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ANGELIQ (ESTRADIOL HEMIHYDRATE/DROSPIRENONE) by BAYER,PHARM DIV
ANGELIQ (ESTRADIOL HEMIHYDRATE/DROSPIRENONE) BAYER,PHARM DIV

Warning: Do not use if you are pregnant, suspect that you are pregnant, or while breastfeeding. Consult your doctor or pharmacist.

Smoking should be avoided while taking this medication.

May cause headache.

May cause dizziness

Avoid prolonged or excessive exposure to direct and/or artificial sunlight while taking this medication.

WARNING: Rarely, very serious side effects have occurred when estrogen-only and combination hormone replacement therapies (estrogen and progestin HRT) are used after menopause. Discuss the risks and benefits of hormone treatment and your personal health history with your doctor. Combination HRT should not be used to prevent heart disease or dementia. Combination HRT can rarely cause heart disease (e.g., heart attacks), stroke, serious blood clots (pulmonary embolism and deep venous thrombosis), dementia, and breast cancer. The risk for stroke and breast cancer increases with age, especially for women older than 75. Estrogens may also increase the risk of cancer of the ovaries. Some of these risks appear to depend on the length of time this drug is used and the amount of estrogen per dose. Therefore, this medication should be used for the shortest possible length of time at the lowest effective dose, so you can obtain the benefits and minimize the chance of serious side effects from long-term treatment. Discuss the details with your doctor and check with him/her regularly (e.g., every 3-6 months) to see if you still need to take this medication. If you use this drug for an extended time, you should have a complete physical exam at regular intervals (e.g., once a year) or as directed by your doctor. See Notes section.

INDICATIONS:
Disease of Ovaries with Cysts
Wasting of Tissues of the Vulva
"Change of Life" Signs
Vaginal Inflammation due to Loss of Hormone Stimulation

CONTRAINDICATIONS:
DROSPIRENONE: Adrenocortical Insufficiency
DROSPIRENONE: Bed-Ridden
DROSPIRENONE: Breast Carcinoma
DROSPIRENONE: Cerebrovascular Accident
DROSPIRENONE: Coronary Artery Disease
DROSPIRENONE: Deep Venous Thrombosis
DROSPIRENONE: Diplopia
DROSPIRENONE: Disease of Liver
DROSPIRENONE: Hyperkalemia
DROSPIRENONE: Metrorrhagia
DROSPIRENONE: Myocardial Infarction
DROSPIRENONE: Pregnancy
DROSPIRENONE: Pulmonary Thromboembolism
DROSPIRENONE: Retinal Thrombosis
DROSPIRENONE: Severe Renal Disease
DROSPIRENONE: Thromboembolic Disorder
DROSPIRENONE: Diabetes Mellitus
DROSPIRENONE: Hyperlipidemia
DROSPIRENONE: Hypertension
DROSPIRENONE: Migraine
DROSPIRENONE: Obesity
DROSPIRENONE: Papilledema
DROSPIRENONE: Porphyria
DROSPIRENONE: Retinal Hemorrhage
DROSPIRENONE: Systemic Lupus Erythematosus
DROSPIRENONE: Tobacco Smoker
DROSPIRENONE: Vision Loss
DROSPIRENONE: Body Fluid Retention
DROSPIRENONE: Bronchial Asthma
DROSPIRENONE: Chronic Heart Failure
DROSPIRENONE: Depression
DROSPIRENONE: Ovarian Carcinoma
DROSPIRENONE: Renal Disease
DROSPIRENONE: Seizure Disorder
ESTROGENIC AGENTS: Breast Carcinoma
ESTROGENIC AGENTS: Cerebrovascular Accident
ESTROGENIC AGENTS: Deep Venous Thrombosis
ESTROGENIC AGENTS: Disease of Liver
ESTROGENIC AGENTS: Estrogen-Dependent Neoplasm
ESTROGENIC AGENTS: Hypercoagulability States
ESTROGENIC AGENTS: Metrorrhagia
ESTROGENIC AGENTS: Myocardial Infarction
ESTROGENIC AGENTS: Pregnancy
ESTROGENIC AGENTS: Pulmonary Thromboembolism
ESTROGENIC AGENTS: Severe Uncontrolled Hypertension
ESTROGENIC AGENTS: Thromboembolic Disorder
ESTROGENIC AGENTS: Coronary Artery Disease
ESTROGENIC AGENTS: Dementia
ESTROGENIC AGENTS: Endometrial Carcinoma
ESTROGENIC AGENTS: Familial History of Breast Carcinoma
ESTROGENIC AGENTS: Gallbladder Disease
ESTROGENIC AGENTS: Hypercalcemia associated with Metastatic Breast Carcinoma
ESTROGENIC AGENTS: Hypercholesterolemia
ESTROGENIC AGENTS: Hyperlipoproteinemia
ESTROGENIC AGENTS: Hypertension
ESTROGENIC AGENTS: Increased Cardiovascular Event Risk
ESTROGENIC AGENTS: Obesity
ESTROGENIC AGENTS: Ovarian Carcinoma
ESTROGENIC AGENTS: Retinal Thrombosis
ESTROGENIC AGENTS: Thrombophlebitis
ESTROGENIC AGENTS: Tobacco Smoker
ESTROGENIC AGENTS: Vision Loss
ESTROGENIC AGENTS: Body Fluid Retention
ESTROGENIC AGENTS: Bronchial Asthma
ESTROGENIC AGENTS: Chloasma
ESTROGENIC AGENTS: Chorea
ESTROGENIC AGENTS: Diabetes Mellitus
ESTROGENIC AGENTS: Endometriosis
ESTROGENIC AGENTS: Epilepsy
ESTROGENIC AGENTS: Hepatic Porphyria
ESTROGENIC AGENTS: Hypertriglyceridemia
ESTROGENIC AGENTS: Hypocalcemia
ESTROGENIC AGENTS: Hypothyroidism
ESTROGENIC AGENTS: Lumps in Breasts
ESTROGENIC AGENTS: Mammography Abnormal
ESTROGENIC AGENTS: Migraine
ESTROGENIC AGENTS: Systemic Lupus Erythematosus
ESTROGENIC AGENTS: Uterine Fibroids

MONOGRAPH - PATIENT:
IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

DROSPIRENONE/ESTRADIOL - ORAL (droh-SPYE-re-none/ess-truh-DYE-all)

COMMON BRAND NAME(S): Angeliq

WARNING: Rarely, very serious side effects have occurred when estrogen-only and combination hormone replacement therapies (estrogen and progestin HRT) are used after menopause. Discuss the risks and benefits of hormone treatment and your personal health history with your doctor. Combination HRT should not be used to prevent heart disease or dementia. Combination HRT can rarely cause heart disease (e.g., heart attacks), stroke, serious blood clots (pulmonary embolism and deep venous thrombosis), dementia, and breast cancer. The risk for stroke and breast cancer increases with age, especially for women older than 75. Estrogens may also increase the risk of cancer of the ovaries. Some of these risks appear to depend on the length of time this drug is used and the amount of estrogen per dose. Therefore, this medication should be used for the shortest possible length of time at the lowest effective dose, so you can obtain the benefits and minimize the chance of serious side effects from long-term treatment. Discuss the details with your doctor and check with him/her regularly (e.g., every 3-6 months) to see if you still need to take this medication. If you use this drug for an extended time, you should have a complete physical exam at regular intervals (e.g., once a year) or as directed by your doctor. See Notes section.

USES: This medication is used to reduce menopause symptoms. It helps reduce episodes of flushing and sweating of the upper body and face, commonly called hot flashes. It also helps treat dryness, itching, and burning around the vagina. These symptoms occur when a woman's body no longer makes the usual amount of female hormone (estrogen). This medication is a combination of 2 types of female hormones: an estrogen (estradiol) and a progestin (drospirenone). A progestin is added to estrogen replacement therapy to reduce the risk of cancer of the uterus. A woman who has had her uterus removed does not need progestin and should not be treated with this combination medication. If you need treatment only for vaginal menopause symptoms, products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional. Certain combination HRT products may also be used to prevent bone loss (osteoporosis) in people at high risk who cannot take other drugs that are safe and effective to prevent or treat bone loss (e.g., raloxifene, bisphosphonates such as alendronate). These medicines should be considered for use before estrogen/progestin HRT therapy for osteoporosis.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this medication and each time you get a refill. If you have any questions, consult your doctor or pharmacist. Take this medication by mouth, usually once daily or as directed by your doctor. Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Inform your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: Dizziness, lightheadedness, headache, stomach upset, bloating, irritability, changes in sleep patterns, nausea, weight changes, increased/decreased interest in sex, change in vaginal discharge, or breast tenderness may occur. If any of these persist or worsen, tell your doctor promptly. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., depression, memory loss), breast lumps, nipple discharge, swelling of the hands/feet, unusual vaginal bleeding (e.g., spotting, breakthrough bleeding, prolonged/returning bleeding), yellowing eyes/skin, stomach/abdominal pain, worsening of a seizure condition, muscle weakness, signs of worsening diabetes control (e.g., increased thirst and urination). This medication may rarely cause very serious problems such as heart attacks, stroke, and blood clots. Seek immediate medical attention if you experience any of the following: chest/jaw/left arm pain, sudden severe headache, weakness on one side of the body, confusion, slurred speech, sudden vision changes (e.g., double vision, loss of vision), pain/redness/swelling/weakness of the arms/legs, calf pain/swelling that is warm to the touch, trouble breathing, coughing up blood, sudden dizziness/fainting. A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to drospirenone or estradiol; or to spironolactone; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: vaginal bleeding of unknown cause, certain types of cancer (breast, ovary, uterus), current/history of blood clots, history of stroke or heart attack, liver disease, kidney disease, adrenal gland problems. Before using this medication, tell your doctor or pharmacist your medical history, especially of: family medical history (including blood clots, breast lumps/cancer), asthma, diabetes, seizures, migraine headaches, heart disease (e.g., high blood pressure, congestive heart failure), underactive thyroid (hypothyroidism), a certain hormone problem (hypoparathyroidism), mineral imbalance (high or low calcium blood level, high potassium blood level, low sodium blood level), mental/mood disorders (e.g., depression, memory loss), high blood pressure during pregnancy (toxemia), yellowing eyes/skin (cholestatic jaundice) during pregnancy or with past estrogen use, uterus problems (e.g., uterine fibroids, endometriosis), high blood cholesterol/fat (triglyceride) levels, gallbladder disease, obesity, a certain metabolic disorder (porphyria), lupus. This drug may make you dizzy or lightheaded. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages. If you are nearsighted or wear contact lenses, you may develop vision problems or trouble wearing your contact lenses. Consult your eye doctor if these problems occur. This drug may cause a patchy darkening of the skin on the face (melasma). Sunlight may worsen this darkening. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors. Do not smoke cigarettes or use tobacco. Smoking/using tobacco while taking this medication further increase your risk for stroke, blood clots, high blood pressure, and heart attacks, especially in women older than 35. If you will be having surgery or will be confined to a chair or bed for a long time (e.g., a long plane flight), tell your doctor beforehand. Special precautions may need to be taken in these circumstances while you are taking this drug because of the increased risk for blood clots. This medication must not be used during pregnancy. If you become pregnant or think you may be pregnant, tell your doctor immediately. This medication is not effective for preventing a miscarriage and should not be used for this purpose. Small amounts of this medication pass into breast milk. This drug may reduce the quality and amount of breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first. This drug should not be used with the following medications because very serious interactions may occur: aromatase inhibitors (e.g., anastrozole, exemestane). If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting drospirenone/estradiol. Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: corticosteroids (e.g., prednisone), raloxifene, tamoxifen, tizanidine, warfarin, drugs affecting liver enzymes that remove estrogens from your body (such as azole antifungals including itraconazole, macrolide antibiotics including erythromycin, rifamycins including rifabutin, St. John's wort, certain anti-seizure medications including carbamazepine, phenobarbital, phenytoin). Drospirenone may increase the level of potassium in your blood. Before taking drospirenone/estradiol, tell your doctor or pharmacist if you are taking other medications that can raise potassium blood levels. A potassium level in the blood that is too high may cause serious side effects. Follow your doctor's instructions carefully, and continue taking medications for your condition as directed. Keep all medical/laboratory appointments so your doctor can monitor your potassium levels. Check with your doctor or pharmacist if you are taking any of the following: ACE inhibitors (e.g., benazepril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), heparin, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen), potassium supplements (e.g., potassium chloride), salt substitutes that contain potassium, certain "water pills" (potassium-sparing diuretics such as amiloride, eplerenone, spironolactone, triamterene). This product can affect the results of certain lab tests. Make sure laboratory personnel and all your doctors know you use this drug. This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe nausea/vomiting, unusual vaginal bleeding in females.

NOTES: Do not share this medication with others. Keep all medical and laboratory appointments. You should have a complete physical examination that includes blood pressure measurements and breast/pelvic examinations at regular intervals (e.g., once a year) or as directed by your doctor. Follow your doctor's instructions on how to examine your own breasts and report any lumps immediately. You should also be regularly screened for cervical cancer (e.g., Pap test) and have periodic mammograms as determined by your doctor. Consult your doctor for more details. Lifestyle changes that help promote healthy bones include increasing weight-bearing exercise, stopping smoking, limiting alcohol, and eating well-balanced meals that contain adequate calcium and vitamin D. Since you may also need to take calcium and vitamin D supplements and make lifestyle changes, consult your doctor for specific advice. Additional lifestyle changes (e.g., reducing stress, eating a low fat/low salt diet, losing weight if you are overweight) to control or prevent high blood pressure, high cholesterol, and diabetes help to prevent heart disease and strokes. Keep your mind active with mental exercises to help prevent dementia. Discuss with your doctor lifestyle changes that might benefit you. You can also manage hot flashes by keeping a cool body temperature (e.g., using a fan, drinking cool beverages, dressing lightly/in layers, avoiding hot/spicy foods). Limiting caffeine and alcohol, exercising regularly, and learning relaxation techniques may help reduce hot flashes. Vaginal lubricants can help lessen discomfort during intercourse.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010 Copyright(c) 2010 First DataBank, Inc.


MONOGRAPH - FOOD & DRUG:
MONOGRAPH TITLE: Estrogens/Grapefruit Juice Interaction

SIGNIFICANCE LEVEL: 3-Significant; Documented (more clinical data may be needed): Conservative measures are recommended until more is known.

MECHANISM OF ACTION: CYP P-450-3A4 and isoenzymes of CYP P-450-2C and P-450-Ce take part in 2-hydroxylation of ethinyl estradiol. In 2-hydroxylation of ethinyl estradiol, isoenzymes of CYP P-450-3A4(1) as well as CYP P-450-2C and CYO P-450-2E are involved.(2) Flavonoids present in grapefruit juice inhibit CYP P-450-3A4 greatly.(3) Thus, it is believed that naringin (a grapefruit flavonoid) or naringenin (its aglycon) prevent the 2-hydroxylation of ethinyl estradiol by inhibition of CYP P-450-3A4 in the gut. Grapefruit juice may affect other estrogens similarly.(5-7)

CLINICAL EFFECTS: Increases in estrogen serum concentrations.

PATIENT MANAGEMENT: Co-administration of grapefruit juice can lead to elevated estrogen levels. Since the extent of this interaction varies among subjects, monitoring of patients is recommended.

DISCUSSION: 13 healthy females participated in a randomized, cross-over study in order to determine the effects of grapefruit juice on exogenously administered ethinyl estradiol. The subjects were to stop using steroid contraceptives at least a month prior to this experiment. After an overnight fast, on day 411 of the menstrual cycle, each subject ingested 100 mL of either herbal tea or grapefruit juice (naringin concentration 887 mg/mL). Each subject received 0.05 mg of 17?-ethinyl estradiol with 100 mL of the initial corresponding fluid thirty minutes following the administration of first 100 mL of fluids. Then, the volunteers consumed 200 mL of corresponding fluid every three hours, up to four times on the day of the study. Blood samples obtained following administration of ethinyl estradiol, revealed that grapefruit juice increased maximum plasma concentration (Cmax) of ethinyl estradiol from 85 pg/mL to 117 pg/ml when compared to herbal tea (p = 0.009). The 0-6 hours and 0-8 areas-under-curve (AUC) also elevated significantly with p values of 0.0192 and 0.0186, respectively. The Cmax variability was -19% to +80% and the AUC (0-8 hours) was 16% to +114%.(4) In an open, randomized, cross-over study in 8 ovariectomized women, subjects received single doses of 2 mg micronized 17 beta-estradiol with and without grapefruit juice. Grapefruit juice increased peak and AUC estrone levels significantly.(5) Grapefruit juice was also found to inhibit 17 beta-estradiol metabolism in human liver microsomes.(6) Grapefruit juice may increase levels of conjugated estrogens as well.(7)

REFERENCES:

1.Guengerich FP. Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 1988 May;33(5):500-8. 2.Ball SE, Forrester LM, Wolf CR, Back DJ. Differences in the cytochrome P-450 isoenzymes involved in the 2-hydroxylation of oestradiol and 17 alpha-ethinyloestradiol. Relative activities of rat and human liver enzymes. Biochem J 1990 Apr 1;267(1):221-6. 3.Miniscalco A, Lundahl J, Regardh CG, Edgar B, Eriksson UG. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J Pharmacol Exp Ther 1992 Jun;261(3):1195-9. 4.Schubert W, Cullberg G, Edgar B, Hedner T. Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women. Maturitas 1994 Dec;20(2-3):155-63. 5.Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-24. 6.Fingerova H, Oborna I, Petrova P, Budikova M, Jezdinsky J. Does grapefruit juice increase the bioavailability of orally administered sex steroids?. Ceska Gynekol 2003 Mar;68(2):117-21. 7.Premarin (conjugated estrogen tablets, USP) US prescribing information. Wyeth Pharmaceuticals Inc. April, 2005.

RELATED DISEASES:
Increased Cardiovascular Event Risk
Metabolic Syndrome X
Ovarian Cyst
Polycystic Ovarian Syndrome
Post-Menopausal Symptoms
Reproductive System Disorder
Vaginitis

RELATED ICD CODES:
Atrophic Vaginitis [627.3]
Atrophy of Vulva [624.1]
Hormone Replacement Therapy (Postmenopausal) [V07.4]
Menopausal Disorder Not Otherwise Specified [627.9]
Menopausal Disorders [627]
Menopausal Disorders Not Elsewhere Classified [627.8]
Noninflammatory Disorder of Vulva Not Otherwise Specified [624.9]
Noninflammatory Disorders of Vulva and Perineum [624]
Ovarian Dysfunction [256]
Ovarian Dysfunction Not Elsewhere Classified [256.8]
Ovarian Dysfunction Not Otherwise Specified [256.9]
Polycystic Ovaries [256.4]
Symptomatic Female Climacteric State [627.2]
Symptomatic States associated with Artificial Menopause [627.4]

Indication: "Change of Life" Signs:

take 1 tablet by oral route once daily

Indication: Vaginal Inflammation due to Loss of Hormone Stimulation:

take 1 tablet by oral route once daily

Indication: Wasting of Tissues of the Vulva:

take 1 tablet by oral route once daily

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