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Apr.18.2022

Raloxifene

Indications/Dosage

Labeled

  • breast cancer prophylaxis
  • osteoporosis
  • osteoporosis prophylaxis

Recommendations for calcium and vitamin D intake:

  • To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years. Daily vitamin D intake of 25 to 25 mcg (800 to 1,000 international units) is recommended for patients 50 years of age and older.[66837][67122][67123][67144]

Off-Label

  • uterine leiomyomata
† Off-label indication

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.[29603] 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.[66837] [67122] [67125] 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.[66837]

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.[29603] 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).[32138] 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).[32460]

For the treatment of uterine leiomyomata† in postmenopausal women

Oral dosage

Adults

60 mg PO once daily.[26611]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • 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.

Patients with Hepatic Impairment Dosing

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.

Patients with Renal Impairment Dosing

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.

† Off-label indication
Revision Date: 04/18/2022, 08:43:01 AM

References

26611 - Palomba S, Sammartino A, Di Carlo C, et al. Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 2001;76:38-43.29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.32138 - Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:1751-61.32460 - Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-37.66837 - Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract 2020;26(Suppl 1):1-46.67122 - Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. 2021;28:973-997.67123 - Osteoporosis Prevention, Screening, and Diagnosis: ACOG Clinical Practice Guideline No 1. Obstet Gynecol 2021;138:494-506.67125 - Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2019;104:1595-1622.67144 - Cosman F, de Beur SJ, LeBoff MS, et al.; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int 2014;25:2359-2381.

How Supplied

Raloxifene Hydrochloride Oral tablet

Evista 60mg Tablet (00002-4165) (Eli Lilly and Co) (off market)Evista 60mg Tablet package photo

Raloxifene Hydrochloride Oral tablet

Evista 60mg Tablet (00002-4165) (Eli Lilly and Co) (off market)

Raloxifene Hydrochloride Oral tablet

Evista 60mg Tablet (00002-4184) (Eli Lilly and Co) null

Raloxifene Hydrochloride Oral tablet

Evista 60mg Tablet (55289-0266) (PD-Rx Pharmaceuticals, Inc.) (off market)

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (52343-0137) (Acetris Health, LLC) (off market)

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (60687-0266) (American Health Packaging) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (68084-0871) (American Health Packaging) (off market)

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (65162-0057) (Amneal Pharmaceuticals LLC) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (65862-0709) (Aurobindo Pharma USA Inc.) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (42291-0726) (AvKARE, Inc.) (off market)

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (50268-0694) (AvPAK; a Division of AvKARE Inc) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (31722-0256) (Camber Pharmaceuticals Inc) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (69097-0825) (Cipla USA, Inc) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (43598-0505) (Dr. Reddy's Laboratories, Inc.) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (76282-0256) (Exelan Pharmaceuticals, Inc.) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (68462-0393) (Glenmark Pharmaceuticals) (off market)

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (00904-6902) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (72241-0010) (Modavar Pharmaceuticals, LLC) nullRaloxifene Hydrochloride 60mg Tablet package photo

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (16714-0213) (NorthStar Rx LLC) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (66993-0417) (Prasco Laboratories) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (66993-0661) (Prasco Laboratories) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (00093-7290) (Teva Pharmaceuticals USA) null

Raloxifene Hydrochloride Oral tablet

Raloxifene Hydrochloride 60mg Tablet (00591-2367) (Teva/Actavis US) (off market)

Description/Classification

Description

Raloxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene class. Similar to tamoxifen, raloxifene produces estrogen-like effects on bone and lipid metabolism, while antagonizing the effects of estrogen on mammary tissue. However, unlike estrogen or tamoxifen, it does not stimulate uterine tissue and behaves as an estrogen antagonist in the uterus. Raloxifene's pharmacologic effects make it a useful agent for the prevention of postmenopausal osteoporosis; although it is not useful for postmenopausal hot flashes. The effect of 60 mg/day on total-body bone mineral density is similar to that of estrogen/progestin HRT or alendronate 5 mg/day, but, the effect on bone mineral density of the lumbar spine may be less.[25061] Raloxifene has been shown to significantly decrease the incidence of vertebral fractures, but not other fractures, during clinical trials. According to the North American Menopause Society (NAMS), it may be considered for women who are at increased risk of vertebral fracture versus hip fracture.[67122] Raloxifene is also indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for breast cancer. Large clinical trials examining the long-term effects of raloxifene have been completed and include: the Raloxifene Use for the Heart (RUTH) study, to determine its effects on cardiovascular events and invasive breast cancer in women with established coronary heart disease (CHD) or at risk for CHD; the Multiple Outcomes of Raloxifene Evaluation (MORE), that evaluates effectiveness for osteoporosis and effect on the risk of cardiovascular events and breast cancer in postmenopausal women up to 80 years of age with osteoporosis; and the Study of Tamoxifen and Raloxifene (STAR), designed to compare efficacy in the prevention of breast cancer. Based on results from the MORE trial, raloxifene therapy for 4 years does not appear to significantly affect the risk of cardiovascular events overall, but does significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk.[27056] In results reported from the MORE trial among postmenopausal women, the risk of invasive breast cancer is decreased by 76% during 3 years, and by 72% after 4 years, of treatment with raloxifene relative to placebo.[27057] Results from the Continuing Outcomes Relevant to Evista (CORE) study (a 4-year extension of the MORE trial), indicate that 8 years of raloxifene therapy reduces the risk of invasive breast cancer by 66% (hazard ratio 0.34, 95% CI 0.22 to 0.5).[32138] It should be noted that findings from the CORE and MORE trials indicate that the risk of estrogen-receptor negative breast cancer is not reduced by raloxifene. The STAR study results confirm the findings of the MORE and CORE studies; four years of either tamoxifen or raloxifene reduces the risk of invasive breast cancer at a similar rate (by approximately 50%). A benefit of raloxifene over tamoxifen is a reduced rate of venous thromboembolism (RR 0.7, 95% CI 0.54 to 0.99); however, the risk of non-invasive breast cancer is reduced by tamoxifen, but not raloxifene. Furthermore, the risk of uterine cancer is reduced, although non-significantly, with raloxifene (RR 0.62, 95% CI 0.35 to 1.08).[32250] Results from the RUTH trial also confirm that raloxifene reduces the risk of invasive breast cancer (HR 0.56, 95% CI 0.38 to 0.83) relative to placebo; the mean baseline 5-year risk of breast cancer in the women participating in this study was 1.73%, with 41% of patients having a score of 1.66% or more. However, the risk of coronary events (death from coronary causes, myocardial infarction, or hospitalization for acute coronary syndrome) was not different between raloxifene or placebo in this population of women with existing or at increased risk of CHD. Additionally, the risk of fatal stroke and venous thromboembolism were increased in patients taking raloxifene (HR 1.49, 95% CI 1 to 2.24 for fatal stroke and HR 1.44, 95% CI 1.06 to 1.95).[32460] Raloxifene does appear to reduce the risk of invasive breast cancer; however, the benefits of breast cancer risk reduction have to be balanced with the increased risks of thromboembolic events in each individual patient.

Classifications

  • Genito-urinary System and Sex Hormones
    • Sex Hormones and Modulators of the Genital System
      • Selective Estrogen Receptor Modulators/SERMS
Revision Date: 12/12/2021, 04:34:37 PM

References

25061 - Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.27056 - Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in postmenopausal women four year results from the MORE (Multiple Outcomes of Raloxifene Evalulation) randomized trial. JAMA 2002;287:847-857.27057 - Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women results from the MORE randomized trial. JAMA 1999;281:2189-2197.32138 - Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:1751-61.32250 - Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-41.32460 - Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-37.67122 - Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. 2021;28:973-997.

Administration Information

General Administration Information

For storage information, see specific product information within the How Supplied section.

Hazardous Drugs Classification

  • NIOSH 2016 List: Group 2 [63664]
  • 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.[63664][67506][67507]

Route-Specific Administration

Oral Administration

  • May administer without regard to meals.[29603]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/18/2022, 04:44:10 PM

    References

    29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167506 - American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031.67507 - NIOSH [2016]. NIOSH Alert: Preventing Occupational Exposures to Antineoplastics and Other Hazardous Drugs in Health Care Settings. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-161.

    Adverse Reactions

    Mild

    • abdominal pain
    • arthralgia
    • cough
    • diarrhea
    • dyspepsia
    • fever
    • flatulence
    • headache
    • hyperhidrosis
    • hypoesthesia
    • infection
    • influenza
    • insomnia
    • laryngitis
    • leukorrhea
    • mastalgia
    • muscle cramps
    • myalgia
    • nausea
    • pharyngitis
    • rash
    • rhinitis
    • sinusitis
    • syncope
    • vertigo
    • vomiting
    • weight gain

    Moderate

    • chest pain (unspecified)
    • cholelithiasis
    • conjunctivitis
    • cystitis
    • depression
    • hot flashes
    • migraine
    • neuropathic pain
    • peripheral edema
    • phlebitis
    • vaginal bleeding
    • vaginitis

    Severe

    • pulmonary embolism
    • retinal thrombosis
    • stroke
    • thromboembolism
    • thrombosis

    During clinical trials, the most common treatment-related adverse event associated with use of raloxifene was hot flashes (7.8% to 28.7%). Hot flashes were usually reported within the first 6 months of treatment and were not different from placebo thereafter. In controlled clinical trials, drug discontinuation due to hot flashes was similar among patients receiving raloxifene (1.7%) and those receiving placebo (2.2%). Sweating or hyperhidrosis occurred in 2.5% to 3.1% of patients taking raloxifene vs. 1.7% to 2% of patients taking placebo.[29603]

    In placebo-controlled clinical trials, raloxifene was associated with an increased risk of venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonary embolism (PE) compared to placebo. An increased risk for and superficial thrombo-phlebitis also occurred. During an average of 2.6 years of drug exposure in patients taking raloxifene for the treatment of osteoporosis, VTE occurred in about 1 of 100 patients treated with raloxifene (HR 2.4, 95% CI 1.2 to 4.5). In patients with an increased risk for major coronary events (RUTH trial), VTE occurred in 2% of patients receiving raloxifene vs. 1.4% of patients taking placebo. The greatest risk occurs within the first 4 months of treatment. Of note, the increased risk of venous thromboembolism is similar in magnitude to that reported with hormone replacement therapy. The mechanisms by which raloxifene increases VTE is unknown. Unlike estrogens, raloxifene does not appear to enhance fibrinolysis. Varicose vein was reported in 2.2% of patients taking raloxifene vs. 1.5% of patients taking placebo in clinical trials. Adverse reactions reported very rarely since market introduction include retinal vein occlusion (retinal thrombosis) and death associated with VTE.[29603]

    Raloxifene may increase the risk for death from stroke in at-risk patients. In the Raloxifene Use for The Heart (RUTH) trial of postmenopausal women with documented coronary artery disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene relative to placebo. 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 overall incidence of stroke (4.9% for raloxifene vs. 4.4% for placebo). Raloxifene use had no significant effect on all-cause mortality.[29603] [32460] In the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial, the risk of stroke was found to be similar between tamoxifen and raloxifene, with annual rates of 1.39 per 1,000 patients taking tamoxifen and 1.33 per 1,000 patients taking raloxifene.[32250]

    Cardiovascular related adverse events reported during clinical trials of raloxifene and occurring at rates higher than with placebo included chest pain (unspecified) (2.8% to 4%), syncope (2.3%), and peripheral edema (3.3% to 14.1%).[29603]

    Arthralgia (10.7% to 15.5%) and muscle cramps, specifically leg cramps, were some of the most commonly reported treatment-related adverse events in patients taking raloxifene (5.9% to 12.1%) and occurring at an incidence greater than with placebo. Other reported musculoskeletal adverse events with raloxifene include myalgia (7.7%), arthritis (4%), and tendon disorder (3.6%).[29603]

    Central nervous system reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include headache (9.2%), migraine (2.4%), mental depression (6.4%), insomnia (5.5%), vertigo (4.1%), neuralgia or neuropathic pain (2.4%), and hypoesthesia (2.1%).[29603]

    Gastrointestinal (GI) adverse events that have been reported during clinical trials of raloxifene at incidences higher than with placebo include nausea (9.7% to 24.6%), diarrhea (7.2%), dyspepsia (5.9%), vomiting (3.4% to 4.8%), flatulence (3.1%), abdominal pain (6.6%), cholelithiasis (3.3%), gastroenteritis (2.6%), and gastrointestinal disorder (3.3%).[29603]

    Urogenital adverse reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include vaginitis (4.3%), leukorrhea (3.3%), uterine disorder (3.3%), endometrial disorder (3.1%), and vaginal bleeding (2.5%). The incidence of vaginal bleeding is significantly lower in patients treated with raloxifene vs. those treated with hormone replacement therapy (6.2% for raloxifene vs. 64.2 to 88.5% for hormone replacement therapy). Although breast pain (mastalgia) has been reported in 4.4% of women treated with raloxifene for osteoporosis prevention, the incidence was significantly lower than the incidence in patients treated with hormone replacement therapy (29.7 to 37.5%); further, the incidence and severity of mastalgia was similar when comparing patients taking raloxifene to placebo.[29603] In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months in 831 women. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo.[25061] The incidence of endometrial cancer and ovarian cancer were similar between patients taking raloxifene and placebo.[29603]

    Rash (unspecified) (5.5%) has been reported during clinical trials of raloxifene.[29603]

    Weight gain (8.8%) has been reported during clinical trials of raloxifene.[29603]

    Infectious and/or respiratory-related adverse reactions that have been reported during clinical trials of raloxifene and at incidences higher than placebo include infection (11% to 15.1%); examples of specific infections include sinusitis (7.9% to 10.3%), rhinitis (10.2%), bronchitis (9.5%), pharyngitis (5.3% to 7.6%), laryngitis (2.2%), influenza (13.5% to 14.6%), urinary tract infection (4%), conjunctivitis (2.2%), and cystitis (3.3% to 4.6%). Increased cough (6% to 9.3%) and fever (3.1% to 3.9%) have also been reported.[29603]

    Revision Date: 02/28/2018, 06:11:00 PM

    References

    25061 - Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.32250 - Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-41.32460 - Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-37.43854 - Walsh BW, Kuller LH, Wild A, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279(18):1445-51.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • breast-feeding
    • pregnancy
    • thromboembolic disease
    • atrial fibrillation
    • breast cancer
    • cardiac disease
    • cerebrovascular disease
    • children
    • coronary artery disease
    • heart failure
    • hepatic disease
    • hypertension
    • hypertriglyceridemia
    • infants
    • infertility
    • mortality
    • neoplastic disease
    • renal failure
    • renal impairment
    • reproductive risk
    • stroke
    • surgery
    • thromboembolism
    • thrombophlebitis
    • tobacco smoking
    • vaginal bleeding

    Safety and efficacy of raloxifene have not been evaluated in men.[29603]

     

    Raloxifene is not indicated for use in premenopausal females. Safety has not been established and its use is not recommended in this population.[29603]

    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.[29603]

    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.[29603]

    Raloxifene should be used with caution in patients with hepatic disease. Safety and efficacy have not been established in patients with hepatic impairment. In patients with mild hepatic impairment (Child Pugh A, serum bilirubin 0.6 to 2 mg/dL), the clearance of raloxifene was reduced 56% and plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene have not been evaluated in patients with moderate or severe hepatic insufficiency.[29603]

    Raloxifene should be used with caution in patients with moderate or severe renal impairment, as evidenced by a creatinine clearance (CrCl) of 50 mL/minute or less. Safety and efficacy have not been established in patients with moderate or severe renal impairment or renal failure.[29603]

    Any unexplained uterine or vaginal bleeding occurring in a female taking raloxifene should be investigated as clinically indicated. Raloxifene is not associated with endometrial hyperplasia. Raloxifene-treated and placebo-treated groups had similar incidences of endometrial proliferation.[29603]

    Raloxifene has not been adequately studied in patients with a prior history of breast cancer. While raloxifene is approved to reduce the risk of invasive breast cancer in postmenopausal women, it is not approved for the treatment of invasive breast cancer, to reduce the risk of non-invasive breast cancer, nor to reduce the risk of recurrence of breast cancer. Furthermore, there are no data regarding the effects of raloxifene on invasive breast cancer risk in women with inherited mutations (e.g., BRCA1, BRCA2). Any unexplained breast abnormality occurring during raloxifene therapy should be investigated as raloxifene use does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with the drug.[29603]

    Women with a history of marked hypertriglyceridemia (more than 5.6 mmol/L or more than 500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin therapy should have serum triglycerides monitored during raloxifene therapy. Limited clinical data suggests that these women may develop increased levels of triglycerides during raloxifene treatment.[29603]

    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.[29603]

    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.[29603]

    The reproductive and developmental effects observed in animal studies are consistent with the estrogen receptor activity of raloxifene. In female animals, raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. Raloxifene also delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. It is unknown if reproductive risk or issues relating to infertility would occur in humans.[29603]

    Safety and effectiveness of raloxifene in pediatric patients have not been established. Raloxifene is not recommended for use in infants, children, adolescents, or premenopausal females.[29603]

    Revision Date: 07/06/2018, 11:19:20 AM

    References

    29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.

    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.

    Revision Date: 02/07/2009, 03:35:53 AM

    References

    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).

    Route-Specific Pharmacokinetics

    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.

    Special Populations

    Hepatic Impairment

    In patients with cirrhosis (serum bilirubin 0.6—2 mg/dl), plasma raloxifene concentrations are approximately 2.5 times higher than in patients without hepatic dysfunction.

     

    In 9 patients with mild hepatic impairment (Child-Pugh Class A, total bilirubin 0.6—2 mg/dl), the apparent clearance of raloxifene was reduced by 56% and the plasma concentrations were approximately 150% higher when compared to 8 patients with normal hepatic function; the half-life of raloxifene in patients with mild hepatic impairment was not changed.

    Renal Impairment

    The pharmacokinetic disposition of raloxifene is similar among patients with impaired renal function (i.e., CrCl as low as 23 ml/min).

     

    After a single dose of raloxifene 120 mg, in males with moderate renal impairment (CrCl 31—50 ml/min; N=7) or severe renal impairment (CrCl <= 30 ml/min; N=3), plasma raloxifene concentrations were 122% higher than in males with normal renal function (CrCl > 80 ml/min; N=10).

    Elderly

    The pharmacokinetic disposition of raloxifene is similar among young adults and the elderly.

    Revision Date: 02/10/2010, 10:18:04 AM

    Pregnancy/Breast-feeding

    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.[29603]

    breast-feeding

    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.[29603]

    Revision Date: 07/06/2018, 11:19:20 AM

    References

    29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.

    Interactions

    Level 2 (Major)

    • Conjugated Estrogens
    • Conjugated Estrogens; Bazedoxifene
    • Conjugated Estrogens; Medroxyprogesterone
    • Desogestrel; Ethinyl Estradiol
    • Dienogest; Estradiol valerate
    • Diethylstilbestrol, DES
    • Drospirenone; Estetrol
    • Drospirenone; Estradiol
    • Drospirenone; Ethinyl Estradiol
    • Drospirenone; Ethinyl Estradiol; Levomefolate
    • Elagolix; Estradiol; Norethindrone acetate
    • Esterified Estrogens
    • Esterified Estrogens; Methyltestosterone
    • Estradiol
    • Estradiol Cypionate; Medroxyprogesterone
    • Estradiol; Levonorgestrel
    • Estradiol; Norethindrone
    • Estradiol; Norgestimate
    • Estradiol; Progesterone
    • Estrogens
    • Estropipate
    • Ethinyl Estradiol
    • Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate
    • Ethinyl Estradiol; Norelgestromin
    • Ethinyl Estradiol; Norethindrone Acetate
    • Ethinyl Estradiol; Norgestrel
    • Ethynodiol Diacetate; Ethinyl Estradiol
    • Etonogestrel; Ethinyl Estradiol
    • Fluoroestradiol F 18
    • Levonorgestrel; Ethinyl Estradiol
    • Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate
    • Mestranol; Norethindrone
    • Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate
    • Norethindrone; Ethinyl Estradiol
    • Norethindrone; Ethinyl Estradiol; Ferrous fumarate
    • Norgestimate; Ethinyl Estradiol
    • Ospemifene
    • Relugolix; Estradiol; Norethindrone acetate
    • Segesterone Acetate; Ethinyl Estradiol

    Level 3 (Moderate)

    • Cholestyramine
    • Levothyroxine
    • Levothyroxine; Liothyronine (Porcine)
    • Levothyroxine; Liothyronine (Synthetic)
    • Liothyronine
    • Thyroid hormones
    • Warfarin
    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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] Estradiol Cypionate; 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] Ethinyl Estradiol; Levonorgestrel; Folic Acid; 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [28822] [29603] [63589] [65471] 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. [29603] 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. [29603] 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. [27484] 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. [27484] 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. [27484] 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. [27484] Mestranol; 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [29603] 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. [53344] 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. [29603] 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. [29603] 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. [27484] Warfarin: (Moderate) Monitor INR closely when warfarin is coadministered with raloxifene. Raloxifene may decrease prothrombin time. [29603]
    Revision Date: 09/17/2021, 02:35:00 AM

    References

    27484 - Siraj ES, Gupta MK, Reddy SK. Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 2003;163:1367-70.28822 - Fareston (toremifene citrate) tablets package insert. Bedminster, NJ: Kyowa Kirin Inc.; 2017 May.29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.53344 - Osphena (ospemifene) tablets package insert. Florham Park, N.J: Shionogi, Inc.; 2019 Jan.63589 - Soltamox (tamoxifen) oral solution package insert. Raleigh, NC: Midatech Pharma US Inc.; 2019 April.65471 - Cerianna (fluoroestradiol F 18 injection) package insert. New York, NY: Zionexa US Corp; 2020 May.

    Monitoring Parameters

    • LFTs

    US Drug Names

    • Evista
    ;