EVIFEN

Raloxifene is a second generation selective estrogen receptor modulator (SERM) that mediates anti-estrogenic effects on breast and uterine tissues, and estrogenic effects on bone, lipid metabolism, and blood coagulation. 6, 12 Exhibiting tissue-specific effects distinct from estradiol, raloxifene is the first of the benzothiophene group of antiestrogens to be labelled a SERM.

Available in many countries worldwide, raloxifene was initially approved by the FDA in December, 1997 under the market name Evista® for the management and prevention of osteoporosis in postmenopausal women and reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis or those who are at high risk for invasive breast cancer.

However, it has a negligible effect on altering the development and progression of breast cancer itself.

The most common causes of osteoporosis include postmenopausal deficiency of estrogen and age-related deterioration in bone homeostasis.

Due to the risk of bone fractures that may lead to morbidities and reduced quality of life, the management of osteoporosis in postmenopausal women with the use of therapeutic agents in addition to concurrent therapies is critical.

Due to the decline in estrogen levels in postmenopausal osteoporosis, hormone replacement therapy (HRT), such as estradiol, has been used to ameliorate the condition.

However, due to the off-target actions by HRT, newer non-hormonal agents such as raloxifene and tamoxifen have been developed to reduce adverse events through selective pharmacological actions on tissue-specific therapeutic targets.

The main effects of raloxifene are to preserve the bone mineral density and decrease the risk of breast cancer in postmenopausal women.

Compared to estrogen and tamoxifen, raloxifene was not associated with an increased risk of uterine cancer and it does not cause endometrial proliferation.

Although rare, there was an increased risk of venous thromboembolism during clinical trials of postmenopausal women receiving raloxifene.

In addition, a clinical study consisting of postmenopausal women with documented coronary heart disease or at increased risk for coronary events showed an increased risk for fatal stroke with raloxifene therapy compared to placebo.

It is strongly advised that the risk-benefit ratio is considered before starting raloxifene therapy in women at risk of thromboembolic disease or strokes, such as the prior history of stroke, transient ischemic attack, atrial fibrillation, hypertension, or cigarette smoking.

Indicated for the prevention and treatment of osteoporosis in postmenopausal women, as well as prevention and treatment of corticosteroid-induced bone loss.

Indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women with a high risk for invasive breast cancer.

**Label

Raloxifene belongs to the selective estrogen receptor modulator (SERM) drug class that exhibits estrogenic effects on bone and lipid metabolism while mediating anti-estrogenic effects on uterine endometrium and breast tissues.

On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts to augument bone mineral density.

Raloxifene produces estrogen-like effects on bone, reducing the resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss.

In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene at variable doses of 30-150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo.

In the MORE and

RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo.

In a eight-week study evaluating short-term effects of raloxifene in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion.

Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells in vitro and development of induced mammary tumors in rats in vivo.

In adult female rats, raloxifene produced a greater regression of the mammary gland than tamoxifen.

MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene for 40 months.

Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials.

Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis.

There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer.

Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue.

Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium.

Raloxifene promotes estrogen-like effects on lipid metabolism.

In a

European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy.

Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides.

As the

HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene were questioned.

Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy.

Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration.

Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%.

Following oral ingestion of a single dose or multiple dose of raloxifen in healthy postmenopausal women, the mean peak plasma concentrations (Cmax) were 0.50 and 1.36 ng/mL, respectively, and the AUC values were 27.2 and 24.2 ngxhr/mL, respectively.

The time to reach

Cmax following a single or multiple oral doses were 27.7 and 32.5 hours, respectively.

Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drug by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively.

Following oral administration of single doses randing from 30-150 mg in postmenopausal women, the volume of distribution was about 2348 L/kg. Following oral administration of multiple doses, the value increased to 2853 L/kg. Raloxifene is widely distributed in the tissues.

It is not known whether raloxifene is excreted in human milk.

Raloxifene is reported to undergo metabolism in the intestines and liver devoid of cytochrome P450 pathway.

It is extensively metabolized, where less than 1% of the total dose exists as unchanged compound.

It mainly undergoes first-pass metabolism to form glucuronide conjugates, raloxifene-4'-glucuronide (raloxifene-4'-β-glucuronide), raloxifene-6-glucuronide (raloxifene-6-β-glucuronide), and raloxifene-6,4'-diglucuronide.

No other metabolites have been detected in human 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.

Label Hover over products below to view reaction partners Raloxifene Raloxifene-4′-glucuronide + Raloxifene-6, 4′-diglucuronide + Raloxifene-6-glucuronide.

Raloxifene predominantly undergoes fecal excretion, with less than 0.2% of the dose being excreted in the urine as unchanged form of the compound and less than 6% of the dose being excreted as glucuronide conjugates.

Co-administration with cholestyramine, a bile acid sequestrant, was shown to reduce the enterohepatic recycling of raloxifene by 60%.

The average plasma elimination half-life of raloxifene ranges from 27-32 hours. 7, 12 The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.

Following intravenous administration, raloxifene was shown to be cleared at a rate approximating hepatic blood flow.

The apparent oral clearance is reported to be 44.1 L/kgxhr.

The clearance can range from 40-60 L/kgxhr following chronic dosing.

In healthy postmenopausal women receiving multiple oral dose, the mean clearance was 47.4 L/kgxhr.

Apparent clearance can be reduced by 56% in patients with hepatic impairment.

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and Overdose The oral LD 50 value in rats is > 5000 mg/kg, which is about 810 times the human dose.

In monkeys, no mortality was seen after a single oral dose of 1000 mg/kg.

A rare postmarketing report of a non-fatal overdose after oral ingestion of 1.5 g has been reported.

Common adverse events of leg cramps, hot flushes, and dizziness have been reported with the use of raloxifene at doses of greater than 180 mg. More serious adverse event of venous thromboembolic events were observed with raloxifene.

Two 18-month-old children accidentally ingested 180 mg of raloxifene and symptoms of ataxia, dizziness, vomiting, rash, diarrhea, tremor, flushing, and elevated alkaline phosphatase levels were reported.

There is no known antidote for raloxifene.

In a two-year mouse carcinogenicity study at raloxifene doses that are higher than the human therapeutic doses, there was an increased incidence of benign and malignant ovarian tumors of granulosa or theca cell origin.

Another study showed an increased incidence of testicular interstitial cell tumors, prostatic adenomas, adenocarcinomas, and prostatic leiomyoblastoma in male mice receiving doses higher than human therapeutic doses.

There was no evidence of the genotoxic potential of raloxifene in bacterial mutagenicity assays, in vitro rat DNA assays, or other in vitro rodent cell line assays.

When assessing effects on the reproductive system of male and female rats, raloxifene caused lack of pregnancy and disruptions in estrous cycles and inhibited ovulation at dose of 0.1-10 mg/kg/day. Administration of raloxifene during the preimplantation period at doses greater than 0.1 mg/kg resulted in delayed and disrupted embryo implantation, further leading to prolonged gestation and reduced litter size.

There were no effects on sperm production or quality or reproductive performance in male rats.

The effects on the fertility by raloxifene were reversible.

Label Use in special populations

The use of raloxifene in pregnant or nursing women is not advised.

Although there are no specific dosing adjustment guidelines, caution should be undertaken when administering raloxifene in geriatric patients or patients with renal or hepatic impairment.

Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

Pregnancy 4.1 Venous Thromboembolism Raloxifene hydrochloride tablets are contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. 4.2 Pregnancy Raloxifene hydrochloride is contraindicated for use in pregnancy, as it may cause fetal harm.

mg tablet orally once daily. 2.1 Recommended Dosing The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals.

For the indications in risk of invasive breast cancer the optimum duration of treatment is not known. 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 to 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.

USP, 60 mg are white to off-white, elliptical, film-coated tablets debossed with ‘X’ on one side and ‘57’ on other side.

Bottles of 30 NDC 16714-213-01 Bottles of 100 NDC 16714-213-02 Bottles of 1,000 NDC 16714-213-03 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) .

USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Raloxifene hydrochloride is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential.

Based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has during all stages of pregnancy.

Limited data with raloxifene hydrochloride use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage.

In rabbits and rats dosed during organogenesis or during gestation and lactation, raloxifene hydrochloride produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose (based on human body surface area comparison).

In the developmental and reproductive toxicity studies conducted with raloxifene hydrochloride, numerous adverse effects were observed in multiple animal species.

In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ).

In rats dosed during organogenesis, retardation of fetal growth and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m 2 ).

Treatment of rats during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) produced effects that included delayed and disrupted parturition, decreased neonatal survival and altered physical development, sex.

• and age-specific reductions in growth and changes in pituitary hormone content, and decreased lymphoid compartment size in offspring.

At 10 mg/kg, the disruption of parturition resulted in maternal and progeny morbidity and death.

Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride, 61% were and over, while 15.5% were 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.