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
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.)
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.)
Estrogen agonist-antagonist; a nonsteroidal benzothiophene derivative.1 2 3 13 14 15 16 17 55 69 70
Uses for Raloxifene Hydrochloride
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
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
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
Administer orally once daily without regard to meals or time of day.1 2 55
Available as raloxifene hydrochloride; dosage expressed in terms of the salt.1
Prevention in Postmenopausal WomenOral
60 mg daily.1 2 55
Treatment in Postmenopausal WomenOral
60 mg daily.1 98
Reduction in the Incidence of Invasive Breast CancerOral
60 mg daily.1 Optimum duration of therapy unknown.1
Cautions for Raloxifene Hydrochloride
Active or past episodes of venous thrombosis, including DVT, pulmonary embolism, or retinal vein thrombosis.1 52
Women who are or may become pregnant.1
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.)
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
Not associated with endometrial proliferation.1 Investigate unexplained uterine bleeding.1
Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)
Not known whether raloxifene is distributed into milk.1
No substantial differences in safety, efficacy, or pharmacokinetic profile relative to younger adults.1
Use with caution; safety and efficacy not established in patients with hepatic impairment.1 (See Special Populations under Pharmacokinetics.)
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
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
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
Decreased warfarin effects; no effect on warfarin pharmacokinetics observed1
Monitor PT carefully1
Concomitant use not specifically studied1
Potential for altered protein binding of diazepam1
Potential for altered protein binding of diazoxide1
No change in digoxin pharmacokinetics1
Can be administered concomitantly1
Concomitant use not recommended1
No substantial change in plasma raloxifene concentrations1
Potential for altered protein binding of lidocaine1
No change in methylprednisolone pharmacokinetics1
Can be administered concomitantly with corticosteroids1
No change in protein binding of phenytoin1
Raloxifene Hydrochloride Pharmacokinetics
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
High-fat meal increases peak plasma concentration and extent of absorption of raloxifene, but does not substantially affect systemic exposure.1
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 (Clcr 31–50 mL/minute) or severe renal impairment (Clcr ≤30 mL/minute) than in individuals with normal renal function.1
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
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
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
32.5 hours.1 55
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
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
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
Inhibits estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro.7 16 17 43 69
Advice to Patients
Importance of providing patient a copy of manufacturer’s patient information.1
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
Potential for increased incidence of hot flushes (flashes); drug is not effective in reducing hot flushes associated with estrogen deficiency.1
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
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
Importance for women who are or may become pregnant or who are lactating to avoid taking the drug.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS DI Essentials. © Copyright 2018, Selected Revisions April 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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