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 off-white to pale-yellow solid that is very slightly soluble in water.

CLINICAL PHARMACOLOGY

Decrease in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. This imbalance between resorption and formation is related to loss of estrogen, and may also involve age-related impairment of osteoblasts or their precursors.

Raloxifene’s biological actions, like those of estrogen, are mediated through binding to estrogen receptors. This binding results in differential expression of multiple estrogen-regulated genes in different tissues.

Clinical data indicate that raloxifene, a selective estrogen receptor modulator (SERM), has estrogen-like effects on bone (increase in BMD) and on lipid (decrease in total and LDL cholesterol levels) metabolism. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. Preliminary clinical data (through 30 months) suggest Raloxifene lacks estrogen-like effects on uterus and breast tissue.

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 2.0%.

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. ESTROACT can be administered without regard to meals.

Raloxifene and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and D 1-acid glycoprotein, but not to sex steroid binding globulin. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen to plasma proteins.

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. In the osteoporosis prevention trials, raloxifene and metabolite concentrations are similar for women with estimated creatinine clearance as low as 23 mL/min.

Special Populations

Geriatric: No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years).

Pediatric: The pharmacokinetics of raloxifene have not been evaluated in a pediatric population.

Gender: Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers.

Renal Insufficiency: Since negligible amounts of raloxifene are eliminated in urine, a study in patients with renal insufficiency was not conducted.

Hepatic Dysfunction: Raloxifene was studied, as a single dose, in Child-Pugh Class A patients with cirrhosis and total serum bilirubin ranging from 0.6 to 2.0 mg/dL. Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with hepatic insufficiency.

PRECAUTIONS

Antacids: Concurrent administration of calcium carbonate or aluminium and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene.

Corticosteroids: The co-administration of ESTROACT with corticosteroids has not been evaluated.

Cyclosporine: The co-administration of ESTROACT with cyclosporine has not been evaluated.

Digoxin: Raloxifene has no effect on the pharmacokinetics of digoxin.

INDICATIONS

ESTROACT is indicated for the prevention of osteoporosis in postmenopausal women.

Supplemental calcium should be added to the diet if daily intake is inadequate.

DOSAGE AND ADMINISTRATION
The recommended dosage is one 60-mg ESTROACT tablet daily which may be administered any time of day without regard to meals.

SIDE EFFECTS
The majority of adverse events occurring during clinical trials were mild and generally did not require discontinuation of therapy.

Common adverse events considered to be drug-related were hot flashes and leg cramps. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.

DRUG INTERACTIONS

Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with ESTROACT.

Warfarin: The coadministration of ESTROACT and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If ESTROACT is given concurrently with warfarin, prothrombin time should be monitored.

Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when ESTROACT is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide.

Premenopausal Use: There is no indication for premenopausal use of ESTROACT. Safety of ESTROACT in premenopausal women has not been established and its use is not recommended.

Hepatic Dysfunction: Raloxifene was studied, as a single dose, in Child-Pugh Class A patients with cirrhosis and serum total bilirubin ranging from 0.6 to 2.0 mg/dL. Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with total bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with severe hepatic insufficiency.

PRECAUTIONS
General

Concurrent Estrogen Therapy: The concurrent use of ESTROACT and systemic estrogen or hormone replacement therapy (ERT or HRT) has not been studied in prospective clinical trials and therefore concomitant use of ESTROACT with systemic estrogens is not recommended.

Lipid Metabolism: ESTROACT lowers serum total and LDL cholesterol by 6% to 11%, but does not affect serum concentrations of total HDL cholesterol or triglycerides. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidemia. Concurrent use of ESTROACT and lipid-lowering agents has not been studied.

Endometrium: ESTROACT has not been associated with endometrial proliferation. Unexplained uterine bleeding should be investigated as clinically indicated.

Breast: ESTROACT has not been associated with breast enlargement, breast pain, or an increased risk of breast cancer. Any unexplained breast abnormality occurring during ESTROACT therapy should be investigated.

Use in Men: Safety and efficacy have not been evaluated in men.

Pregnancy

ESTROACT should not be used in women who are or may become pregnant.

Nursing Mothers

ESTROACT should not be used by lactating women. It is not known whether raloxifene is excreted in human milk.

Pediatric Use

ESTROACT should not be used in pediatric patients.

CONTRAINDICATIONS

ESTROACT is contraindicated in women who are or may become pregnant. ESTROACT may causefetal harm when administered to a pregnant woman. ESTROACT is contraindicated in women with active or past history of venous thromboembolic events, including deepvein thrombosispulmonary embolism, and retinalvein thrombosis.

ESTROACT is contraindicated in women known to be hypersensitive to raloxifene or other constituents of the tablets.

PATIENT INFORMATION

For safe and effective use of ESTROACT, the physician should inform patients about the following:

Patient Immobilization: ESTROACT 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.

Hot flashes or flushes: ESTROACT is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning ESTROACT therapy.

Other Preventive Measures: Patients should be instructed to takesupplementalcalcium and vitamin D, if daily dietaryintake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking, and/or alcohol consumption, if these factors exist.