Raloxifene

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# Black Box Warning

# Overview
Raloxifene is an selective estrogen receptor modulator that is FDA approved for the {{{indicationType}}} of osteoporosis in postmenopausal women, reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Recommended Dosing
- The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals.
- For the indications in risk of invasive breast cancer the optimum duration of treatment is not known.
- Recommendations for Calcium and Vitamin D Supplementation
- For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
- Recommended Dosing
- The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals.
- For the indications in risk of invasive breast cancer the optimum duration of treatment is not known.
- Recommendations for Calcium and Vitamin D Supplementation
- For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
- Raloxifene hydrochloride is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer.
- The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known.
- High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer 1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.
- After an assessment of the risk of developing breast cancer, the decision regarding therapy with raloxifene hydrochloride should be based upon an individual assessment of the benefits and risks.
- Raloxifene hydrochloride does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride.
- Important Limitations of Use for Breast Cancer Risk Reduction
- There are no data available regarding the effect of raloxifene hydrochloride on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene hydrochloride.
- Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
- Raloxifene hydrochloride is not indicated for the reduction in the risk of noninvasive breast cancer.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in adult patients.

### NonGuideline-Supported Use
- Dosing Information
- Oral raloxifene 60 mg/day.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Raloxifene in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Raloxifene in pediatric patients.

# Contraindications
- Venous Thromboembolism
- Raloxifene hydrochloride is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
- Pregnancy, Women Who May Become Pregnant, and Nursing Mothers
- Raloxifene hydrochloride is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers. Raloxifene hydrochloride may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses 0.1 mg/kg (0.04 times the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses 10 mg/kg (4 times the human dose based on surface area, mg/m2). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses 1 mg/kg (0.2 times the human dose based on surface area, mg/m2). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

# Warnings

### Precautions
- Venous Thromboembolism
- In clinical trials, raloxifene hydrochloride-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolismOther venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with raloxifene hydrochloride than with placebo. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride should be advised to move about periodically during prolonged travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy.
- Death Due to Stroke
- In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene hydrochloride. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride  versus 224 placebo ). Raloxifene hydrochloride had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking.
- Cardiovascular Disease
- Raloxifene hydrochloride should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years.
- Premenopausal Use
- There is no indication for premenopausal use of raloxifene hydrochloride. Safety of raloxifene hydrochloride in premenopausal women has not been established and its use is not recommended.
- Hepatic Impairment
- Raloxifene hydrochloride should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment.
- Concomitant Estrogen Therapy
- The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.
- History of Hypertriglyceridemia when Treated with Estrogens
- Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene hydrochloride. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride.
- Renal Impairment
- Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment. Safety and efficacy have not been established in patients with moderate or severe renal impairment.
- History of Breast Cancer
- Raloxifene hydrochloride has not been adequately studied in women with a prior history of breast cancer.
- Use in Men
- There is no indication for the use of raloxifene hydrochloride in men. Raloxifene hydrochloride has not been adequately studied in men and its use is not recommended.
- Unexplained Uterine Bleeding
- Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial proliferation.
- Breast Abnormalities
- Any unexplained breast abnormality occurring during raloxifene hydrochloride therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described below reflect exposure to raloxifene hydrochloride in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years.
- Osteoporosis Treatment Clinical Trial (MORE)  The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women.
- Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride. Twenty-six raloxifene hydrochloride-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment.
- Common adverse reactions considered to be related to raloxifene hydrochloride therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride.
- Placebo-Controlled Osteoporosis Prevention Clinical Trials  The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2036 women were exposed to raloxifene HCl (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day).
- Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene hydrochloride-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride and placebo groups (1.7% and 2.2%, respectively).
- Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on raloxifene hydrochloride versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.
- Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency 2.0% in either group and in more raloxifene hydrochloride-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy.
- Comparison of Raloxifene hydrochloride and Hormone Therapy  Raloxifene hydrochloride was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence 2.0% in any group. Adverse reactions are shown without attribution of causality.
- Breast Pain  Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin.
- Gynecologic Cancers  Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer.
- Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH)  The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups. Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene hydrochloride-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups.
- Adverse reactions reported more frequently in raloxifene hydrochloride-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo).
- Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR)  The safety of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials.

## Postmarketing Experience
- Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).

# Drug Interactions
- Cholestyramine
- Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins.
- Warfarin
- If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride.
- Other Highly Protein-Bound Drugs
- Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins.
- Systemic Estrogens
- The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.
- Other Concomitant Medications
- Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin.
- The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Raloxifene hydrochloride should not be used in women who are or may become pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raloxifene in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Raloxifene during labor and delivery.

### Nursing Mothers
- Raloxifene hydrochloride should not be used by lactating women. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when raloxifene is administered to a nursing woman.

### Pediatric Use
There is no FDA guidance on the use of Raloxifene with respect to pediatric patients.

### Geriatic Use
- Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients.

### Gender
There is no FDA guidance on the use of Raloxifene with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Raloxifene with respect to specific racial populations.

### Renal Impairment
- Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment.

### Hepatic Impairment
- Raloxifene hydrochloride should be used with caution in patients with moderate or severe hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Raloxifene in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Raloxifene in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Raloxifene in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Raloxifene in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride (HCl) 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported.
- In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000  patients treated). The highest overdose has been approximately 1.5 grams. No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took 180 mg raloxifene HCl and included leg cramps and dizziness.
- Two 18-month-old children each ingested raloxifene HCl 180 mg. In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase.
- No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m2) or in monkeys at 1000 mg/kg (80 times the AUC in humans).

### Management
- There is no specific antidote for raloxifene.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Raloxifene in the drug label.

# Pharmacology

## Mechanism of Action
- Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters.
- Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue.

## Structure
- Raloxifene hydrochloride is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is:
- The chemical designation is methanone, thien-3-yl]-phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4SHCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water.
- Raloxifene hydrochloride is supplied in a tablet dosage form for oral administration. Each raloxifene hydrochloride tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

## Pharmacodynamics
- Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.
- In both the osteoporosis treatment and prevention trials, raloxifene hydrochloride therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods.
- In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily raloxifene hydrochloride 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month ), or no treatment. Treatment with either raloxifene hydrochloride or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for raloxifene hydrochloride and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy).
- There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy.

## Pharmacokinetics
- The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene.
- Absorption  Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.
- Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (Cmax 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. Raloxifene hydrochloride can be administered without regard to meals.
- Distribution  Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent.
- Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins. Raloxifene binds to both albumin and 1-acid glycoprotein, but not to sex-steroid binding globulin.
- Metabolism  Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.
- Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kghr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing.
- Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kghr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC).
- Excretion  Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates.
- Special Populations
- Pediatric  The pharmacokinetics of raloxifene has not been evaluated in a pediatric population.
- Geriatric  No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years).
- Gender  Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers.
- Race  Pharmacokinetic differences due to race have been studied in 1712 women, including 97.5% White, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in raloxifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined.
- Renal Impairment  In the osteoporosis treatment and prevention trials, raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg raloxifene HCl was administered to 10 renally impaired males  and to 10 healthy males (CrCl >80 mL/min), plasma raloxifene concentrations were 122% (AUC0-) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment.
- Hepatic Impairment  The disposition of raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg raloxifene HCl. Apparent clearance of raloxifene was reduced 56% and the half-life of raloxifene was not altered in patients with mild hepatic impairment. Plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene has not been studied in patients with moderate or severe hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment.
- Drug Interactions
- Cholestyramine  Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.
- Warfarin  In vitro, raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene.
- Other Highly Protein-Bound Drugs  In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro, raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin (see above).
- Ampicillin and Amoxicillin  Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations.
- Antacids  Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene.
- Corticosteroids  The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose.
- Digoxin  Raloxifene has no effect on the pharmacokinetics of digoxin.
- Cyclosporine  Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied.
- Lipid-Lowering Agents  Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied.

## Nonclinical Toxicology
- Carcinogenesis  In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60 mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans) and prostatic leiomyoblastoma in male mice given 210 mg/kg.
- In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in female rats given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation.
- Mutagenesis  Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice.
- Impairment of Fertility  When male and female rats were given daily doses 5 mg/kg (0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2) for at least 2 weeks did not affect sperm production or quality or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses 0.1 mg/kg (0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene.
- The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine.
- Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects.
- These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of raloxifene hydrochloride as a skeletal antiresorptive agent.

# Clinical Studies
- Effect on Fracture Incidence
- The effects of raloxifene hydrochloride on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years.
- Effect on Bone Mineral Density
- Raloxifene hydrochloride, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. Raloxifene hydrochloride decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for raloxifene hydrochloride (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for raloxifene hydrochloride (relative risk reduction = 30%) (see Table 4). All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene hydrochloride reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry. The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone.
- The mean percentage change in BMD from baseline for raloxifene hydrochloride was statistically significantly greater than for placebo at each skeletal site (see Table 5).
- Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene hydrochloride group (1.1%).
- Bone Histology
- Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. There were 56 paired biopsies evaluable for all indices. In raloxifene hydrochloride-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment.
- Effect on Endometrium
- Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene hydrochloride-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease. This study was not specifically designed to detect endometrial polyps. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 raloxifene hydrochloride-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day. There was no difference between raloxifene hydrochloride- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge.
- The effects of raloxifene hydrochloride on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene hydrochloride, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD.
- Effect on Bone Mineral Density
- Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months (see Table 6). The placebo groups lost approximately 1% of BMD over 24 months.
- Raloxifene hydrochloride also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward's Triangle (hip) by 3.1% to 4.0%. The effects of raloxifene hydrochloride on forearm BMD were inconsistent between studies. In Study EU, raloxifene hydrochloride prevented bone loss at the ultradistal radius, whereas in Study NA, it did not (see Figure 1).
- Effect on Endometrium
- In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU). A total of 2978 TVU measurements were collected from 831 women in all dose groups. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the raloxifene hydrochloride-treated women had a 0.09 mm mean increase. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding.
- MORE Trial
- The effect of raloxifene hydrochloride on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women. After 4 years, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67). Raloxifene hydrochloride reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. Table 7 presents efficacy and selected safety outcomes.
- CORE Trial
- The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene hydrochloride and placebo groups. Table 7 presents efficacy and selected safety outcomes.
- In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene hydrochloride (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo.
- RUTH Trial
- The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Women in this study had a median age of 67.6 years (range 55-92) and were followed for a median of 5.6 years (range 0.01-7.1). Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer 1.66%, based on the modified Gail model.
- Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo ; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer. Table 8 presents efficacy and selected safety outcomes.
- The effect of raloxifene hydrochloride in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, <1.66%, or 1.66%.
- STAR Trial
- The effects of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomized, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute. Women in this study had a mean age of 58.5 years (range 35-83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66-23.61%), and 9.1% had a history of lobular carcinoma in situ (LCIS). More than 93% of participants were White. As of 31 December 2005, the median time of follow-up was 4.3 years (range 0.07-6.50 years).
- Raloxifene hydrochloride was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were raloxifene hydrochloride 4.4 and tamoxifen 4.3 per 1000 women per year. The results from a noninferiority analysis are consistent with raloxifene hydrochloride potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer. Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene hydrochloride group. Table 9 presents efficacy and selected safety outcomes.
- Effects on Cardiovascular Disease
- In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene hydrochloride 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with raloxifene hydrochloride was observed: 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with raloxifene hydrochloride  versus 224 with placebo ; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years).

# How Supplied
- Raloxifene hydrochloride 60 mg tablets are white, elliptical, and film coated. They are imprinted on one side with the tablet code 4810 in edible blue ink. They are available as follows:
- Bottles of 30 (unit of use)     NDC 0002-4165-30
- Bottles of 100 (unit of use)     NDC 0002-4165-02
- Bottles of 2000     NDC 0002-4165-07
- Storage and Handling
- Store at controlled room temperature, 20 to 25C (68 to 77F). The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20 to 25C (68 to 77F); that results in a mean kinetic temperature calculated to be not more than 25C; and that allows for excursions between 15 and 30C (59 and 86F) that are experienced in pharmacies, hospitals, and warehouses.

## Storage
There is limited information regarding Raloxifene Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation
- Patient Immobilization
- Raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events.
- Hot Flashes or Flushes
- Raloxifene hydrochloride may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning raloxifene hydrochloride therapy.
- Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer
- Use of raloxifene hydrochloride is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. Raloxifene hydrochloride has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of raloxifene hydrochloride treatment with the patient.
- Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
- Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride.

# Precautions with Alcohol
- Alcohol-Raloxifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Evista

# Look-Alike Drug Names
- Evista AVINza

# Drug Shortage Status

# Price