Raloxifene Hydrochloride 60 MG Oral Tablet
DRUG INTERACTIONS
7 Cholestyramine: Use with EVISTA is not recommended.
Reduces the absorption and enterohepatic cycling of raloxifene.
(7.1, 12.3) Warfarin: Monitor prothrombin time when starting or stopping EVISTA.
(7.2, 12.3) Highly Protein-Bound Drugs: Use with EVISTA with caution.
Highly protein-bound drugs include diazepam, diazoxide, and lidocaine.
EVISTA is more than 95% bound to plasma proteins.
(7.3, 12.3) 7.1 Cholestyramine Concomitant administration of cholestyramine with EVISTA is not recommended.
Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.
EVISTA should not be co-administered with other anion exchange resins [see Clinical Pharmacology (12.3)] .
7.2 Warfarin If EVISTA is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with EVISTA [see Clinical Pharmacology (12.3)] .
7.3 Other Highly Protein-Bound Drugs EVISTA should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine.
Although not examined, EVISTA might affect the protein binding of other drugs.
Raloxifene is more than 95% bound to plasma proteins [see Clinical Pharmacology (12.3)] .
7.4 Systemic Estrogens The safety of concomitant use of EVISTA with systemic estrogens has not been established and its use is not recommended.
7.5 Other Concomitant Medications EVISTA can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3)] .
The concomitant use of EVISTA and lipid-lowering agents has not been studied.
OVERDOSAGE
10 In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride (HCl) 600 mg/day was safely tolerated.
In clinical trials, no raloxifene overdose has been reported.
In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 [<0.01%] patients treated).
The highest overdose has been approximately 1.5 grams.
No fatalities associated with raloxifene overdose have been reported.
Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene HCl and included leg cramps and dizziness.
Two 18-month-old children each ingested raloxifene HCl 180 mg.
In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase.
There is no specific antidote for raloxifene.
No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m2) or in monkeys at 1000 mg/kg (80 times the AUC in humans).
DESCRIPTION
11 EVISTA (raloxifene hydrochloride) is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds.
The chemical structure is: The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride.
Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05.
Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water.
EVISTA is supplied in a tablet dosage form for oral administration.
Each EVISTA tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base.
Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No.
2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.
chemical structure
CLINICAL STUDIES
14 Figure 1 14.1 Treatment of Postmenopausal Osteoporosis Effect on Fracture Incidence The effects of EVISTA on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE).
All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures).
The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures.
Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years.
Effect on Bone Mineral Density EVISTA, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%.
EVISTA decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for EVISTA (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for EVISTA (relative risk reduction = 30%) (see Table 4).
All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day).
EVISTA reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry.
The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone.
Table 4: Effect of EVISTA on Risk of Vertebral Fractures Number of Patients Absolute Risk Reduction (ARR) Relative Risk Reduction (95% CI) EVISTA Placebo Fractures diagnosed radiographically Patients with no baseline fractureIncludes all patients with baseline and at least one follow-up radiograph.
n=1401 n=1457 Number (%) of patients with ≥1 new vertebral fracture 27 (1.9%) 62 (4.3%) 2.4% 55% (29%, 71%) Patients with ≥1 baseline fracture n=858 n=835 Number (%) of patients with ≥1 new vertebral fracture 121 (14.1%) 169 (20.2%) 6.1% 30% (14%, 44%) Symptomatic vertebral fractures All randomized patients n=2557 n=2576 Number (%) of patients with ≥1 new clinical (painful) vertebral fracture 47 (1.8%) 81 (3.1%) 1.3% 41% (17%, 59%) The mean percentage change in BMD from baseline for EVISTA was statistically significantly greater than for placebo at each skeletal site (see Table 5).
Table 5: EVISTA- (60 mg Once Daily) Related Increases in BMD for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase vs.
Placebo , Time Site 12 Months % 24 Months % 36 Months % Lumbar Spine 2.0 2.6 2.6 Femoral Neck 1.3 1.9 2.1 Ultradistal Radius NDND = not done (total body and radius BMD were measured only at 24 months).
2.2 ND Distal Radius ND 0.9 ND Total Body ND 1.1 ND Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred.
Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the EVISTA group (1.1%).
Bone Histology Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment.
There were 56 paired biopsies evaluable for all indices.
In EVISTA-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover.
Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment.
Effect on Endometrium Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years.
Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the EVISTA-treated women had a 0.06 mm mean increase.
Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease.
This study was not specifically designed to detect endometrial polyps.
Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 EVISTA-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day.
There was no difference between EVISTA- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge.
14.2 Prevention of Postmenopausal Osteoporosis The effects of EVISTA on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy.
In these trials, all women received calcium supplementation (400 to 600 mg/day).
Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause).
The majority of the women were White (93.5%).
Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women.
The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD.
EVISTA, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD.
Effect on Bone Mineral Density Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months (see Table 6).
The placebo groups lost approximately 1% of BMD over 24 months.
Table 6: EVISTA- (60 mg Once Daily) Related Increases in BMD for the Three Osteoporosis Prevention Studies Expressed as Mean Percentage Increase vs.
Placebo at 24 Months Study Site NAAbbreviations: NA = North American, EU = European, INT = International.
% EU % INT , % Total Hip 2.0 2.4 1.3 Femoral Neck 2.1 2.5 1.6 Trochanter 2.2 2.7 1.3 Intertrochanter 2.3 2.4 1.3 Lumbar Spine 2.0 2.4 1.8 EVISTA also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward’s Triangle (hip) by 3.1% to 4.0%.
The effects of EVISTA on forearm BMD were inconsistent between studies.
In Study EU, EVISTA prevented bone loss at the ultradistal radius, whereas in Study NA, it did not (see Figure 1).
Figure 1: Total hip bone mineral density mean percentage change from baseline Effect on Endometrium In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU).
A total of 2978 TVU measurements were collected from 831 women in all dose groups.
Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the EVISTA-treated women had a 0.09 mm mean increase.
Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo.
There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding.
14.3 Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis MORE Trial The effect of EVISTA on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women [see Clinical Studies (14.1)] .
After 4 years, EVISTA, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67).
EVISTA reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the EVISTA group compared with placebo.
Table 7 presents efficacy and selected safety outcomes.
CORE Trial The effect of EVISTA on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial.
Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study.
EVISTA, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the EVISTA group compared with placebo.
There was no reduction in the incidence of ER-negative breast cancer.
In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the EVISTA and placebo groups.
Table 7 presents efficacy and selected safety outcomes.
In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, EVISTA, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned EVISTA (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the EVISTA group compared with placebo.
Table 7: EVISTA (60 mg Once Daily) vs.
Placebo on Outcomes in Postmenopausal Women with Osteoporosis MORE 4 years CORE 4 years Outcomes Placebo (N=2576) EVISTA (N=2557) HR (95% CI)Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women; N/A = not applicable.
Placebo (N=1286) EVISTA (N=2725) HR (95% CI) n IR n IR n IR n IR InvasiveIncluded 1274 patients in placebo and 2716 patients in EVISTA who were not diagnosed with breast cancer prior to CORE enrollment.
breast cancer 38 4.36 11 1.26 0.29 (0.15, 0.56)p<0.05, obtained from the log-rank test, and not adjusted for multiple comparisons in MORE.
20 5.41 19 2.43 0.44 (0.24, 0.83) ER , positive 29 3.33 6 0.69 0.20 (0.08, 0.49) 15 4.05 12 1.54 0.37 (0.17, 0.79) ER , negative 4 0.46 5 0.57 1.23 (0.33, 4.60) 3 0.81 6 0.77 0.95 (0.24, 3.79) ER , unknown 5 0.57 0 0.00 N/A 2 0.54 1 0.13 N/A Noninvasive , breast cancer 5 0.57 3 0.34 0.59 (0.14, 2.47) 2 0.54 5 0.64 1.18 (0.23, 6.07) Clinical vertebral fractures 107 12.27 62 7.08 0.57 (0.42, 0.78) N/A N/A N/A N/A N/A Death 36 4.13 23 2.63 0.63 (0.38, 1.07) 29 7.76 47 5.99 0.77 (0.49, 1.23) Death due to stroke 6 0.69 3 0.34 0.49 (0.12, 1.98) 1 0.27 6 0.76 2.87 (0.35, 23.80) Stroke 56 6.42 43 4.91 0.76 (0.51, 1.14) 14 3.75 49 6.24 1.67 (0.92, 3.03) Deep vein thrombosis 8 0.92 20 2.28 2.50 (1.10, 5.68) 4 1.07 17 2.17 2.03 (0.68, 6.03) Pulmonary embolism 4 0.46 11 1.26 2.76 (0.88, 8.67) 0 0.00 9 1.15 N/A Endometrial and uterine cancer 5 0.74 5 0.74 1.01 (0.29, 3.49) 3 1.02 4 0.65 0.64 (0.14, 2.85) Ovarian cancer 6 0.69 3 0.34 0.49 (0.12, 1.95) 2 0.54 2 0.25 0.47 (0.07, 3.36) Hot flashes 151 17.31 237 27.06 1.61 (1.31, 1.97) 11 2.94 26 3.31 1.12 (0.55, 2.27) Peripheral edema 134 15.36 164 18.73 1.23 (0.98, 1.54) 30 8.03 61 7.77 0.96 (0.62, 1.49) Cholelithiasis 45 5.16 53 6.05 1.18 (0.79, 1.75) 12 3.21 35 4.46 1.39 (0.72, 2.67) RUTH Trial The effect of EVISTA on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events.
Women in this study had a median age of 67.6 years (range 55-92) and were followed for a median of 5.6 years (range 0.01–7.1).
Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer ≥1.66%, based on the modified Gail model.
EVISTA, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo [absolute risk reduction (ARR) 1.2 per 1000 women-years]; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the EVISTA group compared with placebo (ARR 1.2 per 1000 women-years).
There was no reduction in ER-negative invasive breast cancer.
Table 8 presents efficacy and selected safety outcomes.
Table 8: EVISTA (60 mg Once Daily) vs.
Placebo on Outcomes in Postmenopausal Women at Increased Risk for Major Coronary Events PlaceboNote: There were a total of 76 breast cancer cases in the placebo group and 52 in the EVISTA group.
For two cases, one in each treatment group, invasive status was unknown.
EVISTA HR (N=5057) (N=5044) (95% CI)Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women.
Outcomes n IR n IR Invasive breast cancer 70 2.66 40 1.50 0.56 (0.38, 0.83) ER positive 55 2.09 25 0.94 0.45 (0.28, 0.72) ER negative 9 0.34 13 0.49 1.44 (0.61, 3.36) ER unknown 6 0.23 2 0.07 0.33 (0.07, 1.63) Noninvasive breast cancer 5 0.19 11 0.41 2.17 (0.75, 6.24) Clinical vertebral fractures 97 3.70 64 2.40 0.65 (0.47, 0.89) Death 595 22.45 554 20.68 0.92 (0.82, 1.03) Death due to stroke 39 1.47 59 2.20 1.49 (1.00, 2.24) Stroke 224 8.60 249 9.46 1.10 (0.92, 1.32) Deep vein thrombosis 47 1.78 65 2.44 1.37 (0.94, 1.99) Pulmonary embolism 24 0.91 36 1.35 1.49 (0.89, 2.49) Endometrial and uterine cancer 17 0.83 21 1.01 1.21 (0.64 – 2.30) Ovarian cancer 10 0.41 17 0.70 1.69 (0.78, 3.70) Hot flashes 241 9.09 397 14.82 1.68 (1.43, 1.97) Peripheral edema 583 22.00 706 26.36 1.22 (1.09, 1.36) Cholelithiasis 131 6.20 168 7.83 1.26 (1.01, 1.59) The effect of EVISTA in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, <1.66%, or ≥1.66%.
14.4 Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer STAR Trial The effects of EVISTA 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomized, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute.
Women in this study had a mean age of 58.5 years (range 35-83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66-23.61%), and 9.1% had a history of lobular carcinoma in situ (LCIS).
More than 93% of participants were White.
As of 31 December 2005, the median time of follow-up was 4.3 years (range 0.07-6.50 years).
EVISTA was not superior to tamoxifen in reducing the incidence of invasive breast cancer.
The observed incidence rates of invasive breast cancer were EVISTA 4.4 and tamoxifen 4.3 per 1000 women per year.
The results from a noninferiority analysis are consistent with EVISTA potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer.
The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer.
Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the EVISTA group.
Table 9 presents efficacy and selected safety outcomes.
Table 9: EVISTA (60 mg Once Daily) vs.
Tamoxifen (20 mg Once Daily) on Outcomes in Postmenopausal Women at Increased Risk for Invasive Breast Cancer EVISTA (N=9751) Tamoxifen (N=9736) RR (95% CI)Abbreviations: CI = confidence interval; DCIS = ductal carcinoma in situ; ER = estrogen receptor; IR = annual incidence rate per 1000 women; LCIS = lobular carcinoma in situ; RR = risk ratio for women in the EVISTA group compared with those in the tamoxifen group.
Outcomes n IR n IR Invasive breast cancer 173 4.40 168 4.30 1.02 (0.82, 1.27) ER positive 115 2.93 120 3.07 0.95 (0.73, 1.24) ER negative 52 1.32 46 1.18 1.12 (0.74, 1.71) ER unknown 6 0.15 2 0.05 2.98 (0.53, 30.21) Noninvasive breast cancer 83 2.12 60 1.54 1.38 (0.98, 1.95) DCIS 47 1.20 32 0.82 1.46 (0.91, 2.37) LCIS 29 0.74 23 0.59 1.26 (0.70, 2.27) Uterine cancerOnly patients with an intact uterus at baseline were included (tamoxifen = 4739, EVISTA = 4715).
23 1.21 37 1.99 0.61 (0.34, 1.05) Endometrial hyperplasia 17 0.90 100 5.42 0.17 (0.09, 0.28) Hysterectomy 92 4.84 246 13.25 0.37 (0.28, 0.47) Ovarian cancer 18 0.66 14 0.52 1.27 (0.60, 2.76) Ischemic heart disease 138 3.50 125 3.19 1.10 (0.86, 1.41) Stroke 54 1.36 56 1.42 0.96 (0.65, 1.42) Deep vein thrombosis 67 1.69 92 2.35 0.72 (0.52, 1.00) Pulmonary embolism 38 0.96 58 1.47 0.65 (0.42, 1.00) Clinical vertebral fractures 58 1.46 58 1.47 0.99 (0.68, 1.46) CataractsOnly patients who were free of cataracts at baseline were included (tamoxifen = 8342, EVISTA = 8333).
343 10.34 435 13.19 0.78 (0.68, 0.91) Cataract surgery 240 7.17 295 8.85 0.81 (0.68, 0.96) Death 104 2.62 109 2.76 0.95 (0.72, 1.25) Edema 741 18.66 664 16.83 1.11 (1.00, 1.23) Hot flashes 6748 169.91 7170 181.71 0.94 (0.90, 0.97) 14.5 Effects on Cardiovascular Disease In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with EVISTA 60 mg once daily for a median follow-up of 5.6 years.
No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome).
An increased risk of death due to stroke after treatment with EVISTA was observed: 59 (1.2%) EVISTA-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499).
The incidence of stroke did not differ significantly between treatment groups (249 with EVISTA [4.9%] versus 224 with placebo [4.4%]; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years) [see Warnings and Precautions (5.2, 5.3)] .
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied EVISTA 60 mg tablets are white, elliptical, and film coated.
They are imprinted on one side with LILLY and the tablet code 4165 in edible blue ink.
They are available as follows: Bottles of 30 (unit of use) NDC 54868-4170-0 Bottles of 60 NDC 54868-4170-1 16.2 Storage and Handling Store at controlled room temperature, 20º to 25ºC (68º to 77ºF) [see USP].
The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF); that results in a mean kinetic temperature calculated to be not more than 25ºC; and that allows for excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, and warehouses.
RECENT MAJOR CHANGES
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients in placebo-controlled clinical studies of EVISTA, 61% were 65 and over, while 15.5% were 75 and over.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology (12.3)] .
DOSAGE FORMS AND STRENGTHS
3 60 mg, white, elliptical, film-coated tablets (not scored).
They are imprinted on one side with LILLY and the tablet code 4165 in edible blue ink.
Tablets (not scored): 60 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM).
The biological actions of raloxifene are largely mediated through binding to estrogen receptors.
This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).
The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors.
Raloxifene appears to act as an estrogen agonist in bone.
It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence.
Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues.
These results are consistent with findings in clinical trials, which suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.
INDICATIONS AND USAGE
1 EVISTA® is an estrogen agonist/antagonist indicated for: Treatment and prevention of osteoporosis in postmenopausal women.
(1.1) Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis.
(1.2) Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer.
(1.3) Important Limitations: EVISTA is not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer.
(1.3) 1.1 Treatment and Prevention of Osteoporosis in Postmenopausal Women EVISTA is indicated for the treatment and prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.1, 14.2)] .
1.2 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [see Clinical Studies (14.3)] .
1.3 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [see Clinical Studies (14.4)] .
The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see Clinical Studies (14.4)] .
Twenty-seven percent of the participants received drug for 5 years.
The long-term effects and the recommended length of treatment are not known.
High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model).
Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth.
Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979.
Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.
After an assessment of the risk of developing breast cancer, the decision regarding therapy with EVISTA should be based upon an individual assessment of the benefits and risks.
EVISTA does not eliminate the risk of breast cancer.
Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.
Important Limitations of Use for Breast Cancer Risk Reduction There are no data available regarding the effect of EVISTA on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of EVISTA.
EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
EVISTA is not indicated for the reduction in the risk of noninvasive breast cancer.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category X.
EVISTA should not be used in women who are or may become pregnant [see Contraindications (4.2)] .
NUSRING MOTHERS
8.3 Nursing Mothers EVISTA should not be used by lactating women [see Contraindications (4.2)] .
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when raloxifene is administered to a nursing woman.
BOXED WARNING
WARNING: INCREASED RISK OF VENOUS THROMBOEMBOLISM AND DEATH FROM STROKE Increased risk of deep vein thrombosis and pulmonary embolism have been reported with EVISTA [see Warnings and Precautions (5.1)].
Women with active or past history of venous thromboembolism should not take EVISTA [see Contraindications (4.1)].
Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events.
Consider risk-benefit balance in women at risk for stroke [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].
WARNING: INCREASED RISK OF VENOUS THROMBOEMBOLISM AND DEATH FROM STROKE See full prescribing information for complete boxed warning.
Increased risk of deep vein thrombosis and pulmonary embolism have been reported with EVISTA (5.1) .
Women with active or past history of venous thromboembolism should not take EVISTA (4.1) .
Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events.
Consider risk-benefit balance in women at risk for stroke (5.2, 14.5) .
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Venous Thromboembolism: Increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
Discontinue use 72 hours prior to and during prolonged immobilization.
(5.1, 6.1) Death Due to Stroke: Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events.
No increased risk of stroke was seen in this trial.
Consider risk-benefit balance in women at risk for stroke.
(5.2, 14.5) Cardiovascular Disease: EVISTA should not be used for the primary or secondary prevention of cardiovascular disease.
(5.3, 14.5) Premenopausal Women: Use is not recommended.
(5.4) Hepatic Impairment: Use with caution.
(5.5) Concomitant Use with Systemic Estrogens: Not recommended.
(5.6) Hypertriglyceridemia: If previous treatment with estrogen resulted in hypertriglyceridemia, monitor serum triglycerides.
(5.7) 5.1 Venous Thromboembolism In clinical trials, EVISTA-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 EVISTA than with placebo.
The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy.
Because immobilization increases the risk for venous thromboembolic events independent of therapy, EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and EVISTA therapy should be resumed only after the patient is fully ambulatory.
In addition, women taking EVISTA should be advised to move about periodically during prolonged travel.
The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy [see Contraindications (4.1) and Adverse Reactions (6.1)] .
5.2 Death Due to Stroke In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with EVISTA.
During an average follow-up of 5.6 years, 59 (1.2%) EVISTA-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499).
There was no statistically significant difference between treatment groups in the incidence of stroke (249 in EVISTA [4.9%] versus 224 placebo [4.4%]).
EVISTA had no significant effect on all-cause mortality.
The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking [see Clinical Studies (14.5)] .
5.3 Cardiovascular Disease EVISTA should not be used for the primary or secondary prevention of cardiovascular disease.
In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years [see Clinical Studies (14.5)] .
5.4 Premenopausal Use There is no indication for premenopausal use of EVISTA.
Safety of EVISTA in premenopausal women has not been established and its use is not recommended.
5.5 Hepatic Impairment EVISTA should be used with caution in patients with hepatic impairment.
Safety and efficacy have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)] .
5.6 Concomitant Estrogen Therapy The safety of concomitant use of EVISTA with systemic estrogens has not been established and its use is not recommended.
5.7 History of Hypertriglyceridemia when Treated with Estrogens Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with EVISTA.
Women with this medical history should have serum triglycerides monitored when taking EVISTA.
5.8 Renal Impairment EVISTA should be used with caution in patients with moderate or severe renal impairment.
Safety and efficacy have not been established in patients with moderate or severe renal impairment [see Clinical Pharmacology (12.3)] .
5.9 History of Breast Cancer EVISTA has not been adequately studied in women with a prior history of breast cancer.
5.10 Use in Men There is no indication for the use of EVISTA in men.
EVISTA has not been adequately studied in men and its use is not recommended.
5.11 Unexplained Uterine Bleeding Any unexplained uterine bleeding should be investigated as clinically indicated.
EVISTA-treated and placebo-treated groups had similar incidences of endometrial proliferation [see Clinical Studies (14.1, 14.2)] .
5.12 Breast Abnormalities Any unexplained breast abnormality occurring during EVISTA therapy should be investigated.
EVISTA does not eliminate the risk of breast cancer [see Clinical Studies (14.4)] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide.
Physicians should instruct their patients to read the Medication Guide before starting therapy with EVISTA and to reread it each time the prescription is renewed.
17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation For osteoporosis treatment or prevention, patients should be instructed to take supplemental calcium and/or vitamin D if intake is inadequate.
Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, chronically ill, or with gastrointestinal malabsorption syndromes) should be instructed to take additional vitamin D if needed.
Weight-bearing exercises should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.
17.2 Patient Immobilization EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events [see Warnings and Precautions (5.1)] .
17.3 Hot Flashes or Flushes EVISTA may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency.
In some asymptomatic patients, hot flashes may occur upon beginning EVISTA therapy.
17.4 Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer Use of EVISTA is associated with the reduction of the risk of invasive breast cancer in postmenopausal women.
EVISTA has not been shown to reduce the risk of noninvasive breast cancer.
When considering treatment, physicians need to discuss the potential benefits and risks of EVISTA treatment with the patient.
EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.
DOSAGE AND ADMINISTRATION
2 60 mg tablet orally once daily.
(2.1) 2.1 Recommended Dosing The recommended dosage is one 60 mg EVISTA (raloxifene hydrochloride tablets) tablet daily, which may be administered any time of day without regard to meals [see Clinical Pharmacology (12.3)] .
For the indications in risk of invasive breast cancer the optimum duration of treatment is not known [see Clinical Studies (14.3, 14.4)] .
2.2 Recommendations for Calcium and Vitamin D Supplementation For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.
Postmenopausal women require an average of 1500 mg/day of elemental calcium.
Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones.
The recommended intake of vitamin D is 400-800 IU daily.
Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements.
Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.