Test-Estro

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Test-Estro uses

Test-Estro consists of Estradiol Cypionate, Testosterone Cypionate.

Estradiol Cypionate:


WARNINGS

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women taking estrogens 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 currently no evidence that the use of "natural" estrogens results in a different endometrial risk profile than "synthetic" estrogens at equivalent estrogen doses.

CARDIOVASCULAR AND OTHER RISKS

Estrogens with and without progestins should not be used for the prevention of cardiovascular disease.

The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies. )

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen-alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

Other doses of conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

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DESCRIPTION

Test-Estro (Estradiol Cypionate) Injection contains Test-Estro (Estradiol Cypionate) for intramuscular use. Each mL contains:

5 mg/mL-5 mg Test-Estro (Estradiol Cypionate), 5.4 mg chlorobutanol anhydrous (chloral derivative) added as preservative; in 913 mg cottonseed oil.

Warning: Chlorobutanol may be habit forming. The structural formula is represented below:

Test-Estro (Estradiol Cypionate) contains an oil soluble ester of estradiol 17β. The chemical name for Test-Estro (Estradiol Cypionate) is estradiol 17-cyclopentanepropionate.

Chemical Structure Logo

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

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

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

Absorption

When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or Test-Estro (Estradiol Cypionate) is absorbed over several weeks.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Estrogen drug products administered by non oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.

Clinical Studies

Women's Health Initiative Studies

The Women's Health Initiative enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:

Event a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD Relative Risk

CE/MPA vs placebo

at 5.2 Years

(95% CInominal confidence intervals unadjusted for multiple looks and multiple comparisons)

Placebo

n = 8102

CE/MPA

n = 8506

Absolute Risk per 10,000 Person-years
CHD events 1.29 (1.02–1.63) 30 37
Non-fatal MI 1.32 (1.02–1.72) 23 30
CHD death 1.18 (0.70–1.97) 6 7
Invasive breast cancer includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer 1.26 (1.00–1.59) 30 38
Stroke 1.41 (1.07–1.85) 21 29
Pulmonary embolism 2.13 (1.39–3.25) 8 16
Colorectal cancer 0.63 (0.43–0.92) 16 10
Endometrial cancer 0.83 (0.47–1.47) 6 5
Hip fracture 0.66 (0.45–0.98) 15 10
Death due to causes other than the events above 0.92 (0.74–1.14) 40 37
Global index 1.15 (1.03–1.28) 151 170
Deep vein thrombosis not included in Global Index 2.07 (1.49–2.87) 13 26
Vertebral fractures 0.66 (0.44–0.98) 15 9
Other osteoporotic fractures 0.77 (0.69–0.86) 170 131

For those outcomes included in the "global index," the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Women's Health Initiative Memory Study

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

Comparative clinical studies have demonstrated that Test-Estro (Estradiol Cypionate) produces estrogenic effects that are qualitatively the same as those produced by other estradiol esters. In menopausal women, the average duration of estrogenic effect (as measured by vaginal smear) following a single injection of 5 mg of Test-Estro (Estradiol Cypionate) was found to be approximately 3 to 4 weeks. Relief of vasomotor symptoms was observed to occur within 1 to 5 days and to be maintained for 1 to 8 weeks, with an average of approximately 5 weeks.

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INDICATIONS AND USAGE

Test-Estro (Estradiol Cypionate) Injection is indicated in the treatment of:

  • Moderate to severe vasomotor symptoms associated with the menopause.
  • Hypoestrogenism due to hypogonadism.

CONTRAINDICATIONS

Estrogens should not be used in individuals with any of the following conditions:

  • Undiagnosed abnormal genital bleeding.
  • Known or suspected cancer of the breast.
  • Known or suspected estrogen-dependent neoplasia.
  • Active deep vein thrombosis, pulmonary embolism or history of these conditions.
  • Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  • Liver dysfunction or disease.
  • Test-Estro (Estradiol Cypionate) should not be used in patients with known hypersensitivity to its ingredients.
  • Known or suspected pregnancy. There is no indication for Test-Estro (Estradiol Cypionate) 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.

WARNINGS

See BOXED WARNINGS

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapy have 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, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies .)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal 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 (0.625 mg/2.5 mg 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, in women receiving CE compared to placebo, the risk of VTE (including both DVT and PE) was increased 33% (28 vs. 21 per 10,000 person-years) although only the increased rate of DVT reached statistical significance (p = 0.03). (See CLINICAL PHARMACOLOGY, Clinical Studies .)

In the CE/MPA treatment substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving treatment with CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-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 was 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 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 hormone 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 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. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

4. Gallbladder disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogen 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.

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PRECAUTIONS

A. General

1. Addition of 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, adverse effects on lipoprotein metabolism and impairment of glucose tolerance.

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 estrogens 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, require 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 20 versus 12 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

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.

B. PATIENT INFORMATION

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

C. LABORATORY TESTS

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

D. DRUG/LABORATORY TEST INTERACTIONS

  • 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  • Increased thyroid-binding globulin levels leading to increased circulating total thyroid hormone, 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.
  • Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone levels concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-anti-trypsin, ceruloplasmin).
  • Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
  • Impaired glucose tolerance.
  • Reduced response to metyrapone test.
  • Reduced serum folate concentration.

E. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

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. (See BOXED WARINGS, WARNINGS and PRECAUTIONS.)

F. PREGNANCY

Test-Estro should not be used during pregnancy. See CONTRAINDICATIONS and Boxed WARNINGS.

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 Test-Estro (Estradiol Cypionate) is administered to a nursing woman.

H. GERIATRIC USE

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 women that were older than 70. (See WARNINGS, Dementia.)

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ADVERSE REACTIONS

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

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

  • 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.

  • Breasts

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

  • Cardiovascular

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

  • Gastrointestinal

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

  • Skin

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

  • Eyes

    Retinal vascular thrombosis; steepening of corneal curvature; intolerance to contact lenses.

  • Central nervous system

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

  • Miscellaneous

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

DRUG ABUSE AND DEPENDENCE

Chlorobutanol anhydrous (chloral derivative) added as a preservative may be habit forming.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

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

Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.

Test-Estro (Estradiol Cypionate) INJECTION IS FOR INTRAMUSCULAR USE ONLY.

When estrogen is prescribed for a 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.

  • Short-term cyclic use for treatment of moderate to severe vasomotor symptoms, vulval 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.


    Attempts to discontinue or taper medication should be made at 3- to 6-month intervals. The usual dosage range is 1 to 5 mg injected every 3 to 4 weeks.

  • For treatment of female hypoestrogenism due to hypogonadism 1.5 to 2 mg injected at monthly intervals.

HOW SUPPLIED

Test-Estro (Estradiol Cypionate) Injection is available in the following concentration containing per mL:

5 mg Test-Estro (Estradiol Cypionate); also 5.4 mg chlorobutanol anhydrous (chloral deriv.) added as preservative; in 913 mg cottonseed oil- in 5 mL vials, NDC 0009-0271-01.

WARNING: Chlorobutanol may be habit forming.

Store at controlled room temperature 20° to 25° C (68° to 77° F).

REFERENCES

  • Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167–1170, 1975.
  • Smith DC, Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164–1167, 1975.
  • Mack TM, Pike MC, Henderson BE, et al: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294:1262–1267, 1976.
  • Weiss NS, Szekely DR, Austin DF: Increasing incidence of endometrial cancer in the United States. N Engl J Med 294:1259–1262, 1976.
  • Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881, 1971.
  • Greenwald P, Barlow JJ, Nasca PC, Burnett WS: Vaginal cancer after maternal treatment with synthetic estrogens. N Engl J Med 285:390–392, 1971.
  • Lanier AP, Noller KL, Decker DG, Elveback LR, Kurland LT: Cancer and stilbestrol. A follow-up of 1,719 persons exposed to estrogens in utero and born 1943–1959. Mayo Clin Proc 48:793–799, 1973.
  • Herbst AL, Kurman RJ, Scully RE: Vaginal and cervical abnormalities after exposure to stilbestrol in utero. Obstet Gynecol 40:287–298, 1972.
  • Herbst AL, Robboy SJ, Macdonald GJ, Scully RE: The effects of local progesterone on stilbestrol-associated vaginal adenosis. Am J Obstet Gynecol 118:607–615, 1974.
  • Herbst AL, Poskanzer DC, Robboy SJ, Friedlander L, Scully RE: Prenatal exposure to stilbestrol. A prospective comparison of exposed female offspring with unexposed control. N Engl J Med 292:334–339, 1975.
  • Stafl A, Mattingly RF, Foley DV, Fetherston WC: Clinical diagnosis of vaginal adenosis. Obstet Gynecol 43:118–128, 1974.
  • Sherman AL, Goldrath M, Berlin A, et al: Cervical-vaginal adenosis after in utero exposure to synthetic estrogens. Obstet Gynecol 44:531545, 1974.
  • Gall, Kirman B, Stern J: Hormonal pregnancy tests and congenital malformation. Nature 216:83, 1967.
  • Levy EP, Cohen A, Fraser FC: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973.
  • Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941–942, 1973.
  • Janerich DT, Piper JM, Glebatis DM: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697–700, 1974.
  • Boston Collaborative Drug Surveillance Program: Surgically confirmed gall bladder disease, venous thromboembolism, and breast tumors in relation to post-menopausal estrogen therapy. N Engl J Med 290:15–19, 1974.
  • Hoover R, Gray LA, Cole P, MacMahon B: Menopausal estrogens and breast cancer. N Engl J Med 295:401–405, 1976.
  • Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gall bladder disease, and breast tumors. Lancet 1:1399–1404, 1973.
  • Daniel DG, Campbell H, Turnbull AC: Puerperal thromboembolism and suppression of lactation. Lancet 2:287–289, 1967.
  • The Veterans Administration Cooperative Urological Research Group: Carcinoma of the prostate: Treatment comparisons. J Urol 98:516522, 1967.
  • Bailar JC: Thromboembolism and estrogen therapy. Lancet 2:560, 1967.
  • Blackard CE, Doe RP, Mellinger GT, Byar DP: Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer 26:249–256, 1970.
  • Royal College of General Practitioners: Oral contraception and thromboembolic disease. J R Coll Gen Pract 13:267–279, 1967.
  • Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of childbearing age. Br Med J 2:193–199, 1968.
  • Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 2:651–657, 1969.
  • Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiologic case-control study. Am J Epidemiol 90:365–380, 1969.
  • Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 288:871–878, 1973.
  • Collaborative Group for the Study of Stroke in Young Women: Oral contraceptives and stroke in young women: Associated risk factors. JAMA 231:718–722, 1975.
  • Mann JI, Inman WHW: Oral contraceptives and death from myocardial infarction. Br Med J 2:245–248, 1975.
  • Mann JI, Vessey MP, Thorogood M, Doll R: Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 2:241–245, 1975.
  • Inman WHW, Vessey MP, Westerholm B, Engelund A: Thromboembolic disease and the steroidal content of oral contraceptives. Br Med J 2:203–209, 1970.
  • Stolley PD, Tonascia JA, Tockman MS, et al: Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol 102:197–208, 1975.
  • Vessey MP, Doll R, Fairbairn AS, Glober G: Postoperative thromboembolism and the use of oral contraceptives. Br Med J 3:123–126, 1970.
  • Greene GR, Sartwell PE: Oral contraceptive use in patients with thromboembolism following surgery, trauma or infection. Am J Public Health 62:680–685, 1972.
  • Rosenberg L, Armstrong B, Phil D, Jick H: Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 294:1256–1259, 1976.
  • Coronary Drug Project Research Group: The Coronary Drug Project: Initial findings leading to modifications of its research protocol. JAMA 214:1303–1313, 1970.
  • Baum J, Holtz F, Bookstein JJ, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926–929, 1973.
  • Mays ET, Christopherson WM, Mahr MM, Williams HC: Hepatic changes in young women ingesting contraceptive steroids. Hepatic hemorrhage and primary hepatic tumors. JAMA 235:730–732, 1976.
  • Edmondson HA, Henderson B, Benton B: Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med 294:470–472, 1976.
  • Pfeffer RI, VanDenNoort S: Estrogen use and stroke risk in post-menopausal women. Am J Epidemiol 103:445–456, 1976.

LAB-0083-4.0

November 2016

PATIENT INFORMATION

Test-Estro (Estradiol Cypionate)®

Brand of Test-Estro (Estradiol Cypionate) injection, USP

Read this PATIENT INFORMATION before you start taking Test-Estro (Estradiol Cypionate) and read what you get each time you refill Test-Estro (Estradiol Cypionate). 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 Test-Estro (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 uterine (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. You and your healthcare provider should talk regularly about whether you still need treatment with Test-Estro (Estradiol Cypionate).

What is Test-Estro (Estradiol Cypionate)?

Test-Estro (Estradiol Cypionate) injection is an estrogen product. The information below is that which the U.S. Food and Drug Administration requires be provided for all patients taking estrogens. For further information ask your doctor.

What is Test-Estro (Estradiol Cypionate) used for?

Test-Estro (Estradiol Cypionate) is used during and after menopause to:

  • reduce moderate or severe menopausal symptoms. 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 (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"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. Most women have only mild menopause symptoms or none at all and do not need estrogen drugs for these symptoms.

  • treat moderate to severe itching, burning, and dryness in or around the vagina.

    You and your healthcare provider should talk regularly about whether you still need treatment with Test-Estro (Estradiol Cypionate) to control these problems.


Test-Estro (Estradiol Cypionate) is also used to:

  • treat certain conditions in women before menopause if their ovaries do not make enough estrogen.

Who should not take Test-Estro (Estradiol Cypionate)?

Do not start taking Test-Estro (Estradiol Cypionate) 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 Test-Estro (Estradiol Cypionate).

  • had a stroke or heart attack in the past year.
  • currently have or have had blood clots.
  • are allergic to Test-Estro (Estradiol Cypionate) or any of its ingredients.
  • think you may be pregnant.

Tell your healthcare provider:

  • if you are breastfeeding.

The hormone in Test-Estro (Estradiol Cypionate) 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, or 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 Test-Estro (Estradiol Cypionate) works. Test-Estro (Estradiol Cypionate) 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 Test-Estro (Estradiol Cypionate)?

Take Test-Estro (Estradiol Cypionate) as directed by your healthcare provider.

Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with Test-Estro (Estradiol Cypionate).

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
  • 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

Other side effects include:

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

These are not all the possible side effects of Test-Estro (Estradiol Cypionate). For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with Test-Estro (Estradiol Cypionate)?

  • Talk with your healthcare provider regularly about whether you should continue taking Test-Estro (Estradiol Cypionate). 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 Test-Estro (Estradiol Cypionate). 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 examinations 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 Test-Estro (Estradiol Cypionate)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Test-Estro (Estradiol Cypionate) for conditions for which it was not prescribed. Do not give Test-Estro (Estradiol Cypionate) to other people, even if they have the same symptoms you have. It may harm them. Keep Test-Estro (Estradiol Cypionate) out of the reach of children.

This leaflet provides a summary of the most important information about Test-Estro (Estradiol Cypionate). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Test-Estro (Estradiol Cypionate) that is written for health professionals. You can get more information by calling the toll free number 1-800-438-1985. You are cautioned to discuss very carefully with your doctor or healthcare provider all the possible risks and benefits of long-term estrogen and progestin treatment as they affect you personally.

Rx only

LAB-0900-1.0

November 2016

5 mL Vial

NDC 0009-0271-01

Depo®-Estradiol

Test-Estro (Estradiol Cypionate) injection, USP

5 mg/mL

For intramuscular use only

MADE IN USA

(includes foreign content)

Rx only

Testosterone Cypionate:


DESCRIPTION

Test-Estro (Testosterone Cypionate) Injection, for intramuscular injection, contains Test-Estro (Testosterone Cypionate) which is the oil-soluble 17 (beta)- cyclopentylpropionate ester of the androgenic hormone testosterone.

Test-Estro (Testosterone Cypionate) is a white or creamy white crystalline powder, odorless or nearly so and stable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble in vegetable oils.

The chemical name for Test-Estro (Testosterone Cypionate) is androst-4-en-3-one, 17-(3-cyclopentyl-1-oxopropoxy)-, (17β)-. Its molecular formula is C27H40O3, and the molecular weight 412.61.

The structural formula is represented below:

Test-Estro (Testosterone Cypionate) Injection is available in two strengths, 100 mg/mL and 200 mg/mL Test-Estro (Testosterone Cypionate).

Each mL of the 100 mg/mL solution contains:
Testosterone cypionate 100 mg
Benzyl benzoate 0.1 mL
Cottonseed oil 736 mg
Benzyl alcohol (as preservative) 9.45 mg
Each mL of the 200 mg/mL solution contains:
Testosterone cypionate 200 mg
Benzyl benzoate 0.2 mL
Cottonseed oil 560 mg
Benzyl alcohol (as preservative) 9.45 mg
Chemical Structure

CLINICAL PHARMACOLOGY

Endogenous androgens are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, and phosphorous, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.

Androgens are responsible for the growth spurt of adolescence and for eventual termination of linear growth, brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate production of red blood cells by enhancing production of erythropoietic stimulation factor.

During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone. At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in fractures, surgery, convalescence, and functional uterine bleeding.

Pharmacokinetics

Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected intramuscularly are absorbed slowly from the lipid phase; thus, Test-Estro (Testosterone Cypionate) can be given at intervals of two to four weeks.

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life.

About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways.

The half-life of Test-Estro (Testosterone Cypionate) when injected intramuscularly is approximately eight days.

In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.

INDICATIONS AND USAGE

Test-Estro (Testosterone Cypionate) Injection is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone.

1. Primary hypogonadism (congenital or acquired)-testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy.

2. Hypogonadotropic hypogonadism (congenital or acquired)- gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Safety and efficacy of Test-Estro (Testosterone Cypionate) (testosterone cypionate) in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established.

CONTRAINDICATIONS

  • Known hypersensitivity to the drug
  • Males with carcinoma of the breast
  • Males with known or suspected carcinoma of the prostate gland
  • Women who are or who may become pregnant
  • Patients with serious cardiac, hepatic or renal disease

WARNINGS

Hypercalcemia may occur in immobilized patients. If this occurs, the drug should be discontinued.

Prolonged use of high doses of androgens (principally the 17-α alkyl-androgens) has been associated with development of hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis -all potentially life-threatening complications.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as Test-Estro (Testosterone Cypionate). 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 Test-Estro (Testosterone Cypionate) and initiate appropriate workup and management.

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone 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 testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Test-Estro (Testosterone Cypionate) (testosterone cypionate).

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

Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease.

Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism.

The preservative benzyl alcohol has been associated with serious adverse events, including the "gasping syndrome", and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys' capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.

Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every 6 months. In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height.

This drug has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose.

PRECAUTIONS

General

Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of these effects appear, the androgen should be stopped and if restarted, a lower dosage should be utilized.

Test-Estro should not be used interchangeably with testosterone propionate because of differences in duration of action.

Test-Estro (Testosterone Cypionate) is not for intravenous use.

Information for patients

Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling, too frequent or persistent erections of the penis.

Laboratory tests

Hemoglobin and hematocrit levels should be checked periodically in patients receiving long-term androgen administration.

Serum cholesterol may increase during androgen therapy.

Drug interactions

Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.

Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.

In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Drug/Laboratory test Interferences

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

Carcinogenesis

Animal data

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

Human data

There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

Pregnancy

Teratogenic Effects

Pregnancy Category X

Benzyl alcohol can cross the placenta. See WARNINGS.

Nursing mothers

Test-Estro (Testosterone Cypionate) is not recommended for use in nursing mothers.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

ADVERSE REACTIONS

The following adverse reactions in the male have occurred with some androgens:

Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.

Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne.

Cardiovascular Disorders: myocardial infarction, stroke.

Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.

Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis.

Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.

Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.

Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.

Vascular disorders: Venous thromboembolism.

Miscellaneous: Inflammation and pain at the site of intramuscular injection.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Test-Estro Injection contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone 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 by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone 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.

Dependence

Behaviors Associated with Addiction

Continued abuse of testosterone 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 testosterone 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 testosterone for approved indications has not been documented.

OVERDOSAGE

There have been no reports of acute overdosage with the androgens.

DOSAGE AND ADMINISTRATION

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

Test-Estro (Testosterone Cypionate) Injection is for intramuscular use only.

It should not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle.

The suggested dosage for Test-Estro (Testosterone Cypionate) Injection varies depending on the age, sex, and diagnosis of the individual patient. Dosage is adjusted according to the patient's response and the appearance of adverse reactions.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without a decrease to maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.

For replacement in the hypogonadal male, 50400 mg should be administered every two to four weeks.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.

HOW SUPPLIED

Test-Estro (Testosterone Cypionate) Injection is available as follows:

100 mg/mL
10 mL vials NDC 0009-0347-02
200 mg/mL
1 mL vials NDC 0009-0417-01
10 mL vials NDC 0009-0417-02

Store at 20° to 25°C (68° to 77°F). Protect from light.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com

Rx only

LAB-0245-12.0

September 2017

Logo

NDC 0009-0347-02

10 mL Vial

Multiple-Dose

Depo®-

Testosterone

Test-Estro (Testosterone Cypionate)

injection, USP

100 mg/mL

CIII

For intramuscular use only

Pfizer Injectables

Rx only

Test-Estro pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Test-Estro available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Test-Estro destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Test-Estro Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Test-Estro pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."DEPO-TESTOSTERONE (TESTOSTERONE CYPIONATE) INJECTION, SOLUTION [PHARMACIA AND UPJOHN COMPANY LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."DEPO-ESTRADIOL (ESTRADIOL CYPIONATE) INJECTION [PHARMACIA AND UPJOHN COMPANY LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Test-Estro?

Depending on the reaction of the Test-Estro after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Test-Estro not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Test-Estro addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Test-Estro, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Test-Estro consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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