Evista Raloxifene hydrochloride 60 mg Tablet, 100-count — NDC 0002-4184-02 (Billing 00002-4184-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence.

Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.

12.2Pharmacodynamics Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors.

In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. In both the osteoporosis treatment and prevention trials, EVISTA therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products).

The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily EVISTA 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either EVISTA or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for EVISTA and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy).

There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy.

12.3Pharmacokinetics The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters.

Table 3 summarizes the pharmacokinetic parameters of raloxifene. Absorption — Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive.

Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Administration of raloxifene… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence.

Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.

12.3Pharmacokinetics The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters.

Table 3 summarizes the pharmacokinetic parameters of raloxifene. Absorption — Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive.

Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (C max 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure.

EVISTA can be administered without regard to meals. Distribution — Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent. Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins.

Raloxifene binds to both albumin and α1-acid glycoprotein, but not to sex-steroid binding globulin. Metabolism — Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14 C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4′-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide.

No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel.

This is consistent with interconversion of raloxifene and the glucuronide metabolites. Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is

44.1L/kg•hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing. Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics.

Following chronic dosing, clearance ranges from 40 to 60 L/kg•hr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). Excretion — Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine.

Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. Table 3: Summary of Raloxifene Pharmacokinetic Parameters in the Healthy Postmenopausal Woman a Abbreviations: C max = maximum plasma concentration, t 1/2 = half-life, AUC = area under the curve, CL = clearance, V = volume of distribution, F = bioavailability, CV = coefficient of variation. b Data normalized for dose in mg and body weight in kg. c Range of observed half-life. C max a, b (ng/mL)/ (mg/kg) t 1/2 (hr) a AUC 0- ∞ a, b (ng•hr/mL)/ (mg/kg) CL/F a (L/kg•hr) V/F a (L/kg) Single Dose Mean 0.50 27.7 27.2 44.1 2348 CV a (%) 52 10.7 to 273 c 44 46 52 Multiple Dose Mean 1.36 32.5 24.2 47.4 2853 CV a (%) 37 15.8 to 86.6 c 36 41 56 Special Populations Pediatric — The pharmacokinetics of raloxifene has not been evaluated in a pediatric population [see Use in Specific Populations ( 8.4 )] .

Geriatri… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors.

In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. In both the osteoporosis treatment and prevention trials, EVISTA therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products).

The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily EVISTA 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either EVISTA or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for EVISTA and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy).

There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy.

6.1Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to EVISTA in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial.

Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) EVISTA-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of EVISTA-treated women and 8.8% of placebo-treated women.

Venous Thromboembolism : The most serious adverse reaction related to EVISTA was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with EVISTA. Twenty-six EVISTA-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment.

Common adverse reactions considered to be related to EVISTA therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on EVISTA and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on EVISTA.

Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2036 women were exposed to raloxifene HCl (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). Therapy was discontinued due to an adverse reaction in 11.4% of 581 EVISTA-treated women and 12.2% of 584 placebo-treated women.

Discontinuation rates due to hot flashes did not differ significantly between EVISTA and placebo groups (1.7% and 2.2%, respectively). Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on EVISTA versus about one in six on placebo.

The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment. Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥2.0% in either group and in more EVISTA-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality.

The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy. Table 1: Adverse Reactions Occurring in Placebo-Controlled Osteoporosis Clinical Trials at a Frequency ≥2.0% and in More EVISTA-Treated (60 mg Once Daily) Women than Placebo-Treated Women a a A: Placebo incidence greater than or equal to EVISTA incidence; B: Less than 2% incidence and more frequent with EVISTA. b Includes only patients with an intact uterus: Prevention Trials: EVISTA, n=354, Placebo, n=364; Treatment Trial: EVISTA, n=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid.

Treatment Prevention EVISTA (N=2557) % Placebo (N=2576) % EVISTA (N=581) % Placebo (N=584) % Body as a Whole Infe… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/m 2 ) 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/m 2 ) 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/m 2 ), 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/m 2 ), 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.

13.2Animal 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 EVISTA as a skeletal antiresorptive agent.