If this is not your name, click here.
| | If this is not your name, click here. | | |
| | Contact Us | Order Now | Journals | Bookstore | Register a colleague | | |
| |  Merck's Fosamax Expected to have a Major Effect on Osteoporosis WEST POINT, Pa. -- Nov. 30, 1995 -- An editorial in Thursday's New England Journal of Medicine concluded that drugs such as Merck's Fosamax(R) (alendronate sodium) "that can not only prevent further bone loss but also increase bone mass should have a major effect on a disease (osteoporosis) that may reach epidemic proportions during the next several decades." Osteoporosis is a bone-weakening disease that leads to osteoporotic fractures in more than one in three women over age 50. It is characterized by low bone density, which is closely related to bone strength: the lower the bone density, the weaker the bones and the more likely they are to fracture. The editorial cited that in clinical trials with Fosamax over three years, "sustained increases in bone density in the women receiving 10 mg (daily) of alendronate were evident in each year, which is surprising for an antiresorptive agent. This finding suggests that some reversal of osteoporosis may be possible in the long term with the 10-mg. dose." On Sept. 29, the U.S. Food and Drug Administration cleared Fosamax 10 mg daily for marketing to treat osteoporosis in women after menopause. In the accompanying article by Liberman et al. in the Journal, results from two three-year pivotal trials with 994 postmenopausal women with osteoporosis in 16 countries supported the conclusion that Fosamax built healthy bone. According to epidemiological studies, each 10 percent decrease in spinal bone mineral density is associated with a doubling in spinal fracture risk. In clinical trials, Fosamax achieved a mean increase of up to 10 percent in lumbar spine bone mineral density (the primary endpoint) vs. placebo after three years. In patients treated with Fosamax, a progressive increase in bone mineral density also occurred at the hip -- a secondary endpoint -- (7.2 percent), compared with patients treated with placebo. Fosamax also significantly increased total body bone mineral density (another secondary endpoint), suggesting that gains in bone mineral density at the spine and hip did not occur because of a loss of bone mineral density elsewhere in the skeleton. Although the studies were not designed to detect the effect of Fosamax on the incidence of fracture, fracture-related endpoints were assessed in a predefined analyses of supporting parameters -- which included stature, spinal fracture and spine deformity -- from data pooled across all doses from these studies. The effect of individual dosages of Fosamax on fracture incidence cannot be adequately assessed from these studies. Nonetheless, the authors note that the "increases in bone mineral density of the spine, hip, and total body in women with postmenopausal osteoporosis were associated with reductions in the incidence of vertebral fractures, vertebral deformities, and loss of height, as well as a trend toward a reduction in the incidence of fractures at nonvertebral sites." Fosamax reduced by nearly half (48 percent) the proportion of women who suffered new spinal fractures compared with women treated with placebo. Treatment with Fosamax also led to a 63 percent reduction in the total number of new spinal fractures. In the trials, women treated with Fosamax lost an average of 3.0 mm in height, compared with women on placebo who lost an average of 4.6 mm -- a 35 percent reduction in overall height loss. Side Effects Generally Mild Side effects observed in clinical trials were usually mild and generally have not caused patients to stop taking Fosamax. Of patients taking placebo, 6.0 percent (24 of 397) discontinued treatment due to adverse experiences, compared with 4.1 percent (8 of 196) taking Fosamax 10 mg. The most commonly reported drug-related side effects in patients taking Fosamax were abdominal and musculoskeletal pain. Less frequently reported were digestive disturbances such as nausea, heartburn, and irritation or pain of the esophagus. Patients with low levels of calcium in their blood, severe kidney disease or who are pregnant or nursing should not take Fosamax. As with other drugs in its class, caution should be used when Fosamax is given to patients with active upper gastrointestinal problems. The safety of treatment with Fosamax for longer than four years has not been studied; extension studies are ongoing. Fosamax was licensed to Merck & Co. Inc.. by Istituto Gentili SPA of Pisa, Italy, in 1988 and is approved in 18 other countries. The New Drug Application for Fosamax was submitted to the FDA on March 31, 1995. Merck & Co. Inc.. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health. Full prescribing information for Fosamax is attached. Fosamax - pronounced FOS-sah-max -- is the Merck registered trademark for alendronate sodium. FOSAMAX(R) (ALENDRONATE SODIUM TABLETS) DESCRIPTION FOSAMAX (alendronate sodium) is an aminobisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The empirical formula of alendronate sodium is C4H12NNaO7P2 3H2O and its formula weight is: (structure here) Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Tablets FOSAMAX for oral administration contain either 13.05 mg or 52.21 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 10.0 mg and 40.0 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate. CLINICAL PHARMACOLOGY Mechanism of Action Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass. Pharmacokinetics Absorption Relative to an intravenous (IV) reference dose, the mean oral bioavailability of alendronate in women was 0.7% for doses ranging from 5 to 40 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women (0.78%) when administered after an overnight fast and 2 hours before breakfast. A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%. In a trial in elderly patients given 5 mg of alendronate (n = 86) 30 minutes before breakfast, similar bone mineral density changes were noted when compared to the pivotal trials, in which one of the treatment arms was 5 mg alendronate administered 60 minutes before breakfast. Distribution Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%. Metabolism There is no evidence that alendronate is metabolized in animals or humans. Excretion
|
