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DRUGS & SUPPLEMENTS
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Estradiol Valerate:
Cyclo-Menorette (Estradiol Valerate) (estradiol valerate injection, USP) is indicated in the:
Cyclo-Menorette (Estradiol Valerate) should not be used in women with any of the following conditions:
See BOXED WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism. Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
In the Women's Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies ).
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
In the Women's Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies .)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies ). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination hormone therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.
The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use ).
It is unknown whether these findings apply to estrogen alone therapy.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
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.
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.
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.
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
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.
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.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
Estrogens should be used with caution in individuals with severe hypocalcemia.
The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years.
A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
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.
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.
Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies report no such increase.
Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Cyclo-Menorette.
Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).
Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS ).
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Cyclo-Menorette should not be used during pregnancy. (See CONTRAINDICATIONS ).
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 Cyclo-Menorette (Estradiol Valerate) is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete.
Clinical studies of Cyclo-Menorette (Estradiol Valerate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of the women that were older than 70. (See WARNINGS, Dementia ).
It is unknown whether these findings apply to estrogen alone therapy.
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
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.
Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
Retinal vascular thrombosis; intolerance to contact lenses.
Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.
For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch.
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (See BOXED WARNINGS and WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Care should be taken to inject deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Cyclo-Menorette (Estradiol Valerate) (estradiol valerate injection, USP) may be administered with a small gauge needle (i.e., 20 Gauge × 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.
Cyclo-Menorette (Estradiol Valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.
Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.
Patients should be started at the lowest dose for the indication. The lowest effective dose of Cyclo-Menorette (Estradiol Valerate) has not been determined for any indication. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. See PRECAUTIONS concerning addition of a progestin.
The usual dosage is 10 to 20 mg Cyclo-Menorette (Estradiol Valerate) every four weeks.
Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.
The usual dosage is 10 to 20 mg Cyclo-Menorette (Estradiol Valerate) every four weeks.
The usual dosage is 30 mg or more administered every one or two weeks.
Cyclo-Menorette ® (estradiol valerate injection, USP)
Multiple Dose Vials
Store between 20° to 25°C (68° to 77°F).
Keep out of reach of children.
Cyclo-Menorette (Estradiol Valerate)®
(estradiol valerate injection, USP)
Read this PATIENT INFORMATION before you start taking Cyclo-Menorette (Estradiol Valerate) and read what you get each time you refill Cyclo-Menorette (Estradiol Valerate). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Cyclo-Menorette (Estradiol Valerate) (AN ESTROGEN HORMONE)?
Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Cyclo-Menorette (Estradiol Valerate).
What is Cyclo-Menorette (Estradiol Valerate)?
Cyclo-Menorette (Estradiol Valerate) is a medicine that contains estrogen hormones.
What is Cyclo-Menorette (Estradiol Valerate) used for?
Cyclo-Menorette (Estradiol Valerate) is used after menopause to:
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feeling of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Cyclo-Menorette (Estradiol Valerate).
Who should not take Cyclo-Menorette (Estradiol Valerate)?
Do not start taking Cyclo-Menorette (Estradiol Valerate) if you:
Tell your healthcare provider:
How should I take Cyclo-Menorette (Estradiol Valerate)?
Cyclo-Menorette (Estradiol Valerate) should be injected deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Cyclo-Menorette (Estradiol Valerate) (estradiol valerate injection, USP) may be administered with a small gauge needle (i.e., 20 Gauge × 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.
Cyclo-Menorette (Estradiol Valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.
Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.
How should I dispose of used syringes and needles?
http://www.safeneedledisposal.org or refer to the FDA website Needles and Other Sharps at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/Sharps/default.htm
How should I dispose of expired or unused Cyclo-Menorette (Estradiol Valerate)?
Disposal of Unused Medicines: What You Should Know
http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/ensuringsafeuseofmedicine/safedisposalofmedicines/ucm186187.htm
How to Dispose of Unused Medicines http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/ucm107163.pdf
What are the possible side effects of estrogens?
Less common but serious side effects include:
These are some of the warning signs of serious side effects:
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:
Other side effects include:
These are not all the possible side effects of Cyclo-Menorette (Estradiol Valerate). For more information, ask your healthcare provider or pharmacist.
What can I do to lower my chances of a serious side effect with Cyclo-Menorette (Estradiol Valerate)?
Talk with your healthcare provider regularly about whether you should continue taking Cyclo-Menorette (Estradiol Valerate). If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. See your healthcare provider right away if you get vaginal bleeding while taking Cyclo-Menorette (Estradiol Valerate). Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.
General information about safe and effective use of Cyclo-Menorette (Estradiol Valerate)
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Cyclo-Menorette (Estradiol Valerate) for conditions for which it was not prescribed. Do not give Cyclo-Menorette (Estradiol Valerate) to other people, even if they have the same symptoms you have. It may harm them.
Keep Cyclo-Menorette (Estradiol Valerate) out of the reach of children.
This leaflet provides a summary of the most important information about Cyclo-Menorette (Estradiol Valerate). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Cyclo-Menorette (Estradiol Valerate) that is written for health professionals. You can get more information by calling the toll free number 1-800-828-9393.
What are the ingredients in Cyclo-Menorette (Estradiol Valerate)?
Cyclo-Menorette (Estradiol Valerate) is supplied in three 5 mL multiple dose vials; 10 mg/mL, 20 mg/mL, and 40 mg/mL strengths. The 10 mg/mL strength contains 10 mg Cyclo-Menorette (Estradiol Valerate) in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg Cyclo-Menorette (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg Cyclo-Menorette (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil.
How should I store Cyclo-Menorette (Estradiol Valerate)?
Store Cyclo-Menorette (Estradiol Valerate) at room temperature between 20° to 25°C (68° to 77°F).
Manufactured by:
Par Pharmaceutical, Inc.
Chestnut Ridge, NY 10977
Revised: 08/17
OS110J-1-90-03
3001078H
NDC 42023-110-01
Cyclo-Menorette (Estradiol Valerate)®
(estradiol valerate
injection, USP)
50 mg/5 mL
(10 mg/mL)
For Intramuscular Use Only
5 mL Multiple Dose Vial
NDC 42023-111-01
Cyclo-Menorette (Estradiol Valerate) ®
(estradiol valerate
injection, USP)
100 mg/5 mL
(20 mg/mL)
For Intramuscular Use Only
NDC 42023-112-01
Cyclo-Menorette (Estradiol Valerate)®
(estradiol valerate
injection, USP)
200 mg/5 mL
(40 mg/mL)
For Intramuscular Use Only
Estriol:
NADA 141-325, Approved by FDA
For Oral Use in Dogs Only
Federal law restricts this drug to use by or on the order of a licensed veterinarian.
Cyclo-Menorette (Estriol) (estriol) Tablets contain 1 mg of Cyclo-Menorette (Estriol) per tablet.
USP Chemical Name: Estra-1,3,5(10)-triene-3,16,17-triol, (16α,17β)-.
USP Molecular Weight: 288.38
USP Solubility: Soluble in acetone, in chloroform, in dioxane, in ether, and in vegetable oils; sparingly soluble in alcohol; insoluble in water.
Cyclo-Menorette (Estriol) Tablets are indicated for the control of estrogen-responsive urinary incontinence in ovariohysterectomized female dogs.
The dose of Cyclo-Menorette (Estriol) Tablets is not dependent upon body weight. All dogs should receive an initial dose of 2 mg Cyclo-Menorette (Estriol) Tablets (2 tablets) orally once per day for a minimum of 14 days. After urinary incontinence is controlled, the lowest effective daily dose of Cyclo-Menorette (Estriol) Tablets should be determined by decreasing the dose in a step-wise manner from 2 mg once daily (2 tablets) to 1 mg once daily (1 tablet), then 0.5 mg once daily (1/2 tablet) depending upon the response of the individual dog. There should be a minimum of 7 days between each dose adjustment. After the lowest daily dose that controls urinary incontinence is identified, the dose may be decreased further by administering once every two days. Dogs should not receive more than 2 mg Cyclo-Menorette (Estriol) Tablets per day (2 tablets). If the dog does not respond to 2 mg of Cyclo-Menorette (Estriol) Tablets per day, the diagnosis should be re-assessed.
Not for human use. Keep out of the reach of children. Women who are of child-bearing age or those who are breastfeeding should use caution when administering Cyclo-Menorette Tablets. Wash your hands with soap and water after administration to avoid exposure to the drug. Consult a physician in case of accidental ingestion by humans.
Some estrogens have been associated with bone marrow changes and an increased risk of mammary tumors. However, target animal safety study results and foreign post-market pharmacovigilance data for Cyclo-Menorette (Estriol) Tablets have shown that estriol-treated dogs are at low risk for developing these conditions.
Evaluation of factors contributing to urinary incontinence should be considered prior of administration of Cyclo-Menorette (Estriol) Tablets.
Do not use with other estrogens. The concomitant use of Cyclo-Menorette (Estriol)
Tablets with other estrogens has not been evaluated.
The concomitant use of Cyclo-Menorette (Estriol) Tablets with glucocorticoids has not been evaluated.
The use of Cyclo-Menorette (Estriol) Tablets in dogs with liver disease has not been evaluated.
The safe use of Cyclo-Menorette (Estriol) Tablets has not been evaluated in intact female dogs, pregnant or lactating dogs, male dogs, and dogs less than 1 year of age.
In the initial phase of a placebo-controlled field study conducted to determine effectiveness, 115 of 226 dogs were dosed with Cyclo-Menorette Tablets orally at 2 mg per day for 14 days. Adverse reactions during the first study phase included primarily gastrointestinal and estrogenic effects, as summarized in Table 1.
Adverse Reaction | Cyclo-Menorette (Estriol) Tablet Group % of dogs (n = 115) | Placebo Group % of dogs (n = 111) |
---|---|---|
Anorexia | 13.0% | 3.6% |
Emesis | 9.6% | 6.3% |
Polydipsia | 7.0% | 7.2% |
Swollen vulva | 4.3% | 0.0% |
Anxiety | 3.5% | 2.7% |
Sexual attractiveness | 3.5% | 1.8% |
Somnolence | 1.7% | 0.0% |
Hypersalivation | 1.7% | 0.0% |
Estrous behavior | 0.9% | 0.0% |
Mammary hyperplasia | 0.9% | 0.0% |
In the second phase of the field study, all dogs received treatment with Cyclo-Menorette (Estriol) Tablets from Day 14 to Day 42; the drug dose was adjusted up or down (not to exceed 2 mg per day) at weekly intervals depending on whether urinary incontinence was controlled. Table 2 summarizes reported adverse reactions in dogs treated with Cyclo-Menorette (Estriol) Tablets during the second study phase. Adverse reactions tended to lessen when dogs received lower drug doses. One dog that received 10 doses of Cyclo-Menorette (Estriol) was removed due to suspected uterine stump pyometra. The relationship between this adverse reaction and Cyclo-Menorette (Estriol) Tablets could not be determined.
Adverse Reaction | Cyclo-Menorette (Estriol) Tablets Group % of dogs (n = 224) |
---|---|
Anorexia | 12.9% |
Emesis | 7.6% |
Licking vulva | 4.5% |
Swollen vulva | 4.0% |
Vulvovaginitis | 4.0% |
Lethargy | 4.0% |
Polydipsia | 3.6% |
Aggression | 1.8% |
Hyperactivity | 1.8% |
Cystitis | 1.3% |
Anxiety | 0.9% |
Mammary hyperplasia | 0.9% |
Somnolence | 0.9% |
Estrous behavior | 0.9% |
Sexual attractiveness | 0.4% |
Alopecia (local) | 0.4% |
Extended-use studies continued after the field studies involving more than 300 dogs. Additional adverse reactions to those seen in the field studies included hyperpigmentation and lichenification of the vulva. Also, 3 dogs receiving Cyclo-Menorette (Estriol) Tablets were euthanized due to aggressive behavior.
Foreign post-market pharmacovigilance data for Cyclo-Menorette (Estriol) Tablets were collected from the years 2000 through 2010 by Intervet, Inc. Approximately 20% of reported adverse events were for local or general alopecia. Vaginal hemorrhage, possible stump pyometra, an increase in epileptic seizures, and anemia, leukopenia, and thrombocytopenia were seen in 1 or more dogs. Other adverse events reported were similar to those seen during the US studies.
For technical assistance or to report suspected adverse reactions call Intervet at 1-800-224-5318. For a copy of the Material Safety Data Sheet (MSDS), call 1-800-770-8878.
Cyclo-Menorette (Estriol) is a natural estrogen. Estrogens increase the resting muscle tone of the urethra in females and can be used to treat female dogs with urinary incontinence due to estrogen depletion. Cyclo-Menorette (Estriol) is rapidly absorbed after oral administration. It has a high affinity for receptors in cells of the lower urogenital tract, but a short receptor occupancy time that limits the undesirable effects of endometrial proliferation, skeletal muscle growth, and bone marrow suppression associated with long-term estrogen-estrogen receptor binding.
As one of the three naturally occurring estrogens, Cyclo-Menorette (Estriol) is a lipophilic compound that can passively diffuse through cell membranes and bind to estrogen receptors in the nucleus to regulate gene expression. After an oral dose of 2 mg/dog/day in fed female dogs, Tmax occurred between 0.5-2 hrs (average 0.8 hrs) with corresponding Cmax values of 220-1150 pg/mL (average 650 pg/mL). Entero-hepatic recirculation and drug reabsorption may cause a second concentration peak in plasma around 4-12 hrs after dosing. Its elimination T½ ranges from 8 to 12 hours based on a multiple oral dose study in 6 adult female dogs.
However, the apparent Cyclo-Menorette (Estriol) recycling observed in most dogs produced multiple peaks that confound the accurate determination of T½. The effect of prandial state on oral Cyclo-Menorette (Estriol) bioavailability has not been evaluated. Repeated oral administration may result in elevated Cyclo-Menorette (Estriol) systemic exposure.
A multi-site, masked, placebo-controlled field study was conducted to evaluate the effectiveness of Cyclo-Menorette (Estriol) Tablets. Two hundred and twenty-six client-owned, ovariohysterectomized female dogs 1 year of age or older with at least 3 episodes of urinary incontinence each week were randomly allocated to receive either Cyclo-Menorette (Estriol) Tablets or placebo. Two hundred and six dogs (106 treated with Cyclo-Menorette (Estriol) Tablets and 100 treated with placebo) from 22 sites were evaluated for effectiveness. Each dog was dosed orally with either two 1 mg tablets of Cyclo-Menorette (Estriol) Tablets or two tablets of placebo once per day for 14 days. During treatment, owners recorded the frequency of urinary incontinence episodes daily, and investigators rated response to treatment weekly (continent/improved or no change/worse). Treatment success was based upon response to treatment and a targeted reduction in the frequency of urinary incontinence episodes at Day 14 compared to Day 0. The proportion of dogs achieving treatment success was statistically significantly greater (p = 0.0038) in the group treated with Cyclo-Menorette (Estriol) Tablets (66%) than in the placebo-treated group (37%) at Day 14.
A second phase of the study evaluated decreasing doses of Cyclo-Menorette (Estriol) Tablets to control urinary incontinence. After Day 14, all dogs (224) received 2 tablets of Cyclo-Menorette (Estriol) Tablets (2 mg) orally once per day. Starting at Day 21, investigators were permitted to adjust the dose of Cyclo-Menorette (Estriol) Tablets up or down (not to exceed 2 mg per day) at weekly intervals until Day 42 if urinary continence was controlled. Dose information and urinary incontinence scoring was available for 191 dogs at the end of the study; ninety four dogs were receiving 2 mg of Cyclo-Menorette (Estriol) Tablets per day, and the other 96 dogs had dose reductions below 2 mg per day. Of the 94 dogs receiving 2 mg of Cyclo-Menorette (Estriol) Tablets per day during the last week of the study, 81 dogs (86%) had either reduced urinary incontinence (n = 57) or no urinary incontinence (n = 24) compared to Day 0. Of the ninety-seven dogs with dose reductions below 2 mg per day, all dogs receiving 1 mg of Cyclo-Menorette (Estriol) Tablets once daily (n = 41), 1 mg every other day (n = 5), or 0.5 mg every other day (n = 24) had either reduced or no incontinence compared to Day 0. Twenty-five of 26 dogs receiving 0.5 mg once daily had reduced or no incontinence, and one dog dosed with 2 mg of Cyclo-Menorette (Estriol) Tablets every other day had reduced incontinence.
There were no clinically significant changes in hematology or serum chemistry during either phase of the study.
In a 26-week safety study, 24 healthy, ovariohysterectomized female Beagle dogs approximately 1 year of age, weighing 7.3 to 10.5 kg, were randomly divided into 4 groups of 6 animals each. Cyclo-Menorette (Estriol) Tablets were administered orally at doses of 0 (placebo), 1× (2 mg), 3× (6 mg) and 5× (10 mg) the maximum proposed label dose of 2 mg per dog per day. Estrogenic effects such as swollen vulva, mammary hyperplasia, and vulvar discharge occurred frequently in all dogs that received Cyclo-Menorette (Estriol) Tablets and increased in a dose-dependent manner. On gross necropsy, all dogs treated with Cyclo-Menorette (Estriol) Tablets had enlarged vulvas except 1 dog that received 2 mg per day. Microscopically, the vulvas and vaginas of treated dogs had a proestrus-like appearance, with or without a lymphoplasmacytic infiltrate. In addition, approximately one-third of the dogs in each group treated with Cyclo-Menorette (Estriol) Tablets had lymphoplasmacytic infiltrate and urothelium hyperplasia of the renal pelvis. One dog treated with 10 mg per day had urinary bladder inflammation. Dogs that received 6 mg and 10 mg of Cyclo-Menorette (Estriol) Tablets per day had increased white blood cell counts, absolute neutrophil counts and platelet counts compared to dogs in the other 2 groups. There were no changes related to Cyclo-Menorette (Estriol) Tablet administration noted in the microscopic evaluation of bone marrow smears. The myeloid:erythroid (M:E) cell ratios were comparable between dogs that received 10 mg of Cyclo-Menorette (Estriol) Tablets per day and those treated with placebo.
Store at or below 25°C (77°F) with excursions permitted to 40°C (104°F)
Cyclo-Menorette (Estriol) Tablets contain 1 mg of Cyclo-Menorette (Estriol) in each tablet and are supplied in foil-sealed blister packs of 30 single-scored tablets. Two carton sizes containing either 30 tablets (one blister pack) or 90 tablets (three blister packs) are available.
Made in the Netherlands,
May, 2011
Cyclo-Menorette (Estriol) is the property of Intervet International B.V. or affiliated companies or licensors and is protected by copyrights, trademark and other intellectual property laws.
Copyright © 2011
Intervet International B.V.
All rights reserved.
117967 R10
Levonorgestrel:
Indication: For the treatment of menopausal and postmenopausal disorders and alone or in combination with other hormones as an oral contraceptive.
Cyclo-Menorette (Levonorgestrel) is a progestin or a synthetic form of the naturally occurring female sex hormone, progesterone. In a woman's normal menstrual cycle, an egg matures and is released from the ovaries (ovulation). The ovary then produces progesterone, preventing the release of further eggs and priming the lining of the womb for a possible pregnancy. If pregnancy occurs, progesterone levels in the body remain high, maintaining the womb lining. If pregnancy does not occur, progesterone levels in the body fall, resulting in a menstrual period. Cyclo-Menorette (Levonorgestrel) tricks the body processes into thinking that ovulation has already occurred, by maintaining high levels of the synthetic progesterone. This prevents the release of eggs from the ovaries.
Depending on the reaction of the Cyclo-Menorette after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cyclo-Menorette 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 Cyclo-Menorette 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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The information was verified by Dr. Rachana Salvi, MD Pharmacology