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Raloxifene

Pronunciation

Pronunciation

(ral OKS i feen)

Index Terms

  • Keoxifene Hydrochloride
  • Raloxifene HCl
  • Raloxifene Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Evista: 60 mg

Generic: 60 mg

Brand Names: U.S.

  • Evista

Pharmacologic Category

  • Selective Estrogen Receptor Modulator (SERM)

Pharmacology

Raloxifene is an estrogen agonist/antagonist (a selective estrogen receptor modulator [SERM]); selective binding activates estrogenic pathways in some tissues and antagonizes estrogenic pathways in other tissues. Raloxifene acts like an estrogen agonist in the bone to prevent bone loss and has estrogen antagonist activity to block some estrogen effects in the breast and uterine tissues. Raloxifene decreases bone resorption, increasing bone mineral density and decreasing fracture incidence.

Absorption

Rapid; ~60%

Distribution

2,348 L/kg

Metabolism

Hepatic, extensive first-pass metabolism; metabolized to glucuronide conjugates

Excretion

Feces (primarily); urine (<0.2% as unchanged drug; <6% as glucuronide conjugates)

Half-Life Elimination

27.7 hours (following a single dose); 32.5 hours (following multiple doses)

Protein Binding

Highly protein bound (95% to albumin and α-glycoprotein); does not bind to sex-hormone-binding globulin

Special Populations: Renal Function Impairment

Raloxifene AUC was 122% higher in patients with moderate to severe renal impairment.

Special Populations: Hepatic Function Impairment

Raloxifene apparent clearance was reduced 56% and plasma concentrations were increased 150% in patients with mild hepatic impairment.

Use: Labeled Indications

Osteoporosis: Treatment and prevention of osteoporosis in postmenopausal women

Risk reduction for invasive breast cancer: Risk reduction for invasive breast cancer in postmenopausal women with osteoporosis; risk reduction of invasive breast cancer in postmenopausal women with high risk for invasive breast cancer (high risk is defined as at least 1 breast biopsy showing lobular carcinoma in situ or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer 1.66% or more [based on the Gail model]; factors included in the modified Gail model include current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity, or age of first live birth).

Limitations of use: Raloxifene does not eliminate the risk of breast cancer; patients should have a breast exam and mammogram prior to initiating raloxifene and continue regular breast exams and mammograms as per current guideline recommendations. Raloxifene is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. Raloxifene is not indicated for the reduction of the risk of noninvasive breast cancer. There are no data available regarding the effect of raloxifene on invasive breast cancer incidence in women with inherited mutations BRCA1, BRCA2 to be able to make specific recommendations on the effectiveness of raloxifene.

Contraindications

History of or current venous thromboembolic disorders (including deep vein thrombosis [DVT], pulmonary embolism [PE], and retinal vein thrombosis); pregnancy or women who could become pregnant; breast-feeding

Dosing: Adult

Osteoporosis: Females: Oral: 60 mg once daily

Risk reduction for invasive breast cancer: Females (postmenopausal): Oral: 60 mg once daily.

Duration of therapy for breast cancer risk reduction: 5 years; may be used longer than 5 years in women with osteoporosis where breast cancer risk reduction is a secondary benefit (Visvanathan 2013).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≤50 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Administration

May be administered at any time of day without regard to meals.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).

Dietary Considerations

Osteoporosis prevention or treatment: Ensure adequate calcium and vitamin D intake; if dietary intake is inadequate, dietary supplementation is recommended. Women and men should consume:

Calcium: 1,000 mg/day (men: 50 to 70 years) or 1,200 mg/day (women ≥51 years and men ≥71 years) (IOM 2011; NOF [Cosman 2014])

Vitamin D: 800 to 1,000 int. units daily (men and women ≥50 years) (NOF [Cosman 2014]). Recommended Dietary Allowance (RDA): 600 int. units daily (men and women ≤70 years) or 800 int. units daily (men and women ≥71 years) (IOM 2011).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Bile Acid Sequestrants: May decrease the absorption of Raloxifene. Consider therapy modification

Levothyroxine: Raloxifene may decrease the absorption of Levothyroxine. Consider therapy modification

Ospemifene: Selective Estrogen Receptor Modulators may enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators. Avoid combination

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% (Limited to important or life-threatening): 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

ALERT: U.S. Boxed Warning

Increased risk of venous thromboembolism (VTE):

Increased risk of deep vein thrombosis and pulmonary embolism have been reported with raloxifene. Women with active VTE or a history of VTE should not take raloxifene.

Cardiovascular disease:

Increased risk of death caused by stroke occurred in a trial in postmenopausal women with documented coronary heart disease or increased risk for major coronary reactions. Consider the risk-benefit balance in women at risk for stroke.

Warnings/Precautions

Concerns related to adverse effects:

• Thromboembolic events: [US Boxed Warning]: Raloxifene may increase the risk for DVT and PE; use is contraindicated in patients with history of or current venous thromboembolic disorders (including DVT, PE, or retinal vein thrombosis). Consider risks versus benefits in women at risk for thromboembolism (heart failure [HF], superficial thrombophlebitis, active malignancy). The risk for DVT and PE are higher during the first 4 months of treatment. Superficial thrombophlebitis has also been reported.

Disease-related concerns:

• Breast cancer history: The use of raloxifene has not been adequately studied in women with a prior history of breast cancer.

• Cardiovascular disease: [US Boxed Warning]: The risk of death due to stroke is increased in postmenopausal women with coronary heart disease or at increased risk for major coronary events; consider risks versus benefits in women at risk for stroke. Do not use for primary or secondary prevention of cardiovascular disease. Assess risks versus benefits 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.

• Hypertriglyceridemia: Women with a history of marked elevated triglycerides (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogens (or estrogen/progestin) may also develop elevated triglycerides when treated with raloxifene; monitor triglycerides.

• Renal impairment: Use with caution in patients with moderate to severe renal impairment; safety and efficacy have not been established.

• Uterine bleeding: Investigate unexplained uterine bleeding.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Estrogens: Concurrent 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. Raloxifene is not indicated for use in men.

• Premenopausal women: Safety has not been established in premenopausal women; use in premenopausal women is not indicated and not recommended.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: Raloxifene does not eliminate the risk of breast cancer; investigate unexplained breast abnormality that occurs during treatment. Raloxifene is 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. The American Society of Clinical Oncology (ASCO) guidelines for breast cancer risk reduction (Visvanathan 2013) 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.

• Prolonged immobilization: Discontinue raloxifene at least 72 hours prior to and during prolonged immobilization (postoperative recovery or prolonged bed rest); restart only once patient fully ambulatory. Advise patients to move periodically during prolonged travel.

Monitoring Parameters

Lipid profile (in women at risk for hypertriglyceridemia); mammogram and breast exam (prior to and regularly during treatment)

Osteoporosis: Bone mineral density (BMD) should be evaluated 1 to 2 years after initiating therapy and every 2 years thereafter (NOF [Cosman 2014]); annual measurements of height and weight; serum calcium and 25(OH)D; may consider monitoring biochemical markers of bone turnover

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in in animal reproduction studies. Raloxifene is contraindicated for use in women who are or may become pregnant.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hot flashes, joint pain, leg cramps, or sweating a lot. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, vision changes, lump in breast, breast soreness or pain, nipple discharge, enlarged breasts, vaginal bleeding, or flu-like symptoms (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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