Cyclofem

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Cyclofem uses

Cyclofem consists of Estradiol Cypionate, Medroxyprogesterone Acetate.

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

Cyclofem (Estradiol Cypionate) Injection contains Cyclofem (Estradiol Cypionate) for intramuscular use. Each mL contains:

5 mg/mL-5 mg Cyclofem (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:

Cyclofem (Estradiol Cypionate) contains an oil soluble ester of estradiol 17β. The chemical name for Cyclofem (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 Cyclofem (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 Cyclofem (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 Cyclofem (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

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

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

Cyclofem 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 Cyclofem (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.

Cyclofem (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

Cyclofem (Estradiol Cypionate) Injection is available in the following concentration containing per mL:

5 mg Cyclofem (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

Cyclofem (Estradiol Cypionate)®

Brand of Cyclofem (Estradiol Cypionate) injection, USP

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

What is Cyclofem (Estradiol Cypionate)?

Cyclofem (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 Cyclofem (Estradiol Cypionate) used for?

Cyclofem (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 Cyclofem (Estradiol Cypionate) to control these problems.


Cyclofem (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 Cyclofem (Estradiol Cypionate)?

Do not start taking Cyclofem (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 Cyclofem (Estradiol Cypionate).

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

Tell your healthcare provider:

  • if you are breastfeeding.

The hormone in Cyclofem (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 Cyclofem (Estradiol Cypionate) works. Cyclofem (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 Cyclofem (Estradiol Cypionate)?

Take Cyclofem (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 Cyclofem (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 Cyclofem (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 Cyclofem (Estradiol Cypionate)?

  • Talk with your healthcare provider regularly about whether you should continue taking Cyclofem (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 Cyclofem (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 Cyclofem (Estradiol Cypionate)

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

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

Cyclofem (Estradiol Cypionate) injection, USP

5 mg/mL

For intramuscular use only

MADE IN USA

(includes foreign content)

Rx only

Medroxyprogesterone Acetate:


INDICATIONS AND USAGE

Cyclofem (Medroxyprogesterone Acetate) Tablets USP are a progestin indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Cyclofem (Medroxyprogesterone Acetate) Tablets USP are also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg tablets.

CONTRAINDICATIONS

Cyclofem (Medroxyprogesterone Acetate) Tablets USP should not be used in women with any of the following conditions:

  • Undiagnosed abnormal genital bleeding.
  • Known, suspected, or history of cancer of the breast.
  • Known or suspected estrogen- or progesterone-dependent neoplasia.
  • Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  • Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction).
  • Known liver dysfunction or disease.
  • Missed abortion.
  • As a diagnostic test for pregnancy.
  • Known hypersensitivity to the ingredients in Cyclofem (Medroxyprogesterone Acetate) tablets.
  • Known or suspected pregnancy.

WARNINGS

1. Cardiovascular Disorders.

An increased risk of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

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

a. Stroke

In the estrogen plus progestin substudy of the Women’s Health Initiative (WHI) a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) plus Cyclofem (Medroxyprogesterone Acetate) (MPA 2.5 mg) compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted.

b. Coronary heart disease

In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events. An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estro- gen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/ MPA 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 (2,321) 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.

c. Venous thromboembolism (VTE)

In the estrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE/MPA compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted.

2. Malignant Neoplasms

a. Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration.

The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus Cyclofem (Medroxyprogesterone Acetate) (MPA 2.5 mg)

In the estrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nominal confidence interval [nCI], 1.01 to 1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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 versus 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 versus 36 cases per 10,000 women-years, for estrogen plus progestin 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 health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

b. Endometrial cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy 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.

c. Ovarian cancer

The estrogen plus progestin substudy of WHI reported that daily CE/MPA 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 was 4.2 versus 2.7 cases per 10,000 women-years.

3. Dementia

In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily conjugated estrogens (CE 0.625 mg) plus Cyclofem (Medroxyprogesterone Acetate) (MPA 2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). 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.

4. Visual Abnormalities

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, medication should be permanently discontinued.

PRECAUTIONS

A. General

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

  • Undiagnosed abnormal vaginal bleeding

    In cases of undiagnosed abnormal vaginal bleeding, adequate diagnostic measures are indicated.

  • Elevated blood pressure

    Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.

  • Hypertriglyceridemia

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

  • Impaired liver function and past history of cholestatic jaundice

    Estrogens plus progestins 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.

  • Fluid Retention

    Progestins may cause some degree of fluid retention. Patients who have conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen plus progestin are prescribed.

  • Hypocalcemia

    Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia.

  • Exacerbation of other conditions

    Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, 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 Cyclofem (Medroxyprogesterone Acetate).

There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1,000 male births. The risk may be increased with exposure to Cyclofem (Medroxyprogesterone Acetate). Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of Cyclofem (Medroxyprogesterone Acetate) has not been established.

Inform the patient of the importance of reporting exposure to Cyclofem (Medroxyprogesterone Acetate) in early pregnancy.

C. Drug/Laboratory Test Interactions

The following laboratory results may be altered by the use of estrogen plus progestin therapy:

  • 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 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.
  • Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  • Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
  • Impaired glucose metabolism.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term intramuscular administration of Cyclofem (Medroxyprogesterone Acetate) has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of Cyclofem (Medroxyprogesterone Acetate) to rats and mice. Cyclofem (Medroxyprogesterone Acetate) was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

Cyclofem (Medroxyprogesterone Acetate) at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

Long-term continuous administration of estrogen plus progestin therapy, has shown an increased risk of breast cancer and ovarian cancer.

E. Pregnancy

Teratogenic Effects

Pregnancy Category X

Cyclofem should not be used during pregnancy.

There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to Cyclofem (Medroxyprogesterone Acetate) during the first trimester of pregnancy. However, a clear association between these conditions with use of Cyclofem (Medroxyprogesterone Acetate) has not been established.

F. Nursing Mothers

Cyclofem (Medroxyprogesterone Acetate) should not be used during lactation. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins.

G. Pediatric Use

Cyclofem is not intended for pediatric use and no clinical data has been collected in children.

H. Geriatric Use

Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative (WHI), 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 and older compared to women less than 75 years of age, there was a higher relative risk of non-fatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75 years of age, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.

In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to receive daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

Eighty-two percent of the cases of probable dementia occurred in women that were older than 70 in the CE/MPA group. The most common classification of probable dementia in the estrogen plus progestin and placebo groups was Alzheimer’s disease.

When data from the estrogen alone and estrogen plus progestin WHIMS substudies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women.

ADVERSE REACTIONS

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 following adverse reactions have been reported in women taking progestins, including Cyclofem tablets, without concomitant estrogens treatment:

1. Genitourinary System

Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions.

2. Breasts

Breast tenderness, mastodynia or galactorrhea has been reported.

3. Cardiovascular

Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported.

4. Gastrointestinal

Nausea, cholestatic jaundice.

5. Skin

Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.

6. Eyes

Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis.

7. Central Nervous System

Mental depression, insomnia, somnolence, dizziness, headache, nervousness.

8. Miscellaneous

Hypersensitivity reactions, rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.

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

1. Genitourinary System

Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; 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 that 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/anaplylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

OVERDOSAGE

Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE/MPA together with institution of appropriate symptomatic care.

DOSAGE AND ADMINISTRATION

Secondary Amenorrhea

Cyclofem Tablets USP may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of Cyclofem (Medroxyprogesterone Acetate) daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing Cyclofem (Medroxyprogesterone Acetate) therapy.

Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology

Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of Cyclofem (Medroxyprogesterone Acetate) may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of Cyclofem (Medroxyprogesterone Acetate) daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with Cyclofem (Medroxyprogesterone Acetate). Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with Cyclofem (Medroxyprogesterone Acetate).

Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens

When estrogen is prescribed for a postmenopausal woman with a uterus, a 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 re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary. 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.

Cyclofem (Medroxyprogesterone Acetate) Tablets USP may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Patients should be started at the lowest dose.

The lowest effective dose of Cyclofem (Medroxyprogesterone Acetate) has not been determined.

HOW SUPPLIED

Cyclofem (Medroxyprogesterone Acetate) Tablets, USP are available as:

2.5 mg: White, round, scored, biconvex tablet. Debossed with 555/872 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets
5 mg: White, round, scored, biconvex tablet. Debossed with 555/873 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets
10 mg: White, round, scored, biconvex tablet. Debossed with 555/779 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20° to 25°C (68° to 77°F).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 4/2010

PATIENT INFORMATION

Read this PATIENT INFORMATION before you start taking Cyclofem (Medroxyprogesterone Acetate) and read the patient information each time you refill your Cyclofem (Medroxyprogesterone Acetate) prescription. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Cyclofem (Medroxyprogesterone Acetate) (A PROGESTIN HORMONE)?


* Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care 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 chance of getting heart attacks, strokes, breast cancer, and blood clots.

* Using estrogens with or without progestins may increase your risk of dementia, based on a study of women age 65 years or older.

You and your health care provider should talk regularly about whether you still need treatment with Cyclofem (Medroxyprogesterone Acetate).

What is Cyclofem (Medroxyprogesterone Acetate)?

Cyclofem (Medroxyprogesterone Acetate) is a medicine that contains Cyclofem (Medroxyprogesterone Acetate), a progestin hormone.

What is Cyclofem (Medroxyprogesterone Acetate) used for?

Medroxyprogesterone Acetate is used to:

  • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your health care provider about whether Cyclofem (Medroxyprogesterone Acetate) is right for you.
  • Reduce your chances of getting cancer of the uterus. In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chances of getting cancer of the uterus.

Who should not take Cyclofem (Medroxyprogesterone Acetate)?

Do not start taking Cyclofem (Medroxyprogesterone Acetate) if you:

  • Have undiagnosed vaginal bleeding
  • Currently have or have had certain cancers

Estrogen plus progestin may increase your chance of getting certain cancers, including cancer of the breast. If you have or have had cancer, talk with your health care provider about whether you should use Cyclofem (Medroxyprogesterone Acetate).

  • Had a stroke or heart attack in the past year
  • Currently have or have had blood clots
  • Currently have or have had liver problems
  • Think you may be pregnant

Tell your health care provider if you think that you may be pregnant or having a miscarriage. There may be an increased risk of minor birth defects in children whose mothers take this drug during the first 4 months of pregnancy. If you take Cyclofem (Medroxyprogesterone Acetate) and later find out you were pregnant when you took it, be sure to discuss this with your doctor as soon as possible.

Cyclofem (Medroxyprogesterone Acetate) should not be used as a test for pregnancy.

  • Are allergic to any of the ingredients in Cyclofem (Medroxyprogesterone Acetate).

Tell your health care provider:

  • If you are breastfeeding. The hormone in Cyclofem (Medroxyprogesterone Acetate) can pass into your breast milk.
  • About all of your medical problems. Your health care provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing); epilepsy (seizures); migraine headaches; endometriosis (severe pelvic pain); lupus; problems with your heart, liver, thyroid, or kidneys; or if you 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 Cyclofem (Medroxyprogesterone Acetate) works. Cyclofem (Medroxyprogesterone Acetate) may also affect how other medicines work.
  • If you are going to have surgery or will be on bed rest. If you are taking estrogen in addition to Cyclofem (Medroxyprogesterone Acetate), you may need to stop taking estrogen and Cyclofem (Medroxyprogesterone Acetate).

How should I take Cyclofem (Medroxyprogesterone Acetate)?

Start at the lowest dose and talk to your health care provider about how well that dose is working for you. The lowest effective dose of Cyclofem (Medroxyprogesterone Acetate) has not been determined.

You and your health care provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with Cyclofem (Medroxyprogesterone Acetate).

  • Absence of menstrual period: Cyclofem (Medroxyprogesterone Acetate) may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
  • Abnormal Uterine Bleeding: Cyclofem (Medroxyprogesterone Acetate) may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
  • Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, Cyclofem (Medroxyprogesterone Acetate) may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month.

What are the possible side effects of Cyclofem (Medroxyprogesterone Acetate)?

The following side effects have been reported with the use of Cyclofem (Medroxyprogesterone Acetate) alone:

  • Breast tenderness
  • Breast milk secretion
  • Breakthrough bleeding
  • Spotting (minor vaginal bleeding)
  • Irregular periods
  • Amenorrhea (absence of menstrual periods)
  • Vaginal secretions
  • Headaches
  • Nervousness
  • Dizziness
  • Depression
  • Insomnia, sleepiness, fatigue
  • Premenstrual syndrome-like symptoms
  • Thrombophlebitis (inflamed veins)
  • Blood clot
  • Itching, hives, skin rash
  • Acne
  • Hair loss, hair growth
  • Abdominal discomfort
  • Nausea
  • Bloating
  • Fever
  • Increase in weight
  • Swelling
  • Changes in vision and sensitivity to contact lenses

The following side effects have been reported with the use of Cyclofem (Medroxyprogesterone Acetate) with an estrogen.

Side effects are grouped by how serious they are and how often they happen when you are treated:

Serious but less common side effects of estrogen include:

  • Breast cancer
  • Cancer of the uterus
  • Stroke
  • Heart attack
  • Blood clots
  • Dementia
  • Gallbladder disease
  • Ovarian cancer
  • High blood pressure
  • Liver problems
  • High blood sugar
  • Enlargement of benign tumors of the uterus (“fibroids”)

Some of the warning signs of these serious side effects include:

  • 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
  • Yellowing of the skin, eyes or nail beds

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

Less serious but common side effects include:

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

These are not all the possible side effects of Cyclofem (Medroxyprogesterone Acetate) with or without estrogen. For more information, ask your health care provider or pharmacist.

What can I do to lower my chances of a serious side effect with Cyclofem (Medroxyprogesterone Acetate)?

  • Talk with your health care provider regularly about whether you should continue taking Cyclofem (Medroxyprogesterone Acetate). The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus.
  • See your health care provider right away if you get vaginal bleeding while taking Cyclofem (Medroxyprogesterone Acetate).
  • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your health care provider tells you otherwise. 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 a higher chance of getting heart disease. Ask your health care provider for ways to lower your chance of getting heart disease.

General information about safe and effective use of Cyclofem (Medroxyprogesterone Acetate)

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

Keep Cyclofem (Medroxyprogesterone Acetate) out of the reach of children.

This leaflet provides a summary of the most important information about Cyclofem (Medroxyprogesterone Acetate). If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Cyclofem (Medroxyprogesterone Acetate) that is written for health professionals.

What are the ingredients in Cyclofem (Medroxyprogesterone Acetate)?

Each Cyclofem (Medroxyprogesterone Acetate) Tablet USP for oral administration contains 2.5 mg, 5 mg or 10 mg of Cyclofem (Medroxyprogesterone Acetate).

Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized starch, and sodium lauryl sulfate.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 4/2010

Medroxy - Progesterone 2.5mg

Structural Formula

Cyclofem 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.


Cyclofem 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.


Cyclofem 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.


Cyclofem 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.


Cyclofem 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-ESTRADIOL (ESTRADIOL CYPIONATE) INJECTION [PHARMACIA AND UPJOHN COMPANY LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."MEDROXYPROGESTERONE ACETATE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."MEDROXYPROGESTERONE ACETATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Cyclofem?

Depending on the reaction of the Cyclofem after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cyclofem 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 Cyclofem 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 Cyclofem, 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 Cyclofem 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.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Cyclofem drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
11-50mg1
100.0%

One visitor reported time for results

What is the time duration Cyclofem drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 month to notice the result from using Cyclofem drug. The time needed to show improvement in health condition after using the medicine Cyclofem need not be same for all the users. It varies based on other factors.
Visitors%
1 month1
100.0%

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
16-291
100.0%

Visitor reviews


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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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