Evista: drug efficacy and clinical applications

EVISTA® (raloxifene Hydrochloride)

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EVISTA® (trade name) or raloxifene hydrochloride (generic name) is a drug manufactured by Eli Lilly and Company for the prevention and treatment of osteoporosis in post-menopausal women. EVISTA® is classified as a selective estrogen receptor modulator (SERM), which activates the estrogen receptors, but has differential physiological effects on other tissues such as the breast and endometrium (Thiebaud and Secrest 331).

INDICATION of USAGE

EVISTA® is indicated in the prevention and treatment of osteoporosis in postmenopausal women (Itabashi 529).

MECHANISM of ACTION

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. The biological actions of raloxifene are largely mediated through binding to estrogen receptors (Heringa 331).

This binding results in activation of certain estrogenic pathways and blockade of others. Thus, raloxifene is classified as a SERM. Raloxifene decreases resorption of bone and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers (Eng-Wong and Zujewski 525).

PHARMACOKINETICS

The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials (Maricic and Gluck 772).

Administration of raloxifene with a standardized, high-fat meal increases the absorption of raloxifene, but does not lead to clinically meaningful changes in systemic exposure. Thus, EVISTA® may be administered without regard to meals. 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 1-acid glycoprotein, but not to sex-steroid binding globulin (Duschek, Gooren and Netelenbos 542).

METABOLISM

Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4 -glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4 -diglucuronide (Grady et al. 840).

DOSAGE and ADMINISTRATION

EVISTA® is administered orally. The recommended dosage is 60 mg once per day. EVISTA® may be taken at any time of day without regard to timing of meals.

CONTRADICTIONS, PRECAUTIONS, and WARNINGS

EVISTA® is contraindicated in lactating women or women who are or may become pregnant. EVISTA® may cause fetal harm when administered to a pregnant woman. EVISTA® is contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. The concurrent use of EVISTA® and systemic estrogen or hormone replacement therapy has not been studied in prospective clinical trials and therefore concomitant use of EVISTA® with systemic estrogens is not recommended. EVISTA® has not been adequately studied in women with a prior history of breast cancer. Safety and efficacy have not been evaluated in men.

ADVERSE REACTIONS

The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial (Barrett-Connor et al. 1270). Duration of treatment was 36 months and 5129 postmenopausal women were exposed to raloxifene (2557 received 60 mg/day and 2572 received 120 mg/day). The majority of adverse events occurring during the study were mild and generally did not require discontinuation of therapy. Therapy was discontinued due to an adverse event in 11% of EVISTA®-treated women and 9% of placebo-treated women. Common adverse events related to EVISTA® therapy were hot flashes and leg cramps. Hot flashes were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter.

DRUG INTERACTIONS

Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Thus, co-administration of cholestyramine with EVISTA® is not recommended.

COMPARATIVE EFFICACY

Overall, raloxifene exerts similar positive on bone mineral density and bone turnover as other SERMS and estrogen therapy. However, the reduction in fracture risk is improved with SERMs vs. estrogen (Nakamura 632).