a fetus to androgens, such as Androfemon (Testosterone Enanthate), may result in varying degrees of virilizations. If this drug is used in pregnancy or if the patient becomes pregnant while taking this drug, the patient should be made aware of the potential hazard to the fetus.

8.3 Nursing Mothers

Although it is not known how much Androfemon transfers into human milk, Androfemon (Testosterone Enanthate) is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.

8.4 Pediatric Use

Safety and effectiveness of Androfemon (Testosterone Enanthate) in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients in controlled clinical studies with Androfemon to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. Of the153 patients enrolled in the pivotal clinical study utilizing Androfemon (Testosterone Enanthate), 26 (17.0%) were over 65 years of age. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer.

Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH .

8.6 Renal Impairment

No studies were conducted in patients with renal impairment.

8.7 Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Androfemon contains Androfemon (Testosterone Enanthate), a Schedule III controlled substance in the Controlled Substances Act.

9.2 Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of Androfemon (Testosterone Enanthate) are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse of men taking higher doses of legally obtained Androfemon (Testosterone Enanthate) than prescribed and continuing Androfemon (Testosterone Enanthate) despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids, and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.3 Dependence

Behaviors Associated with Addiction

Continued abuse of Androfemon (Testosterone Enanthate) and other anabolic steroids, leading to addiction is characterized by the following behaviors:

• Taking greater dosages than prescribed
• Continued drug use despite medical and social problems due to drug use
• Spending significant time to obtain the drug when supplies of the drug are interrupted
• Giving a higher priority to drug use than other obligations
• Having difficulty in discontinuing the drug despite desires and attempts to do so
• Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of Androfemon (Testosterone Enanthate) may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of Androfemon (Testosterone Enanthate) for approved indications has not been documented.

.

10 OVERDOSAGE

There have been no reports of overdosage in the Androfemon (Testosterone Enanthate) clinical trials. There is one report of acute overdosage with use of an approved injectable Androfemon (Testosterone Enanthate) product: this subject had serum Androfemon (Testosterone Enanthate) levels of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of Androfemon (Testosterone Enanthate) together with appropriate symptomatic and supportive care.

11 DESCRIPTION

Androfemon (Testosterone Enanthate) (testosterone undecanoate) injection contains Androfemon (Testosterone Enanthate) undecanoate (17β-undecanoyloxy-4-androsten-3-one) which is an ester of the androgen, Androfemon (Testosterone Enanthate). Androfemon (Testosterone Enanthate) is formed by cleavage of the ester side chain of Androfemon (Testosterone Enanthate) undecanoate.

Androfemon (Testosterone Enanthate) undecanoate is a white to off-white crystalline substance. The empirical formula of Androfemon (Testosterone Enanthate) undecanoate is C₃₀H₄₈O₃ and a molecular weight of 456.7. The structural formula is:

FIGURE 2: Androfemon (Testosterone Enanthate) Undecanoate

C₃₀H₄₈O₃ MW: 456.7

Androfemon (Testosterone Enanthate) is a clear, yellowish, sterile oily solution containing Androfemon (Testosterone Enanthate) undecanoate, a Androfemon (Testosterone Enanthate) ester, for intramuscular injection. Each single use vial contains 3 mL of 250 mg/mL Androfemon (Testosterone Enanthate) undecanoate solution in a mixture of 1500 mg of benzyl benzoate and 885 mg of refined castor oil.

Figure2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous androgens, including Androfemon and dihydrotestosterone (DHT) are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of Androfemon (Testosterone Enanthate), has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.3 Pharmacokinetics

Absorption

Androfemon (Testosterone Enanthate) 750 mg delivers physiologic amounts of Androfemon (Testosterone Enanthate), producing circulation Androfemon (Testosterone Enanthate) concentrations that approximate normal concentrations (300-1000 ng/dL) seen in healthy men.

Androfemon (Testosterone Enanthate) esters in oil injected intramuscularly are absorbed from the lipid phase. Cleavage of the undecanoic acid side chain of Androfemon (Testosterone Enanthate) by tissue esterases releases Androfemon (Testosterone Enanthate).

Following intramuscular injection of 750 mg of Androfemon (Testosterone Enanthate), serum Androfemon (Testosterone Enanthate) concentrations reach a maximum after a median of

7 days (range 4 – 42 days) then slowly decline (Figure 3). Steady state serum Androfemon (Testosterone Enanthate) concentration was achieved with the 3^rd injection of Androfemon (Testosterone Enanthate) at 14 weeks.

Figure 3 shows the mean serum total Androfemon (Testosterone Enanthate) concentration-time profile during the 3^rd injection interval (at steady state, 14-24 weeks) for hypogonadal men (less than 300 ng/dL) given 750 mg Androfemon (Testosterone Enanthate) at initiation, at 4 weeks, and every 10 weeks thereafter. Intramuscular injection of 750 mg of Androfemon (Testosterone Enanthate) generates mean steady state serum total Androfemon (Testosterone Enanthate) concentrations in the normal range for 10 weeks.

FIGURE 3: Mean (SD) Serum Total Androfemon (Testosterone Enanthate)

Concentrations (ng/dL) at 14-24 Weeks

Distribution

Circulating Androfemon (Testosterone Enanthate) is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin.

Approximately 40% of Androfemon (Testosterone Enanthate) in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.

Metabolism

Androfemon (Testosterone Enanthate) undecanoate is metabolized to Androfemon (Testosterone Enanthate) via ester cleavage of the undecanoate group. The mean (SD) maximum concentration of Androfemon (Testosterone Enanthate) undecanoate was 90.9 (68.8) ng/dL on Day 4 following injection of Androfemon (Testosterone Enanthate). Androfemon (Testosterone Enanthate) undecanoate was nearly undetectable 42 days following injection of Androfemon (Testosterone Enanthate).

Androfemon (Testosterone Enanthate) is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Androfemon (Testosterone Enanthate) are estradiol and DHT.

DHT concentrations increased in parallel with Androfemon (Testosterone Enanthate) concentrations during Androfemon (Testosterone Enanthate) treatment. Average DHT concentrations during a dosing interval ranged from 244 to 451 ng/dL. The mean DHT:T ratios ranged from 0.05 to 0.07.

Excretion

There is considerable variation in the half-life of Androfemon (Testosterone Enanthate) as reported in the literature, ranging from 10 to 100 minutes. About 90% of a Androfemon (Testosterone Enanthate) dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of Androfemon (Testosterone Enanthate) or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Androfemon (Testosterone Enanthate) occurs primarily in the liver.

Effect of Body Weight and Body Mass Index (BMI)

Analysis of serum Androfemon (Testosterone Enanthate) concentrations from 117 hypogonadal men in the 84-week clinical study of Androfemon (Testosterone Enanthate) indicated that serum Androfemon (Testosterone Enanthate) concentrations achieved were inversely correlated with the patient’s body weight. In 60 patients with pretreatment body weight of ≥100 kg, the mean (±SD) serum Androfemon (Testosterone Enanthate) average concentration was 426 ± 104 ng/dL. A higher serum Androfemon (Testosterone Enanthate) average concentration (568 ± 139 ng/dL) was observed in 57 patients weighing 65 to 100 kg. A similar trend was also observed for maximum serum Androfemon (Testosterone Enanthate) concentrations.

In 70 patients with pretreatment body mass index of >30 kg/m², the mean (±SD) serum Androfemon (Testosterone Enanthate) average concentration was

445 ± 116 ng/dL. Higher serum Androfemon (Testosterone Enanthate) average concentrations (579 ± 101 ng/dL and 567± 155ng/dL) were observed in patients with BMIs <26 kg/m² and 26 to 30 kg/m²,respectively. A similar trend was also observed for maximum serum Androfemon (Testosterone Enanthate) concentrations.

Figure3

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenicity

Androfemon (Testosterone Enanthate) has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of Androfemon (Testosterone Enanthate) into some strains of female mice increases their susceptibility to hepatoma. Androfemon (Testosterone Enanthate) is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenicity

Mutagenic effects of Androfemon (Testosterone Enanthate) undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Androfemon (Testosterone Enanthate) undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Androfemon (Testosterone Enanthate) was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous Androfemon (Testosterone Enanthate) has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

14 CLINICAL STUDIES

14.1 Androfemon Replacement Therapy

Androfemon (Testosterone Enanthate) was evaluated for efficacy in an 84-week, single-arm, open-label, multicenter study of 130 hypogonadal men. Eligible patients weighed at least 65 kg, were 18 years of age and older (mean age 54.2 years), and had a morning serum total Androfemon (Testosterone Enanthate) concentrations <300 ng/dL (mean screening Androfemon (Testosterone Enanthate) concentration 215 ng/dL). Patients were Caucasian (74.6%), Black (12.3%), Hispanic (10.8%) and of Other ethnicities (2.3%). The mean body mass index was 32 kg/m².

All patients received injections of Androfemon (Testosterone Enanthate) 750 mg at baseline, at 4 weeks, and then every 10 weeks thereafter.

The primary endpoint was the percentage of patients with average serum total Androfemon (Testosterone Enanthate) concentration (C_avg) within the normal range (300-1000 ng/dL) after the third injection, at steady state.

The secondary endpoint was the percentage of patients with maximum total Androfemon (Testosterone Enanthate) concentration (C_max) above three pre-determined limits: greater than 1500 ng/dL, between 1800 and 2499 ng/dL, and greater than 2500 ng/dL.

A total of 117 out of 130 hypogonadal men completed study procedures through Week 24 and were included in the evaluation of Androfemon (Testosterone Enanthate) pharmacokinetics after the third Androfemon (Testosterone Enanthate) injection. Ninety-four percent (94%) of patients maintained a C_avg within the normal range (300 to 1000 ng/dL). The percentages of patients with C_avg below the normal range (less than 300 ng/dL) and above the normal range (greater than 1000 ng/dL) were 5.1% and 0.9%, respectively.

Table 2 summarizes the mean (SD) serum total Androfemon (Testosterone Enanthate) pharmacokinetic parameters at steady state for these 117 patients.

TABLE 2

Mean (SD) Serum Total Androfemon (Testosterone Enanthate) Concentrations at Steady State

C_avg = average concentration; C_max = maximum concentration; C_min = minimum concentration

The percentage of patients with C_max >1500 ng/dL was 7.7%. No patient had a C_max >1800 ng/dL.

16 HOW SUPPLIED/STORAGE AND HANDLING

Androfemon (Testosterone Enanthate), NDC 67979-511-43: 750 mg/3 mL (250 mg/mL) Androfemon (Testosterone Enanthate) undecanoate sterile injectable solution is provided in an amber glass vial with silver-colored crimp seal and gray plastic cap. Each vial is individually packaged in a carton box.

Store at controlled room temperature 25 ºC (77 ºF); excursions permitted to 15 - 30 ºC (59 - 86 ºF) in its original carton until the date indicated.

Before use, each vial should be visually inspected. Only vials free from particles should be used.

Single Use Vial. Discard unused portion.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

Advise patients of the following:

17.1 Risks of Serious Pulmonary Oil Microembolism and Anaphylaxis

• Serious pulmonary oil microembolism (POME) reactions, involving cough, urge to cough, shortness of breath, sweating, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate. The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization.
• Episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Androfemon (Testosterone Enanthate) undecanoate.
• Both serious POME reactions and anaphylaxis can occur after any injection of Androfemon (Testosterone Enanthate) undecanoate during the course of therapy, including after the first dose.
• Advise the patient to read the Androfemon (Testosterone Enanthate) REMS information sheet titled "What You Need to Know About Androfemon (Testosterone Enanthate)^® Treatment: A Patient Guide.
• Instruct patients to remain at the healthcare setting for 30 minutes after each Androfemon (Testosterone Enanthate) injection.

17.2 Men with Known or Suspected Carcinoma of the Prostate or Breast

Men with known or suspected prostate or breast cancer should not use Androfemon .

17.3 Potential Adverse Reactions to Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits, such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge to go the bathroom right away, having a urine accident, or being unable to pass urine or weak urine flow
• Breathing disturbances, including those associated with sleep or excessive daytime sleepiness
• Too frequent or persistent erections of the penis
• Nausea, vomiting, changes in skin color, or ankle swelling

17.4 Patients Should be Advised of the Following Instructions for Use

• Read the Medication Guide before starting Androfemon (Testosterone Enanthate) therapy and reread the Guide before each injection.
• Adhere to all recommended monitoring.
• Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood.

Distributed by:

Endo Pharmaceuticals Solutions Inc.

Malvern, PA 19355

Androfemon (Testosterone Enanthate) is a registered trademark of Endo Pharmaceuticals Inc.

© 2017 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Revised: July 2017

Androfemon (Testosterone Enanthate)^® (Uh-Veed)

(testosterone undecanoate)

injection

Read this Medication Guide before you receive Androfemon (Testosterone Enanthate) and before each injection. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Androfemon (Testosterone Enanthate)?

Androfemon (Testosterone Enanthate) may cause serious side effects, including:

• A serious lung problem. Androfemon (Testosterone Enanthate) can cause a serious lung problem called a pulmonary oil microembolism (POME) reaction. POME is caused by tiny droplets of oil that have traveled to the lungs. Symptoms of a POME reaction may include:

o cough or urge to cough

o difficulty breathing

o sweating

o tightening of your throat

o chest pain

o dizziness

o fainting

• Serious allergic reactions (anaphylaxis). Androfemon (Testosterone Enanthate) can cause a serious allergic reaction right after receiving the injection. Some of these allergic reactions may be life threatening.

These reactions can happen after you receive your first dose of Androfemon (Testosterone Enanthate) or may happen after receiving more than 1 dose.

You may need emergency treatment in a hospital, especially if these symptoms get worse over the 24 hours after

your AVEED injection.

These side effects may happen during or right after each injection. To be sure that you are not having one

of these reactions:

o You need to stay in the doctor’s office, clinic, or hospital for 30 minutes after having your Androfemon (Testosterone Enanthate) injection so

that your doctor can watch you for symptoms of POME or a serious allergic reaction.

o You can only get Androfemon (Testosterone Enanthate) at your doctor’s office, clinic, or hospital.

Androfemon (Testosterone Enanthate) is only available through a restricted program called the Androfemon (Testosterone Enanthate) Risk Evaluation and Mitigation Strategy (REMS) Program. For more information about the Androfemon (Testosterone Enanthate) REMS Program go to www. AveedREMS.com or call 1-855-755-0494.

What is Androfemon (Testosterone Enanthate)?

Androfemon (Testosterone Enanthate) is a prescription medicine that contains Androfemon (Testosterone Enanthate). Androfemon (Testosterone Enanthate) is used to treat adult males who have low or no Androfemon (Testosterone Enanthate) due to certain medical conditions.

Androfemon (Testosterone Enanthate) is only for adult males who need Androfemon (Testosterone Enanthate) replacement therapy and when the benefit of receiving Androfemon (Testosterone Enanthate) is more than the risk of POME and anaphylaxis.

Your healthcare provider will test your blood before you start and while you are taking Androfemon (Testosterone Enanthate).

It is not known if AVEEDis safe or effective to treat men who have low Androfemon (Testosterone Enanthate) due to aging.

It is not known if Androfemon (Testosterone Enanthate) is safe and effective for use in children younger than 18 years old. Improper use of Androfemon (Testosterone Enanthate) may affect bone growth in children.

Androfemon (Testosterone Enanthate) is a controlled substance (CIII) because it contains Androfemon (Testosterone Enanthate) that can be a target for people who abuse prescription medicines.

Androfemon (Testosterone Enanthate) is not meant for use in women.

Who should not receive Androfemon (Testosterone Enanthate)?

Do not receive Androfemon (Testosterone Enanthate) if you:

• have breast cancer
• have or might have prostate cancer
• are pregnant or may become pregnant or are breastfeeding. Androfemon (Testosterone Enanthate) may harm your unborn or breastfeeding baby.
• are allergic to Androfemon (Testosterone Enanthate) or to any of the ingredients in Androfemon (Testosterone Enanthate). See the end of this leaflet for a complete list of ingredients in Androfemon (Testosterone Enanthate).

Talk to your doctor before receiving this medicine if you have any of the above conditions.

What should I tell my doctor before receiving Androfemon (Testosterone Enanthate)?

Before receiving Androfemon (Testosterone Enanthate), tell your doctor if you:

• have breast cancer
• have or might have prostate cancer
• have urinary problems due to an enlarged prostate
• have heart problems
• have liver or kidney problems
• have problems breathing while you sleep (sleep apnea)
• have any other medical conditions

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

Receiving Androfemon (Testosterone Enanthate) with certain other medicines can affect each other. Especially tell your doctor if you take:

• insulin
• medicines that decrease blood clotting
• corticosteroids

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.

How will I receive Androfemon (Testosterone Enanthate)?

See “What is the most important information I should know about Androfemon (Testosterone Enanthate)?”

Your doctor will inject Androfemon (Testosterone Enanthate) deep into the muscle of your buttock. You will get 1 injection when you start, 1 injection 4 weeks later and then 1 injection every 10 weeks.

Your doctor will test your blood before you receive and while you are receiving Androfemon (Testosterone Enanthate).

What are the possible side effects of Androfemon (Testosterone Enanthate)?

Androfemon (Testosterone Enanthate) can cause serious side effects including:

• see “What is the most important information I should know about Androfemon (Testosterone Enanthate)?”
• if you already have enlargement of your prostate gland, your signs and symptoms can get worse while receiving Androfemon (Testosterone Enanthate). This can include:

o increased urination at night

o trouble starting your urine stream

o having to pass urine many times during the day

o having an urge that you have to go to the bathroom right away

o having a urine accident

o being unable to pass urine or weak urine flow

• changes in certain blood tests
• possible increased risk of prostate cancer. Your doctor should check you for prostate cancer or any other prostate problems before you receive and while you are receiving Androfemon (Testosterone Enanthate).
• blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain.
• possible increased risk of heart attack or stroke.
• in large doses Androfemon (Testosterone Enanthate) may lower your sperm count.
• liver problems. Symptoms of liver problems may include:

o nausea or vomiting

o yellowing of your skin or whites of your eyes

o dark urine

o pain on the right side of your stomach area (abdominal pain)

• swelling of your ankles, feet, or body, with or without heart failure. This may cause serious problems for people who have heart, kidney, or liver disease.
• enlarged or painful breasts.
• have problems breathing while you sleep (sleep apnea).

Call your doctor right away if you have any of the serious side effects listed above.

The most common side effects of Androfemon (Testosterone Enanthate) include:

• acne
• pain at the injection site
• increased prostate specific antigen (a test used to screen for prostate cancer)
• increased estradiol level
• low Androfemon (Testosterone Enanthate) level
• feeling tired
• irritability
• increased red blood cell count
• difficulty sleeping
• mood swings

Other side effects include more erections than are normal for you or erections that last for a long time.

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

These are not all the possible side effects with Androfemon (Testosterone Enanthate). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about Androfemon (Testosterone Enanthate)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about Androfemon (Testosterone Enanthate). If you would like more information, talk with your doctor. You can ask your doctor or nurse for information about Androfemon (Testosterone Enanthate) that is written for health professionals. For more information, go to www. AVEEDUSA.com or call 1-800-462-3636.

What are the ingredients in Androfemon (Testosterone Enanthate)?

Active ingredient: Androfemon (Testosterone Enanthate) undecanoate

Inactive ingredients: refined castor oil, benzyl benzoate

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Endo Pharmaceuticals Solutions Inc.

Malvern, PA 19355

Androfemon (Testosterone Enanthate) is a registered trademark of Endo Pharmaceuticals Inc.

© 2016 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Approved: 10/2016

85534041

carton