Evista

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Evista

Classes

Selective Estrogen Receptor Modulators (SERMs)

Administration

For storage information, see specific product information within the How Supplied section.
Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Oral Administration

May administer without regard to meals.

Adverse Reactions
Severe

thrombosis / Delayed / 1.0-2.0
thromboembolism / Delayed / 1.0-2.0
stroke / Delayed / 0.1-0.1
retinal thrombosis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known

Moderate

hot flashes / Delayed / 7.8-28.7
peripheral edema / Delayed / 3.3-14.1
depression / Delayed / 6.4-6.4
vaginal bleeding / Delayed / 2.5-6.2
cystitis / Delayed / 3.3-4.6
vaginitis / Delayed / 4.3-4.3
chest pain (unspecified) / Early / 2.8-4.0
cholelithiasis / Delayed / 3.3-3.3
migraine / Early / 2.4-2.4
neuropathic pain / Delayed / 2.4-2.4
conjunctivitis / Delayed / 2.2-2.2
phlebitis / Rapid / Incidence not known

Mild

nausea / Early / 9.7-24.6
arthralgia / Delayed / 10.7-15.5
infection / Delayed / 11.0-15.1
influenza / Delayed / 13.5-14.6
muscle cramps / Delayed / 5.9-12.1
sinusitis / Delayed / 7.9-10.3
rhinitis / Early / 10.2-10.2
cough / Delayed / 6.0-9.3
headache / Early / 9.2-9.2
weight gain / Delayed / 8.8-8.8
myalgia / Early / 7.7-7.7
pharyngitis / Delayed / 5.3-7.6
diarrhea / Early / 7.2-7.2
abdominal pain / Early / 6.6-6.6
dyspepsia / Early / 5.9-5.9
insomnia / Early / 5.5-5.5
rash / Early / 5.5-5.5
vomiting / Early / 3.4-4.8
mastalgia / Delayed / 4.4-4.4
vertigo / Early / 4.1-4.1
fever / Early / 3.1-3.9
leukorrhea / Delayed / 3.3-3.3
hyperhidrosis / Delayed / 2.5-3.1
flatulence / Early / 1.3-3.1
syncope / Early / 2.3-2.3
laryngitis / Delayed / 2.2-2.2
hypoesthesia / Delayed / 2.1-2.1

Boxed Warning
Heart failure, neoplastic disease, surgery, thromboembolic disease, thromboembolism, thrombophlebitis

Raloxifene is contraindicated in patients with acute thromboembolism or a past history of thromboembolic disease. The risk and benefit of raloxifene therapy should be considered carefully in patients at risk for thromboembolic events due to other reasons, such as congestive heart failure, superficial thrombophlebitis, and active neoplastic disease. An increased risk of thromboembolic events has been observed in women taking raloxifene. The greatest risk for thromboembolic events 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 estrogen-containing hormone therapy. In clinical trials, raloxifene-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). Other venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with raloxifene than with placebo. Because immobilization increases the risk for venous thromboembolic events independent of therapy, the drug should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgery recovery, prolonged bed rest). Raloxifene should be resumed only after a patient is fully ambulatory. In addition, women taking raloxifene should be advised to move about periodically during prolonged travel.

Atrial fibrillation, cardiac disease, cerebrovascular disease, coronary artery disease, hypertension, mortality, stroke, tobacco smoking

Do not use raloxifene for the primary or secondary prevention of cardiovascular disease. Raloxifene should be used with caution in women with a history of cardiac disease or at increased for stroke including those with previous cerebrovascular disease [e.g., previous stroke or transient ischemic attack (TIA)], atrial fibrillation, hypertension, or tobacco smoking. In a clinical trial of postmenopausal women with documented coronary artery disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years. Raloxifene use had no significant effect on coronary events (e.g., death from coronary causes, nonfatal myocardial infarction, or hospitalization for acute coronary syndromes). Mortality is increased secondary to stroke after treatment with raloxifene. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 vs. 15 per 10,000 women-years; hazard ratio 1.49; 95% CI, 1 to 2.24; p = 0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (4.9% for raloxifene vs. 4.4% for placebo). Raloxifene use had no significant effect on all-cause mortality.

Common Brand Names

Evista

Dea Class

Rx

Description

Oral selective estrogen receptor modulator (SERM)
Approved for the treatment and prevention of postmenopausal osteoporosis and to reduce risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer
Boxed warning regarding an increased risk for thromboembolism and stroke

Dosage And Indications
For the treatment of osteoporosis or for osteoporosis prophylaxis in postmenopausal women. Oral dosage Adult postmenopausal females

60 mg PO once daily. Supplement with calcium and vitamin D if dietary intake is inadequate. During clinical trials, women with known osteoporosis had a median age of 67 years (range 31 to 80 years) and a median time since menopause of 19 years. In clinical trials for osteoporosis prophylaxis, women with low bone mineral density had a median age of 54 years and a median time since menopause of 5 years. LIMITATIONS OF USE: There is no indication for the use of raloxifene in premenopausal women; safety has not been established and use is not recommended. While raloxifene shows benefit in reducing vertebral fractures, it should generally not be considered for first line therapy as raloxifene does not reduce hip fracture or nonvertebral fractures and may be associated with serious harms, including thromboembolism. Per guidelines, first-line agents for osteoporosis and low bone mineral density include alendronate, risedronate, zoledronic acid, or denosumab. For postmenopausal patients with low bone mineral density in the spine but not in the hip, raloxifene may be considered for prevention of bone loss in postmenopausal women with an elevated risk of breast cancer and infrequent vasomotor symptoms. Patients at high risk of hip fracture who are taking raloxifene with the main goal of reducing their risk of breast cancer can reasonably have a bisphosphonate or denosumab added for hip fracture risk reduction; however, the risks and benefits of combined treatment are unknown.

For invasive breast cancer prophylaxis in postmenopausal women with osteoporosis or in postmenopausal women at high risk for developing the disease.
 
Oral dosage Adult postmenopausal females

60 mg PO once daily. The long-term effects and the recommended length of treatment are not known. LIMITATIONS OF USE: There is no indication for the use of raloxifene in premenopausal women; safety has not been established and use in premenopausal women is not recommended. Raloxifene is not indicated for the treatment of invasive breast cancer or for reducing the risk of recurrence. Raloxifene is also not indicated for reducing 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 regarding the drug's effectiveness in these women. In the MORE trial, postmenopausal women (age 31 to 80 years) with osteoporosis taking raloxifene experienced a reduction in the risk of breast cancer of 76% (relative risk 0.24, 95% CI 0.13 to 0.44) after 3 years of treatment. An extension of this trial, the CORE trial, continued to follow patients taking raloxifene for a total of 8 years. Patients taking raloxifene had a reduced risk of invasive breast cancer of 66% at 8 years (HR 0.34, 95% CI 0.22 to 0.5). Results of the STAR trial, which compared raloxifene to tamoxifen for the prevention of breast cancer, indicate that raloxifene is comparable to tamoxifen; both drugs decreased the risk of invasive breast cancer by approximately 50%. The RUTH trial also confirms the decreased risk of breast cancer with raloxifene therapy vs. placebo after 5 years (HR 0.56, 95% CI 0.38 to 0.83).

For the treatment of uterine leiomyomata† in postmenopausal women. Oral dosage Adults

60 mg PO once daily.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

No dosage guidelines are available; however, patients may be at increased risk for side effects. Patients with cirrhosis have up to 2.5-fold higher serum levels of raloxifene than patients with normal hepatic function. Safety and efficacy have not been established in patients with hepatic impairment.

Renal Impairment

No dosage guidelines are available; however, raloxifene should be used with caution in patients with renal impairment. Safety and efficacy have not been established in patients with moderate to severe renal impairment.

Drug Interactions

Cholestyramine: (Moderate) A single dose of cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene. The coadministration of cholestyramine and raloxifene is not recommended.
Conjugated Estrogens: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Conjugated Estrogens; Bazedoxifene: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Conjugated Estrogens; Medroxyprogesterone: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Desogestrel; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Dienogest; Estradiol valerate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Diethylstilbestrol, DES: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Drospirenone; Estetrol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Drospirenone; Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Drospirenone; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Elagolix; Estradiol; Norethindrone acetate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Esterified Estrogens: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Esterified Estrogens; Methyltestosterone: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estradiol; Levonorgestrel: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estradiol; Norethindrone: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estradiol; Norgestimate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estradiol; Progesterone: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estrogens: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Estropipate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Ethinyl Estradiol; Norelgestromin: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Ethinyl Estradiol; Norethindrone Acetate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Ethinyl Estradiol; Norgestrel: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Etonogestrel; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Fluoroestradiol F 18: (Major) Administer fluoroestradiol F 18 before starting an estrogen-receptor (ER) modifier; however, do not delay indicated therapy to administer fluoroestradiol F 18. ER modifiers may block ER for up to 8 weeks and reduce the uptake of fluoroestradiol F 18 and detection of ER-positive lesions.
Levonorgestrel; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Levothyroxine: (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Levothyroxine; Liothyronine (Porcine): (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Liothyronine: (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Norethindrone; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Norgestimate; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Ospemifene: (Major) Ospemifene should not be used concomitantly with estrogen agonists/antagonists such as raloxifene. The safety of concomitant use of ospemifene with estrogen agonists/antagonists has not been studied.
Relugolix; Estradiol; Norethindrone acetate: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Segesterone Acetate; Ethinyl Estradiol: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended.
Soy Isoflavones: (Major) Theoretically, the soy isoflavones may compete with drugs that selectively modulate estrogen receptors. The soy isoflavones have a diphenolic structure similar to that of the potent synthetic and natural estrogens. All isoflavones are competitive ligands of in vitro estrogen receptor assays and appear to function as selective estrogen receptor modifiers (SERMs). Soy isoflavones should be used with caution in patients taking selective estrogen receptor modulators (SERMs, e.g., raloxifene, tamoxifen, or toremifene), as not much is known about how soy might influence side effects or therapeutic efficacy of the SERMs.
Thyroid hormones: (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Warfarin: (Moderate) Monitor INR closely when warfarin is coadministered with raloxifene. Raloxifene may decrease prothrombin time.

How Supplied

Evista/Raloxifene/Raloxifene Hydrochloride Oral Tab: 60mg

Maximum Dosage
Adults

60 mg/day PO.

Elderly

60 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Mechanism Of Action

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, which results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The estrogen receptor can regulate gene expression by at least two distinct pathways, which are ligand-, tissue-, and/or gene-specific. Binding of raloxifene to the estrogen receptor results in differential expression of multiple estrogen-regulated genes in different tissues. Similar to tamoxifen, raloxifene produces estrogen-like effects on bone while antagonizing the effects of estrogen on mammary tissue. However, while tamoxifen stimulates uterine tissue, raloxifene produces a nearly complete blockade of uterotrophic responses to estrogen and can antagonize the uterine stimulatory effect of tamoxifen. Raloxifene appears to act as an estrogen agonist in bone. Raloxifene reduces resorption of bone and increases bone mineral density in postmenopausal women without stimulating the endometrium or breast tissue. Decreases in circulating estrogen after oophorectomy or menopause lead to enhanced bone resorption. Bone loss is initially rapid because the compensatory increase in bone formation is inadequate to offset resorptive losses. The effects of raloxifene on bone are manifested as reductions in serum and urine concentrations of bone turnover markers, decreased bone resorption, and increases in bone mineral density (BMD). In postmenopausal women, raloxifene increases total-body BMD, including BMD of the lumbar spine, hip, and femoral neck, and decreases fracture incidence.Similar to estrogen replacement therapy, raloxifene also decreases total and low-density lipoprotein cholesterol, and lipoprotein(a) concentrations. However, estrogen increases high-density lipoprotein cholesterol and triglycerides, while raloxifene has no effect on these lipoproteins. Unlike estrogen, raloxifene does not stimulate the endometrium in postmenopausal women with an intact uterus.

Pharmacokinetics

Raloxifene is administered orally. Raloxifene has a large volume of distribution (2348 L/kg); the parent drug and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and alpha-1 acid glycoprotein. It does not bind to sex steroid binding globulin. Raloxifene undergoes extensive first-pass metabolism to the following glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4'-diglucuronide. Because no other metabolites have been identified, it is believed that raloxifene is not metabolized by cytochrome P450 pathways. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling. Raloxifene is excreted primarily in feces. Less than 0.2% is excreted unchanged in urine and less than 6% is eliminated in urine as glucuronide conjugates. The plasma elimination half-life of raloxifene is highly variable. Mean elimination half-life after multiple oral doses is 32.5 hours (range: 15.8—86.6 hours).

Oral Route

Absorption is rapid after an oral dose. Although roughly 60% of a dose is absorbed, presystemic glucuronide conjugation is extensive. Thus, absolute bioavailability is only about 2%. Raloxifene and its glucuronide metabolites undergo enterohepatic cycling which affects bioavailability and time to peak plasma concentration. A high-fat meal increases the AUC and Cmax of raloxifene by 16% and 28%, respectively; however, these increases are not considered clinically significant.

Pregnancy And Lactation
Pregnancy

Raloxifene is contraindicated in women during pregnancy. The safety of raloxifene in premenopausal women has not been established. Use in premenopausal women is not recommended due to concern of inadvertent drug exposure during pregnancy and the risk of fetal harm. 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. Animal studies have demonstrated a potential for fetal harm. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses greater than or equal to 0.1 mg/kg (0.04 times or more the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses greater than or equal to 10 mg/kg (4 times or more the human dose based on BSA). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses greater than or equal to 1 mg/kg (0.2 times or more the human dose based on BSA). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on BSA) 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.

Raloxifene is contraindicated in women who are breast-feeding due to the potential risk to a nursing infant, although it is not known if the drug is excreted in human milk.