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| |  FDA Approves Fosamax For Glucocorticoid-Induced Osteoporosis WEST POINT, PA -- June 23, 1999 -- The United States Food and Drug Administration has approved Merck & Co.’s Fosamax(R) (alendronate sodium) for the treatment of glucocorticoid-induced osteoporosis in men and women. The new indication is for men and women receiving glucocorticoids (commonly referred to as corticosteroids or steroids) in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density. The FDA based its approval on two-year studies which demonstrated Fosamax increased BMD at the hip and spine and prevented fractures at the spine. Merck also announced today that the prescribing information for Fosamax has been updated to incorporate five years of clinical data on the efficacy and safety of the medicine for treatment of osteoporosis in postmenopausal women. The addition of these data provides important information regarding the long-term use of Fosamax. Previously, the prescribing information included three years of clinical data. Fosamax already is indicated for the prevention and treatment of osteoporosis and the prevention of osteoporotic fractures in postmenopausal women, and for the treatment of Paget's disease of bone. The FDA's decision to clear Fosamax for glucocorticoid-induced osteoporosis in men and women extends the approved patient population for Fosamax. The recommended dosage is Fosamax 5 mg once daily for the treatment of low BMD in men and women receiving glucocorticoid therapy, and Fosamax 10 mg once daily for the treatment of low BMD in postmenopausal women who receive glucocorticoid therapy but do not take estrogen. Fosamax is the only osteoporosis medicine approved for use in this broad range of men and women. "Fosamax is an important therapeutic advance for a major dilemma physicians have faced over the 40 years that they have been prescribing glucocorticoids to control serious diseases that often cannot be managed without them," said Kenneth Saag, M.D., M.Sc., associate professor of medicine, University of Alabama at Birmingham. "Timely intervention is critical because glucocorticoid users can lose large amounts of bone rapidly -- as much as 15 percent in the first year of treatment alone -- leading to osteoporotic fractures in 30 to 50 percent of patients treated chronically with glucocorticoids." Osteoporosis is widely recognised as a serious consequence of glucocorticoid use. The American College of Rheumatology recommends a baseline BMD measurement before the initiation of long-term glucocorticoid therapy. More than 30 million Americans are estimated to have diseases which may require glucocorticoid use, with nearly 1.5 million Americans using these medications on a chronic basis to manage diseases including rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's), asthma, emphysema and rejection of organ transplantation. While all glucocorticoid users are at risk of bone loss, postmenopausal women are at a particularly high risk for glucocorticoid-induced osteoporosis and its fractures. The new indication for treatment of glucocorticoid-induced osteoporosis with Fosamax was based on two 48-week, double-blind, placebo-controlled, randomised studies involving 232 patients at U.S. centres and 328 patients at multinational centres and a one-year double-blind extension study of 208 of these patients. The studies showed that Fosamax (5 mg once daily and 10 mg once daily) stopped bone loss and rebuilt bone at the spine and hip and prevented fractures at the spine. The results from the studies were consistent, regardless of a person's age, race, gender, underlying disease, baseline BMD and dose of, or duration on, glucocorticoids. The risk versus benefit of Fosamax for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established. The efficacy of Fosamax for glucocorticoid-induced osteoporosis has not been studied beyond two years. Patients in the two 48-week studies included men and women ages 17 to 83 who took at least 7.5 mg of prednisone or its equivalent daily, irrespective of baseline BMD. The median BMD in the studies was 1.2 standard deviations below the mean for healthy young adults. The World Health Organization defines low BMD as more than 1.0 standard deviation below the mean for healthy young adults. Patients were randomised to placebo, Fosamax 2.5 mg once daily, Fosamax 5 mg once daily or Fosamax 10 mg once daily. All patients received 800 to 1,000 mg of calcium and 250 to 500 IU of vitamin D daily. Results of the studies were based on an intention-to-treat analysis. Because the Fosamax 2.5 mg dose was not clinically effective and was used only in the multinational study, the following data analysis included only the 477 patients assigned to the Fosamax 5 mg, Fosamax 10 mg and placebo treatment groups. In the combined analysis of the two 48-week studies, patients treated with both Fosamax 5 mg and Fosamax 10 mg had statistically-significant mean increases in BMD at the spine and hip compared to the placebo-treated group which lost bone. The statistically significant changes in BMD relative to baseline in patients taking Fosamax 5 mg and Fosamax 10 mg, respectively, were: -- lumbar spine: a 2.1 percent increase and a 2.9 percent increase for the groups treated with Fosamax versus a 0.4 percent decrease for the placebo group; In the subgroup of postmenopausal women who were not taking estrogen, Fosamax 10 mg showed a significantly greater increase in BMD relative to baseline at the lumbar spine (4.0 percent) than Fosamax 5 mg (1.5 percent). The placebo group had a 0.1 percent decrease at the lumbar spine. After one year, significant increases in BMD were seen in patients who received Fosamax 5 mg once daily. The increases in BMD with Fosamax 10 mg once daily were similar to those with Fosamax 5 mg once daily in all patients except for postmenopausal women not receiving estrogen. The recommended dosage is Fosamax 5 mg once daily for the treatment of low BMD in men and women receiving glucocorticoid therapy, and Fosamax 10 mg once daily for the treatment of low BMD in postmenopausal women who receive glucocorticoid therapy but do not take estrogen. In the one-year extension study, 208 patients continued taking at least 7.5 mg of prednisone or its equivalent daily and calcium and vitamin D supplements daily. Patients continued on their original blinded therapy except for those who had been assigned to Fosamax 2.5 mg once daily. These patients were blindly switched to receive Fosamax 10 mg once daily. Other treatment groups included placebo, Fosamax 5 mg once daily and Fosamax 10 mg once daily. At the end of two years, lumbar spine BMD increased by 3.7 percent and 5.0 percent relative to placebo with Fosamax 5 mg and Fosamax 10 mg, respectively. Significant increases in BMD also were observed at the trochanter relative to placebo. Although the studies were not specifically designed to detect fracture risk reductions, fewer spinal fractures were observed in patients taking Fosamax compared to placebo with a statistically significant reduction in spinal fractures after two years of treatment with Fosamax. All patients who received placebo or a dose of Fosamax 5 mg or Fosamax 10 mg during the studies were included in the analysis. In the original 48-week studies, 2.3 percent (six of 266) of patients taking Fosamax 5 mg or Fosamax 10 mg had a new vertebral (spine) fracture based on spine X-rays versus 3.7 percent (five of 134) of patients on placebo. The difference in fractures at one year was not statistically significant. However, at the end of the one-year extension of these studies (two years total treatment), Fosamax significantly decreased the incidence of new spinal fractures which occurred primarily in postmenopausal women: 0.7 percent (one of 143) patients taking Fosamax (pooled dosage groups: 5 mg, 10 mg, and 2.5 mg/10 mg) versus 6.8 percent (four of 59) of In the studies on treatment of glucocorticoid-induced osteoporosis, there was no statistical difference in the number of overall, serious adverse experiences or withdrawals from treatment between those taking Fosamax and those on placebo. Despite the concomitant use of glucocorticoids and aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), medications known to cause gastrointestinal (GI) side effects in some patients, there was no difference in the rate of esophageal adverse events or peptic ulcers between people treated with Fosamax and those on placebo. These findings are consistent with other clinical studies with Fosamax in which the overall tolerability profile of Fosamax was found to be similar to placebo. Because NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with Fosamax. In a separate action, the FDA has updated the prescribing information for Fosamax to reflect five years of clinical data on the efficacy of Fosamax for treatment of osteoporosis in postmenopausal women. The previous prescribing information, which included three years of clinical data on the use of Fosamax (10 mg once daily) in the treatment of postmenopausal women with osteoporosis, showed highly significant increases in BMD at the spine, hip and all other skeletal sites measured, relative to baseline and placebo, as early as three months and continued throughout three years of treatment. The two-year extension of the three-year studies (five years total) in 147 patients showed that use of Fosamax (10 mg once daily) resulted in some additional increases in BMD at the lumbar spine and trochanter (absolute additional increases between years three and five: lumbar spine, 0.94 percent; trochanter, 0.88 percent). BMD at the femoral neck, forearm and total body were maintained. Fosamax, like other bisphosphonates, should be used with caution in people with active upper GI disease. Patients with disorders of the esophagus that delay emptying, inability to stand or sit upright for at least 30 minutes, low levels of calcium in their blood, severe kidney disease or who are pregnant or nursing should not take Fosamax. Esophageal adverse experiences such as esophagitis (inflammation of the esophagus), esophageal ulcers and erosions, occasionally with bleeding and rarely followed by esophageal stricture, have been reported in patients receiving treatment with Fosamax. In some cases these have been severe and required hospitalisation. The risk of severe esophageal adverse experiences appears to be greater in patients who fail to follow dosing instructions. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients must take Fosamax upon arising for the day with a full glass of plain water (six to eight ounces). After swallowing Fosamax, patients must not lie down and should stay fully upright (sitting or standing) for at least 30 minutes and until after the first food of the day. Fosamax should not be taken at bedtime or before arising for the day. Patients should not chew or suck on the tablets. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered. A BMD measurement should be made at the initiation of therapy and repeated after six months to 12 months of combined treatment with Fosamax and glucocorticoids Related Links: Fosamax, Merck & Co.,
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