Raloxifene Hydrochloride Tablets

Treatment and Prevention of Osteoporosis in Postmenopausal Women

Raloxifene Hydrochloride Tablets, USP 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

Raloxifene Hydrochloride Tablets, USP 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

Raloxifene Hydrochloride Tablets, USP 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. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with Raloxifene Hydrochloride Tablets, USP should be based upon an individual assessment of the benefits and risks.

Raloxifene Hydrochloride Tablets, USP does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting Raloxifene Hydrochloride Tablets, USP and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with Raloxifene Hydrochloride Tablets, USP.

Important Limitations of Use for Breast Cancer Risk Reduction

• 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 on the effectiveness of Raloxifene Hydrochloride Tablets, USP.
• Raloxifene Hydrochloride Tablets, USP is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
• Raloxifene Hydrochloride Tablets, USP is not indicated for the reduction in the risk of noninvasive breast cancer.

Venous Thromboembolism

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. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene 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 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 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00 to 2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene [4.9%] versus 224 placebo [4.4%]). Raloxifene 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

Raloxifene 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)].

Premenopausal Use

There is no indication for premenopausal use of raloxifene. Safety of raloxifene in premenopausal women has not been established and its use is not recommended.

Hepatic Impairment

Raloxifene 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)].

Concomitant Estrogen Therapy

The safety of concomitant use of raloxifene with systemic estrogens has not been established and its use is not recommended.

History of Hypertriglyceridemia when Treated with Estrogens

Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene. Women with this medical history should have serum triglycerides monitored when taking raloxifene.

5.8 Renal Impairment

Raloxifene 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)].

History of Breast Cancer

Raloxifene has not been adequately studied in women with a prior history of breast cancer.

Use in Men

There is no indication for the use of raloxifene in men. Raloxifene has not been adequately studied in men and its use is not recommended.

Unexplained Uterine Bleeding

Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene-treated and placebo-treated groups had similar incidences of endometrial proliferation [see Clinical Studies (14.1, 14.2)].

Breast Abnormalities

Any unexplained breast abnormality occurring during raloxifene therapy should be investigated. Raloxifene does not eliminate the risk of breast cancer [see Clinical Studies (14.4)].

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 510.04. Raloxifene Hydrochloride USP is an Almost white to pale yellow powder that freely soluble in dimethyl sulfoxide, practically insoluble in ether and in ethyl acetate.

Raloxifene Hydrochloride Tablets USP, 60 mg is supplied in a tablet dosage form for oral administration. Each Raloxifene Hydrochloride Tablets USP, 60 mg contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include citric acid monohydrate, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.

USP Dissolution Test is pending.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60 mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans) and prostatic leiomyoblastoma in male mice given 210 mg/kg.

In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in female rats given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation.

Mutagenesis Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice.

Impairment of Fertility When male and female rats were given daily doses ≥5 mg/kg (≥0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2) for at least 2 weeks did not affect sperm production or quality or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses ≥0.1 mg/kg (≥0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene.

Animal Toxicology and/or Pharmacology

The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine.

Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects.

These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of raloxifene as a skeletal antiresorptive agent.

Treatment of Postmenopausal Osteoporosis

Effect on Fracture Incidence

The effects of raloxifene on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years.

Effect on Bone Mineral Density

Raloxifene 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. Raloxifene decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for raloxifene (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for raloxifene (relative risk reduction = 30%) (see Table 4). All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene 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 Raloxifene on Risk of Vertebral Fractures

a Includes all patients with baseline and at least one follow-up radiograph.
	Number of Patients			Absolute Risk Reduction (ARR)	Relative Risk Reduction (95% CI)
	Raloxifene		Placebo
Fractures diagnosed radiographically   Patients with no baseline fracture a     Number (%) of patients with ≥ 1 new     vertebral fracture	n= 1401 27 (1.9%)	n= 1457 62 (4.3%)		2.4%	55% (29%, 71%)
Patients with ≥ 1 baseline fracturea     Number (%) of patients with ≥ 1     new vertebral fracture	n=858 121 (14.1%)	n=853 169 (20.2%)		6.1%	30% (14%, 44%)
Symptomatic vertebral fractures   All randomized patients    Number (%) of patients with ≥ 1     new clinical (painful) vertebral     fracture	n=2557 47 (1.8%)	n=2576 81 (3.1%)		1.3%	41% (17%, 59%)

The mean percentage change in BMD from baseline for raloxifene was statistically significantly greater than for placebo at each skeletal site (see Table 5).

Table 5: Raloxifene (60 mg Once Daily) Related Increases in BMDa for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase vs. Placebob, c

a Note: all BMD increases were significant (p<0.001).
b Intent-to-treat analysis; last observation carried forward.
c All patients received calcium and vitamin D.
d ND = not done (total body and radius BMD were measured only at 24 months).
	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	NDd	2.2	NDd
Distal Radius	NDd	0.9	NDd
Total Body	NDd	1.1	NDd

Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene group (1.1%).

Bone Histology

Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. There were 56 paired biopsies evaluable for all indices. In raloxifene-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment.

Effect on Endometrium

Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease. This study was not specifically designed to detect endometrial polyps. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 raloxifene- treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day. There was no difference between raloxifene- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge.

Prevention of Postmenopausal Osteoporosis

The effects of raloxifene 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 w omen. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene 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: Raloxifene (60 mg Once Daily) Related Increases in BMDa for the Three Osteoporosis Prevention Studies Expressed as Mean Percentage Increase vs . Placebob at 24 Monthsc

a Note: all BMD increases were significant (p≤0.001).
b All patients received calcium.
c Intent-to-treat analysis; last observation carried forward.
d Abbreviations: NA = North American, EU = European, INT = International.
e All women in the study had previously undergone hysterectomy.
	Study
Site	NAd %	EUd %	INTd, e %
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

Raloxifene also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward’s Triangle (hip) by 3.1% to 4.0%. The effects of raloxifene on forearm BMD were inconsistent between studies. In Study EU, raloxifene 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 raloxifene-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.

Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis

MORE Trial

The effect of raloxifene 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, raloxifene, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22 to 0.67). Raloxifene reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo. Table 7 presents efficacy and selected safety outcomes.

CORE Trial

The effect of raloxifene on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene and placebo groups. Table 7 presents efficacy and selected safety outcomes.

In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo.

Table 7: Raloxifene (60 mg Once Daily) vs . Placebo on Outcomes in Postmenopausal Women with Osteoporosis

a CORE was a follow-up study conducted in a subset of 4011 postmenopausal women who originally enrolled in MORE. Women were not re-randomized; the treatment assignment from MORE was carried forward to this study. At CORE enrollment, the raloxifene group included 2725 total patients with 1355 patients who were originally assigned to raloxifene 60 mg once daily and 1370 patients who were originally assigned to raloxifene 120 mg at MORE randomization.
b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women; N/A = not applicable.
c Included 1274 patients in placebo and 2716 patients in raloxifene who were not diagnosed with breast cancer prior to CORE enrollment.
d p<0.05, obtained from the log-rank test, and not adjusted for multiple comparisons in MORE.
e All cases were ductal carcinoma in situ.
f Only patients with an intact uterus were included (MORE: placebo = 1999, raloxifene = 1950; CORE: placebo = 1008, raloxifene = 2138).
Outcomes	MORE 4 years					COREa 4 years
	Placebo (N=2576)		Raloxifene (N=2557)		HR (95% CI)b	Placebo (N=1286)		Raloxifene (N=2725)		HR (95% CI)b
	n	IRb	n	IRb		n	IRb	n	IRb
Invasivec  breast cancer	38	4.36	11	1.26	0.29 (0.15, 0.56)d	20	5.41	19	2.43	0.44 (0.24, 0.83)d
ERb, c 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)
ERb, c 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)
ERb, c unknown	5	0.57	0	0.00	N/Ab	2	0.54	1	0.13	N/Ab
Noninvasivec, e  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/Ab	N/Ab	N/Ab	N/Ab	N/Ab
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/Ab
Endometrial and uterine  cancerf	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 raloxifene 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 to 92) and were followed for a median of 5.6 years (range 0.01 to 7.1). Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer ≥1.66%, based on the modified Gail model.

Raloxifene 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 raloxifene 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: Raloxifene (60 mg Once Daily) vs . Placebo on Outcomes in Postmenopausal Women at Increased Risk for Major Coronary Events

a Note: There were a total of 76 breast cancer cases in the placebo group and 52 in the raloxifene group. For two cases, one in each treatment group, invasive status was unknown.
b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women.
c p<0.05, obtained from the log-rank test, after adjusting for the co-primary endpoint of major coronary events.
d All cases were ductal carcinoma in situ.
e Only patients with an intact uterus were included (placebo = 3882, raloxifene = 3900).
f Only patients with at least one ovary were included (placebo = 4606, raloxifene = 4559).
g Only patients with an intact gallbladder at baseline were included (placebo = 4111, raloxifene = 4144).
Outcomes	Placeboa (N=5057)		Raloxifene a (N=5044)		HR (95% CI)b
	n	IRb	n	IRb
Invasive breast cancer	70	2.66	40	1.50	0.56 (0.38, 0.83)c
ERb positive	55	2.09	25	0.94	0.45 (0.28, 0.72)
ERb negative	9	0.34	13	0.49	1.44 (0.61, 3.36)
ERb unknown	6	0.23	2	0.07	0.33 (0.07, 1.63)
Noninvasived 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 cancere	17	0.83	21	1.01	1.21 (0.64 - 2.30)
Ovarian cancerf	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)
Cholelithiasisg	131	6.20	168	7.83	1.26 (1.01, 1.59)

The effect of raloxifene 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%.

Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer

STAR Trial

The effects of raloxifene 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 to 83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66 to 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 to 6.50 years).

Raloxifene was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were raloxifene 4.4 and tamoxifen 4.3 per 1000 women per year. The results from a noninferiority analysis are consistent with raloxifene potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer. Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene group. Table 9 presents efficacy and selected safety outcomes.

Table 9: Raloxifene (60 mg Once Daily) vs . Tamoxifen (20 mg Once Daily) on Outcomes in Postmenopausal Women at Increased Risk for Invasive Breast Cancer

a 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 raloxifene group compared with those in the tamoxifen group.
b Of the 60 noninvasive breast cases in the tamoxifen group, 5 were mixed types. Of the 83 noninvasive breast cancers in the raloxifene group, 7 were mixed types.
c Only patients with an intact uterus at baseline were included (tamoxifen = 4739, raloxifene = 4715).
d Only patients with at least one intact ovary at baseline were included (tamoxifen = 6813, raloxifene = 6787).
e Defined as myocardial infarction, severe angina, or acute ischemic syndromes.
f Only patients who were free of cataracts at baseline were included (tamoxifen = 8342, raloxifene = 8333).
g Peripheral edema events are included in the term edema.
Outcomes	Raloxifene (N=9751)		Tamoxifen (N=9736)		RR (95% CI)a
	n	IRa	n	IRa
Invasive breast cancer	173	4.40	168	4.30	1.02 (0.82, 1.27)
ERa positive	115	2.93	120	3.07	0.95 (0.73, 1.24)
ERa negative	52	1.32	46	1.18	1.12 (0.74, 1.71)
ERa unknown	6	0.15	2	0.05	2.98 (0.53, 30.21)
Noninvasive breast cancerb	83	2.12	60	1.54	1.38 (0.98, 1.95)
DCISa	47	1.20	32	0.82	1.46 (0.91, 2.37)
LCISa	29	0.74	23	0.59	1.26 (0.70, 2.27)
Uterine cancerc	23	1.21	37	1.99	0.61 (0.34, 1.05)
Endometrial hyperplasiac	17	0.90	100	5.42	0.17 (0.09, 0.28)
Hysterectomyc	92	4.84	246	13.25	0.37 (0.28, 0.47)
Ovarian cancerd	18	0.66	14	0.52	1.27 (0.60, 2.76)
Ischemic heart diseasee	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)
Cataractsf	343	10.34	435	13.19	0.78 (0.68, 0.91)
Cataract surgeryf	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)
Edemag	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)

Effects on Cardiovascular Disease

In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with raloxifene was observed: 59 (1.2%) raloxifene-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 to 2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with raloxifene [4.9%] versus 224 with placebo [4.4%]; hazard ratio 1.10; 95% confidence interval 0.92 to 1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years) [see Warnings and Precautions (5.2, 5.3)].

See FDA-approved Medication Guide.

Physicians should instruct their patients to read the Medication Guide before starting therapy with Raloxifene Hydrochloride Tablets, USP and to reread it each time the prescription is renewed.

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.

Patient Immobilization

Raloxifene Hydrochloride Tablets, USP 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)].

Hot Flashes or Flushes

Raloxifene Hydrochloride Tablets, USP may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning Raloxifene Hydrochloride Tablets, USP 60 mg therapy.

Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer

Use of Raloxifene Hydrochloride Tablets, USP is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. Raloxifene Hydrochloride Tablets, USP has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of Raloxifene Hydrochloride Tablets, USP treatment with the patient.

Raloxifene Hydrochloride Tablets, USP is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.

Patients should have breast exams and mammograms before starting Raloxifene Hydrochloride Tablets, USP and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with Raloxifene Hydrochloride Tablets, USP.

                                                                        Manufactured by:
                                                            ScieGen Pharmaceuticals, Inc.
                                                               Huappauge, NY 11788, USA

Revision: 02/16

                                                                       Medication Guide

                    RALOXIFENE (ral.ox.i.fene) Hydrochloride Tablets, USP 60 mg for oral use

Read the Medication Guide that comes with Raloxifene Hydrochloride Tablets before you start taking it and each time you refill your prescription. The information may have changed. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk with your doctor about Raloxifene Hydrochloride Tablets when you start taking it and at regular checkups.

What is the most important information I should know about Raloxifene Hydrochloride Tablets?

Serious and life-threatening side effects can occur while taking Raloxifene Hydrochloride Tablets. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with Raloxifene Hydrochloride Tablets. Women who have or have had blood clots in the legs, lungs, or eyes should not take Raloxifene Hydrochloride Tablets.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking Raloxifene Hydrochloride Tablets.

1. Before starting Raloxifene Hydrochloride Tablets, tell your doctor if you have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (transient ischemic attack), or have an irregular heartbeat.
2. Stop taking Raloxifene Hydrochloride Tablets and call your doctor if you have:
   • leg pain or a feeling of warmth in the lower leg (calf).
   • swelling of the legs, hands, or feet.
   • sudden chest pain, shortness of breath, or coughing up blood.
   • sudden change in your vision, such as loss of vision or blurred vision.
3. Being still for a long time (such as sitting still during a long car or airplane trip or being in bed after surgery) can increase your risk of blood clots. (See “What should I avoid if I am taking Raloxifene Hydrochloride Tablets?”)

                                        What is raloxifene hydrochloride?

Raloxifene hydrochloride is a type of prescription medicine called a Selective Estrogen Receptor Modulator (SERM). Raloxifene Hydrochloride Tablets are for women after menopause, and has more than one use:

• Osteoporosis: Raloxifene Hydrochloride Tablets treats and prevents osteoporosis by helping make your bones stronger and less likely to break.
• Invasive Breast Cancer: If you have osteoporosis or are at high risk for breast cancer, Raloxifene Hydrochloride Tablets can be used to lower your chance of getting invasive breast cancer. Raloxifene Hydrochloride Tablets will not totally get rid of your chance of getting breast cancer. Your doctor can estimate your risk of breast cancer by asking you about risk factors, including:
• your age (getting older).
• family history of breast cancer in your mother, sister, or daughter.
• a history of any breast biopsy, especially an abnormal biopsy.

You and your doctor should talk about whether the possible benefit of Raloxifene Hydrochloride Tablets in lowering your chance of getting invasive breast cancer is greater than its possible risks.

Raloxifene Hydrochloride Tablets are not for use in premenopausal women (women who have not passed menopause).

                    Who should not take Raloxifene Hydrochloride Tablets?

Do not take Raloxifene Hydrochloride Tablets if you:

• have or have had blood clots in your legs, lungs, or eyes. Taking Raloxifene Hydrochloride Tablets may increase the risk of getting blood clots.
• are pregnant or could become pregnant. Raloxifene Hydrochloride Tablets could harm your unborn child.
• are nursing a baby. It is not known if raloxifene passes into breast milk or what effect it might have on the baby.

         What should I tell my doctor before taking Raloxifene Hydrochloride Tablets?

Raloxifene Hydrochloride Tablets may not be right for you. Before taking Raloxifene Hydrochloride Tablets, tell your doctor about all your medical conditions, including if you:

• have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (TIA/transient ischemic attack), or a type of irregular heartbeat (atrial fibrillation).
• have had breast cancer. Raloxifene Hydrochloride Tablets have not been fully studied in women who have a history of breast cancer.
• have liver or kidney problems.
• have taken estrogen in the past and had a high increase of triglycerides (a kind of fat in the blood).
• are pregnant, planning to become pregnant, or breast-feeding (see “Who should not take Raloxifene Hydrochloride Tablets?”).

Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine. Especially tell your doctor if you take*:

• warfarin (Coumadin®, Jantoven®)
  If you are taking warfarin or other coumarin blood thinners, your doctor may need to do a blood test when you first start or if you need to stop taking raloxifene hydrochloride tablets. Names for this test include “prothrombin time,” “pro-time,” or “INR.” Your doctor may need to adjust the dose of your warfarin or other coumarin blood thinner.
• cholestyramine
• estrogens

Raloxifene hydrochloride tablets should not be taken with cholestyramine or estrogens.

                        How should I take Raloxifene Hydrochloride Tablets?

• Take Raloxifene Hydrochloride Tablets exactly how your doctor tells you to.
• Keep taking Raloxifene Hydrochloride Tablets for as long as your doctor prescribes it for you. It is not known how long you should keep taking Raloxifene Hydrochloride Tablets to lower your chance of getting invasive breast cancers.
• It is important to get your refills on time so you do not run out of the medicine.
• Take one Raloxifene Hydrochloride Tablets each day.
• Take Raloxifene Hydrochloride Tablets at any time of the day, with or without food.
• To help you remember to take Raloxifene Hydrochloride Tablets, it may be best to take it at about the same time each day.
• Calcium and vitamin D may be taken at the same time as Raloxifene Hydrochloride Tablets. It is important to take calcium and vitamin D, as directed by your physician, to prevent or treat osteoporosis.
• If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take two doses at the same time.

                        What should I avoid while taking Raloxifene Hydrochloride Tablets?

• Being still for a long time (such as during long trips or being in bed after surgery) can increase the risk of blood clots. Raloxifene Hydrochloride Tablets may add to this risk. If you will need to be still for a long time, talk with your doctor about ways to reduce the risk of blood clots. On long trips, move around periodically. Stop taking Raloxifene Hydrochloride Tablets at least 3 days before a planned surgery or before you plan on being still for a long time. You should start taking Raloxifene Hydrochloride Tablets again when you return to your normal activities.
• Some medicines should not be taken with Raloxifene Hydrochloride Tablets (see “What should I tell my doctor before taking Raloxifene Hydrochloride Tablets?”).

                    What are the possible side effects of Raloxifene Hydrochloride Tablets?

Serious and life-threatening side effects can occur while taking Raloxifene Hydrochloride Tablets. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with Raloxifene Hydrochloride Tablets. Women who have or have had blood clots in the legs, lungs, or eyes should not take Raloxifene Hydrochloride Tablets.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking Raloxifene Hydrochloride Tablets .

See “What is the most important information I should know about Raloxifene Hydrochloride Tablets?”

The most common side effects of Raloxifene Hydrochloride Tablets are hot flashes, leg cramps, swelling of the feet, ankles, and legs, flu syndrome, joint pain, and sweating. Hot flashes are more common during the first 6 months after starting treatment.

These are not all the side effects of Raloxifene Hydrochloride Tablets. Tell your doctor about any side effect that bothers you or that does not go away. If you have any problems or questions that concern you while taking Raloxifene Hydrochloride Tablets? ask your doctor or pharmacist for more information.

                           What else should I know about Raloxifene Hydrochloride Tablets?

• Do not use Raloxifene Hydrochloride Tablets to prevent heart disease, heart attack, or strokes.
• To get the calcium and vitamin D you need, your doctor may advise you to change your diet and/or take supplemental calcium and vitamin D. Your doctor may suggest other ways to help treat or prevent osteoporosis, in addition to taking Raloxifene Hydrochloride Tablets and getting the calcium and vitamin D you need. These may include regular exercise, stopping smoking, and drinking less alcohol.
• Women who have hot flashes can take raloxifene hydrochloride. Raloxifene Hydrochloride Tablets do not treat hot flashes, and it may cause hot flashes in some women. (See “What are the possible side effects of raloxifene hydrochloride?”)
• Raloxifene Hydrochloride Tablets have not been found to cause breast tenderness or enlargement. If you notice any changes in your breasts, call your doctor to find out the cause. Before starting and while taking Raloxifene Hydrochloride Tablets you should have breast exams and mammograms, as directed by your doctor. Because Raloxifene Hydrochloride Tablets does not eliminate the chance of developing breast cancers, you need these examinations to find any breast cancers as early as possible.
• Raloxifene Hydrochloride Tablets should not cause spotting or menstrual-type bleeding. If you have any vaginal bleeding, call your doctor to find out the cause. Raloxifene Hydrochloride Tablets have not been found to increase the risk for cancer of the lining of the uterus.
• Women in clinical trials have taken Raloxifene Hydrochloride Tablets for up to eight years.

                               How should I store Raloxifene Hydrochloride Tablets?

• Store Raloxifene Hydrochloride Tablets at 68°F to 77°F (20°C to 25°C).
• Keep Raloxifene Hydrochloride Tablets and all medicines out of the reach of children.

            General Information about the safe and effective use of Raloxifene Hydrochloride Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Raloxifene Hydrochloride Tablets for a condition for which it was not prescribed. Do not give your Raloxifene Hydrochloride Tablets to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide is a summary of the most important information about Raloxifene Hydrochloride Tablets. If you would like more information about Raloxifene Hydrochloride Tablets, talk with your doctor. You can ask your doctor or pharmacist for information about Raloxifene Hydrochloride Tablets that is written for health professionals. For more information, call 1-855-724-3436 (toll-free).

                    What are the ingredients in Raloxifene Hydrochloride Tablets, USP?

Active Ingredient: raloxifene hydrochloride USP

Inactive Ingredients: citric acid monohydrate, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brands listed are trademarks of their respective owners and are not trademarks of ScieGen Pharmaceuticals Inc. The makers of these brands are not affiliated with and do not endorse ScieGen Pharmaceuticals Inc and company or its products.

                                                                        Manufactured by:
                                                            ScieGen Pharmaceuticals, Inc.
                                                               Huappauge, NY 11788, USA

Revision: 02/16