Raloxifene Hydrochloride

Class: Estrogen Agonists-Antagonists
ATC Class: G03XC01
VA Class: HS900
Chemical Name: 6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-piperidinoethoxy)phenyl ketone hydrochloride
Molecular Formula: C₂₈H₂₇NO₄S•ClH
CAS Number: 82640-04-8
Brands: Evista

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  Increased risk for DVT and pulmonary embolism.¹ Contraindicated in women with active or past episodes of venous thrombosis.¹ (See Contraindications and Cardiovascular Effects under Cautions.)

  
  


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  Increased risk of fatal stroke reported in women with CHD or increased risk for CHD.¹ Weigh risks versus benefits in women at risk for stroke.¹ (See Cardiovascular Effects under Cautions.)

  
  

Introduction

Estrogen agonist-antagonist; a nonsteroidal benzothiophene derivative.^{1 2 3 13 14 15 16 17 55 69 70}

Uses for Raloxifene Hydrochloride

Osteoporosis

Prevention of osteoporosis in postmenopausal women.^{1 2 3 4 5 6 7 16 17 23 55 69 108}

Treatment of osteoporosis in postmenopausal women.^{1 53 69 98 99 108}

Use supplemental calcium and/or vitamin D concomitantly if daily dietary intake is considered inadequate.^{1 2 3 4 5 6 7 16 17 23 55 69 108}

Corticosteroid-induced Osteoporosis

May prevent or treat corticosteroid-induced bone loss†.¹⁰⁷ American College of Rheumatology states that raloxifene can be offered to selected postmenopausal corticosteroid-treated women who refuse hormone replacement therapy or other antiresorptive agents (e.g., bisphosphonates, calcitonin) or in whom such therapies are contraindicated.¹⁰⁷

Breast Cancer

Reduction in the incidence of invasive breast cancer in postmenopausal women with osteoporosis.^{1 93 100}

Reduction in the incidence of invasive breast cancer in postmenopausal women at high risk for developing the disease.^{1 109 113} Effect comparable to that of tamoxifen in reducing the risk of invasive breast cancer (STAR trial).^{1 109 113} No effect on the risk of lobular carcinoma in situ or ductal carcinoma in situ (STAR trial).¹¹³ Effect on breast cancer incidence in women with BRCA1 or BRCA2 genetic mutations not established.¹

Not indicated for the treatment of breast cancer or to reduce the risk of recurrence of breast cancer.¹ Not indicated for reduction in the risk of noninvasive breast cancer.¹

Raloxifene Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals or time of day.^{1 2 55}

Dosage

Available as raloxifene hydrochloride; dosage expressed in terms of the salt.¹

Adults

Osteoporosis

Prevention in Postmenopausal Women

Oral

60 mg daily.^{1 2 55}

Treatment in Postmenopausal Women

Oral

60 mg daily.^{1 98}

Breast Cancer

Reduction in the Incidence of Invasive Breast Cancer

Oral

60 mg daily.¹ Optimum duration of therapy unknown.¹

Cautions for Raloxifene Hydrochloride

Contraindications

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  Active or past episodes of venous thrombosis, including DVT, pulmonary embolism, or retinal vein thrombosis.^{1 52}

  
  


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  Women who are or may become pregnant.¹

  
  


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  Lactating women.¹

  
  

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased risk of venous thromboembolic events (e.g., DVT, pulmonary embolism).^{1 55 69 72}

Discontinue raloxifene ≥72 hours before and during prolonged immobilization (e.g., postsurgery recovery, prolonged bed rest); resume therapy once patient is fully ambulatory.^{1 52}

Assess potential benefit versus risk in women at risk of thromboembolic disease secondary to CHF, superficial thrombophlebitis, or active malignancy.^{1 2}

Increased risk for fatal stroke reported in women with CHD or increased risk for CHD (RUTH study).^{1 115} Assess potential benefit versus risk in women at risk of stroke secondary to history of stroke or TIA, atrial fibrillation, hypertension, or cigarette smoking.¹

Not indicated for the primary or secondary prevention of cardiovascular disease.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.^{1 58 59 60 61 62 63} Embryotoxic and teratogenic effects demonstrated in animals.^{1 60 61} If inadvertently used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹ (See Contraindications.)

General Precautions

Use in Premenopausal Women

Not indicated.¹ Safety not established.¹

Effects on Lipids

Potential for increased serum triglyceride concentrations in women with a history of substantial hypertriglyceridemia during oral estrogen therapy; monitor serum triglycerides in these women.¹

Effects on the Breast

Not studied in women with a history of breast cancer.¹

Investigate unexplained breast abnormality.¹ Does not eliminate risk of breast cancer.¹

Use in Men

Safety and efficacy not evaluated.¹

GU Effects

Not associated with endometrial proliferation.¹ Investigate unexplained uterine bleeding.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)

Lactation

Contraindicated.¹

Not known whether raloxifene is distributed into milk.¹

Pediatric Use

Not indicated.¹

Geriatric Use

No substantial differences in safety, efficacy, or pharmacokinetic profile relative to younger adults.¹

Hepatic Impairment

Use with caution; safety and efficacy not established in patients with hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Use with caution in patients with moderate to severe renal impairment; safety and efficacy not established in these patients.¹ (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Hot flushes (flashes), leg cramps, peripheral edema, flu-like syndrome, arthralgia, sweating.^{1 2 23 69 72 88 93 96 98}

Interactions for Raloxifene Hydrochloride

Metabolism apparently not mediated by CYP isoenzymes.¹

Protein-bound Drugs

Concomitant administration with other highly protein-bound drugs not expected to affect plasma raloxifene concentrations.¹ Caution advised if used concomitantly with other highly protein-bound drugs.¹

Specific Drugs

Drug	Interaction	Comments
Amoxicillin and ampicillin	Ampicillin: Decreased peak plasma raloxifene concentrations; no change in systemic exposure to raloxifene1 Amoxicillin: No change in raloxifene concentrations1	Can be administered concomitantly1
Anion-exchange resins (cholestyramine)	Decreased absorption and enterohepatic cycling of raloxifene with concomitant cholestyramine administration; similar interaction expected with other anion-exchange resins1	Concomitant administration with cholestyramine not recommended1 52
Antacids (aluminum- and magnesium-containing, calcium carbonate)	No change in systemic exposure of raloxifene1	Can be administered concomitantly1
Anticoagulants, oral	Decreased warfarin effects; no effect on warfarin pharmacokinetics observed1	Monitor PT carefully1
Antilipemic agents	Concomitant use not specifically studied1
Diazepam	Potential for altered protein binding of diazepam1	Caution advised1
Diazoxide	Potential for altered protein binding of diazoxide1	Caution advised1
Digoxin	No change in digoxin pharmacokinetics1	Can be administered concomitantly1
Estrogens	Not studied1	Concomitant use not recommended1
Gemfibrozil	No substantial change in plasma raloxifene concentrations1
Lidocaine	Potential for altered protein binding of lidocaine1	Caution advised1
Methylprednisolone	No change in methylprednisolone pharmacokinetics1	Can be administered concomitantly with corticosteroids1
Phenytoin	No change in protein binding of phenytoin1

Raloxifene Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract; 60% of an oral dose is absorbed, but absolute bioavailability as unchanged drug is only 2% because of extensive first-pass glucuronidation.^{1 27 33 34 35 45 69}

Following oral administration, peak plasma concentrations achieved at 6 hours (raloxifene) and 1 hour (glucuronide conjugates).^{33 35}

Food

High-fat meal increases peak plasma concentration and extent of absorption of raloxifene, but does not substantially affect systemic exposure.¹

Special Populations

Plasma raloxifene concentrations are 150% higher in patients with cirrhosis (Child-Pugh class A) and total serum bilirubin concentrations of 0.6–2 mg/dL than in individuals with normal hepatic function.¹ Pharmacokinetics not studied in individuals with moderate or severe hepatic impairment.¹

Plasma raloxifene concentrations in those with mild renal impairment are similar to values in women with normal renal function.^{1 96} AUC of raloxifene is 122% higher in individuals with moderate renal impairment (Cl_cr 31–50 mL/minute) or severe renal impairment (Cl_cr ≤30 mL/minute) than in individuals with normal renal function.¹

Distribution

Plasma Protein Binding

Raloxifene and its monoglucuronide conjugates: >95%.^{1 69 96} Raloxifene binds to albumin and α₁-acid glycoprotein but not to testosterone-estradiol binding globulin (sex hormone binding globulin).¹

Elimination

Metabolism

Undergoes extensive first-pass metabolism to glucuronide conjugates.^{1 27 33 34 35 36 55} Does not appear to be metabolized by CYP isoenzymes.¹ Conjugates converted back to the parent drug in various tissues.^{1 27}

Elimination Route

Excreted principally in feces as unabsorbed drug and via biliary elimination as glucuronide conjugates (subsequently metabolized by bacteria in GI tract to the parent drug).^{1 45 55 69 96}

Half-life

32.5 hours.^{1 55}

Stability

Storage

Oral

Tablets

20–25°C.¹

ActionsActions

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  Selective estrogen receptor modulator (SERM); exhibits estrogen agonist activity on bone, but estrogen antagonist activity on breast and uterine tissue.^{1 2 3 4 5 6 7 8 9 13 14 15 16 17 18 21 28 69 70 88 89 101}

  
  


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  Differs chemically and pharmacologically from naturally occurring estrogens, synthetic steroidal and nonsteroidal compounds with estrogenic activity, and agents described as antiestrogens (e.g., clomiphene, tamoxifen, toremifene).^{4 13 14 15 16 17}

  
  


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  In postmenopausal women or women who have undergone oophorectomy, principal action in bone is to decrease the rate of bone resorption, thus slowing the rate of bone loss.^{1 2 3 4 5 6 7 16 17 19 20 23 37}

  
  


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  Inhibits estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro.^{7 16 17 43 69}

  
  

Advice to Patients

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  Importance of providing patient a copy of manufacturer’s patient information.¹

  
  


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  Risk of venous thromboembolic events.¹ Notify clinician if signs or symptoms of thromboembolic disorder occur.⁵² Avoid prolonged restrictions in movement while traveling.^{1 52} Discontinue raloxifene ≥72 hours before and during prolonged immobilization (e.g., postsurgery recovery, prolonged bed rest).¹

  
  


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  Potential for increased incidence of hot flushes (flashes); drug is not effective in reducing hot flushes associated with estrogen deficiency.¹

  
  


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  When used for osteoporosis, importance of taking supplemental calcium and/or vitamin D if daily dietary intake is inadequate.¹ Importance of weight-bearing exercise and modification of other risk factors for osteoporosis (e.g., smoking, alcohol intake) if needed.¹

  
  


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  When used to reduce the incidence of invasive breast cancer, advise patient regarding benefits and risks of therapy as well as appropriate indications.¹ Need for regular breast examinations and mammograms.¹

  
  


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  Importance for women who are or may become pregnant or who are lactating to avoid taking the drug.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Raloxifene Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	60 mg	Evista	Lilly

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Evista 60MG Tablets (LILLY): 30/$139.99 or 90/$369.95

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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