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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ral OKS i feen)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088593.pdf, must be dispensed with this medication.
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Prevention and treatment of osteoporosis in postmenopausal women; risk reduction for invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women with high risk for invasive breast cancer
Pregnancy Risk Factor
X
Pregnancy Considerations
Animal studies have demonstrated teratogenicity and fetal loss. There are no adequate and well-controlled studies in pregnant women. Raloxifene should not be used by women who are or may become pregnant.
Lactation
Excretion in breast milk unknown/contraindicated
Contraindications
History of or current venous thromboembolic disorders (including DVT, PE, and retinal vein thrombosis); pregnancy or women who could become pregnant; breast-feeding
Warnings/Precautions
Boxed warnings:
• Cardiovascular disease: See “Disease-related concerns” below.
• Thromboembolic disease: See “Disease-related concerns” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Disease-related concerns:
• Cardiovascular disease: [U.S. Boxed Warning]: The risk of death due to stroke may be increased in women with coronary heart disease or in women at risk for coronary events; use with caution in patients with cardiovascular disease. Do not use for the prevention of cardiovascular disease. Risk vs benefit should be considered in women at risk for stroke (eg, prior stroke, TIA, atrial fibrillation, hypertension, or smokers).
• Hepatic impairment: Use with caution in patients with hepatic impairment; safety and efficacy have not been established.
• Lipid effects: Women with a history of elevated triglycerides in response to treatment with oral estrogens (or estrogen/progestin) may develop elevated triglycerides when treated with raloxifene; monitor.
• Renal impairment: Use with caution in patients with moderate-to-severe renal impairment; safety and efficacy have not been established.
• Thromboembolic disease: [U.S. Boxed Warning]: May increase the risk for DVT or PE; use contraindicated in patients with history of or current venous thromboembolic disorders. Use with caution in patients at high risk for venous thromboembolism; consider risk vs benefit in women at risk for thromboembolism (HF, superficial thrombophlebitis, malignancy). The risk for DVT and PE are higher during the first 4 months of treatment. Superficial thrombophlebitis has also been reported.
• Uterine bleeding: Investigate unexplained uterine bleeding.
Concurrent drug therapy issues:
• Estrogens: Use with systemic estrogen therapy is not recommended; safety has not been established.
Special populations:
• Males: Safety and efficacy have not been established in men.
• Premenopausal women: Safety has not been established in premenopausal women; not indicated in premenopausal women.
Other warnings/precautions:
• Appropriate use: Not indicated for treatment of invasive breast cancer, to reduce the risk of recurrence of invasive breast cancer, or to reduce the risk of noninvasive breast cancer. The efficacy (for breast cancer risk reduction) in women with inherited BRCA1 and BRCA1 mutations has not been established. Any breast abnormality during treatment should be investigated.
• Prolonged immobilization: Discontinue at least 72 hours prior to and during prolonged immobilization (postoperative recovery or prolonged bedrest); restart only once patient fully ambulatory. Advise patients to move periodically during prolonged travel. The NCCN breast cancer risk reduction guidelines (v.2.2009) recommend stopping raloxifene 2-4 weeks prior to elective surgery.
Adverse Reactions
Note: Raloxifene has been associated with increased risk of thromboembolism (DVT, PE) and superficial thrombophlebitis; risk is similar to reported risk of HRT
>10%:
Cardiovascular: Peripheral edema (3% to 14%)
Endocrine & metabolic: Hot flashes (8% to 29%)
Neuromuscular & skeletal: Arthralgia (11% to 16%), leg cramps/muscle spasm (6% to 12%)
Miscellaneous: Flu syndrome (14% to 15%), infection (11%)
1% to 10%:
Cardiovascular: Chest pain (3%), venous thromboembolism (1% to 2%)
Central nervous system: Insomnia (6%)
Dermatologic: Rash (6%)
Endocrine & metabolic: Breast pain (4%)
Gastrointestinal: Weight gain (9%), abdominal pain (7%), vomiting (5%), flatulence (2% to 3%), cholelithiasis (≤3%), gastroenteritis (≤3%)
Genitourinary: Vaginal bleeding (6%), leukorrhea (3%), urinary tract disorder (3%), uterine disorder (3%), vaginal hemorrhage (3%), endometrial disorder (≤3%)
Neuromuscular & skeletal: Myalgia (8%), tendon disorder (4%)
Respiratory: Bronchitis (10%), sinusitis (10%), pharyngitis (8%), pneumonia (3%), laryngitis (≤2%)
Miscellaneous: Diaphoresis (3%)
<1%, postmarketing, and/or case reports: Apolipoprotein A-1 increased, apolipoprotein B decreased, death related to VTE, fibrinogen decreased, hypertriglyceridemia (in women with a history of increased triglycerides in response to oral estrogens), intermittent claudication, LDL cholesterol decreased, lipoprotein decreased, retinal vein occlusion, stroke related to VTE, superficial thrombophlebitis, total serum cholesterol decreased
Drug Interactions
Bile Acid Sequestrants: May decrease the absorption of Raloxifene. Risk D: Consider therapy modification
Levothyroxine: Raloxifene may decrease the absorption of Levothyroxine. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase risk of osteoporosis).
Storage
Store at controlled room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
A selective estrogen receptor modulator (SERM), meaning that it affects some of the same receptors that estrogen does, but not all, and in some instances, it antagonizes or blocks estrogen; it acts like estrogen to prevent bone loss and has the potential to block some estrogen effects in the breast and uterine tissues. Raloxifene decreases bone resorption, increasing bone mineral density and decreasing fracture incidence.
Pharmacodynamics/Kinetics
Onset of action: 8 weeks
Absorption: Rapid; ~60%
Distribution: 2348 L/kg
Protein binding: >95% to albumin and α-glycoprotein; does not bind to sex-hormone-binding globulin
Metabolism: Hepatic, extensive first-pass effect; metabolized to glucuronide conjugates
Bioavailability: ~2%
Half-life elimination: 28-33 hours
Excretion: Primarily feces; urine (<0.2% as unchanged drug; <6% as glucuronide conjugates)
Dosage
Adults: Females: Oral:
Osteoporosis: 60 mg once daily
Invasive breast cancer risk reduction: 60 mg once daily for 5 years per ASCO guidelines (Visvanathan, 2009)
Dosage adjustment in renal impairment: Moderate-to-severe impairment: Use caution; safety and efficacy have not been established.
Dosage adjustment in hepatic impairment: Mild impairment (Child-Pugh class A): Plasma concentrations were higher and correlated with total bilirubin. Safety and efficacy in hepatic insufficiency have not been established.
Administration: Oral
May be administered without regard to meals
Monitoring Parameters
Bone mineral density (BMD), lipid profile; adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding
Dietary Considerations
May be taken without regard to meals. Osteoporosis prevention or treatment: Ensure adequate calcium and vitamin D intake; postmenopausal women should consume ~1500 mg/day of elemental calcium and 400-800 int. units/day of vitamin D.
Patient Education
Avoid excessive use of alcohol (ethanol may increase risk of osteoporosis). May be taken at similar time each day without regard to meals. Additional vitamin and mineral supplements (vitamin D, calcium) may be recommended by your prescriber. May cause nausea, vomiting, diarrhea, or joint pain. Report immediately any pain, redness, warmth, or swelling in leg; sudden chest pain; respiratory difficulty; or sudden change in vision. Report acute migraine, weight gain, urinary infection, or vaginal burning or itching.
Geriatric Considerations
No need to cycle with progesterone.
Additional Information
The decrease in estrogen-related adverse effects with the selective estrogen-receptor modulators in general and raloxifene in particular should improve compliance and decrease the incidence of cardiovascular events and fractures while not increasing breast cancer.
Oncology Comment: The American Society of Clinical Oncology (ASCO) guidelines for breast cancer risk reduction (Visvanathan, 2009) recommend raloxifene (for 5 years) as an option to reduce the risk of ER-positive invasive breast cancer in postmenopausal women with a 5-year projected risk (based on NCI trial model) of ≥1.66%, or with lobular carcinoma in situ. Raloxifene should not be used in premenopausal women. Women with osteoporosis may use raloxifene beyond 5 years of treatment. According to the NCCN breast cancer risk reduction guidelines (v.2.2009), raloxifene is only recommended for postmenopausal women (≥35 years of age), and is equivalent to tamoxifen although, raloxifene has a better adverse event profile; however, tamoxifen is superior in reducing the risk on noninvasive breast cancer.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause insomnia or depression
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Evaluate lipid profile and BMD. Monitor for DVT, PE, chest pain, migraine, and rash on a regular basis during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as hydrochloride:
Evista®: 60 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Evista)
60 mg (30): $149.99
References
Barrett-Connor E, Mosca L, Collins P, et al, “Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women,” N Engl J Med, 2006, 355(2):125-37.
Chlebowski RT, Col N, Winer EP, et al, “American Society of Clinical Oncology Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene, and Aromatase Inhibition,” J Clin Oncol, 2002, 20(15):3328-43.
Cummings SR, Eckert S, Krueger KA, et al, “The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results from the MORE Randomized Trial,” JAMA, 1999, 281(23) 2189-97.
Delmas PD, Bjarnason NH, Mitlak BH, et al, “Effects of Raloxifene on Bone Mineral Density, Serum Cholesterol Concentrations, and Uterine Endometrium in Postmenopausal Women,” N Engl J Med, 1997, 337(23):1641-7.
Draper MW, Flowers DE, Huster WJ, et al, “A Controlled Trial of Raloxifene (LY139481) HCl: Impact on Bone Turnover and Serum Lipid Profile in Healthy Postmenopausal Women,” J Bone Miner Res, 1996, 11(6):835-42.
Heaney RP and Draper MW, “Raloxifene and Estrogen: Comparative Bone-Remodeling Kinetics,” J Clin Endocrinol Metab, 1997, 2(10):3425-9.
Land SR, Wickerham DL, Costantino JP, et al, “Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial,” JAMA, 2006, 295(23):2742-51.
Martino S, Cauley JA, Barrett-Connor E, et al, “Continuing Outcomes Relevant to Evista: Breast Cancer Incident in Postmenopausal Women in a Randomized Trial of Raloxifene,” J Natl Cancer Inst, 2004, 96(23):1751-61.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Breast Cancer,” Version 1.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Breast Cancer Risk Reduction,” Version 2.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf
Siris ES, Harrris ST, Eastell R, et al, “Skeletal Effects of Raloxifene After 8 Years: Results From the Continuing Outcomes Relevant to Evista (CORE) Study,” J Bone Miner Res, 2005, 20(9):1514-24.
Visvanathan K, Chlebowski RT, Hurley P, et al, “American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction,” J Clin Oncol, 2009, 27(19):3235-58.
Vogel VG, Costantino JP, Wickerham DL, “Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial,” JAMA, 2006, 295(23):2727-41.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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