21 . June , 2018 - Thursday
Check todays hot topics or new products

Find a Drug: Advanced

Please Sign in or Register

All about: Fosamax

Big Image
Generic Name: alendronate
Dosage Form: Tablets, oral solution

Fosamax Description

Fosamax1 (alendronate sodium) is a bisphosphonate 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 325.12. The structural formula is:

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 6.53, 13.05, 45.68, 52.21 or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5, 10, 35, 40 and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate. Tablets Fosamax 10 mg also contain carnauba wax.

Each bottle of the oral solution contains 91.35 mg of alendronate monosodium salt trihydrate, which is the molar equivalent to 70 mg of free acid. Each bottle also contains the following inactive ingredients: sodium citrate dihydrate and citric acid anhydrous as buffering agents, sodium saccharin, artificial raspberry flavor, and purified water. Added as preservatives are sodium propylparaben 0.0225% and sodium butylparaben 0.0075%.

1

Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1995, 1997, 2000 MERCK & CO., Inc.
All rights reserved

Fosamax - 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 0.64% for doses ranging from 5 to 70 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 when administered after an overnight fast and 2 hours before breakfast.

Fosamax 70 mg oral solution and Fosamax 70 mg tablet are equally bioavailable.

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. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

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%.

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

Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with Fosamax (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Special Populations

Pediatric:

The oral bioavailability in children was similar to that observed in adults; however, Fosamax is not indicated for use in children (see PRECAUTIONS, Pediatric Use).

Gender:

Bioavailability and the fraction of an IV dose excreted in urine were similar in men and women.

Geriatric:

Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).

Race:

Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency:

Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative IV doses of 35 mg/kg in young male rats. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Fosamax is not recommended for patients with more severe renal insufficiency (creatinine clearance <35 mL/min) due to lack of experience with alendronate in renal failure.

Hepatic Insufficiency:

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary.

Drug Interactions

(also see PRECAUTIONS, Drug Interactions)

Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.

In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).

Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.

Pharmacodynamics

Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.

Osteoporosis in postmenopausal women

Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.

Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.

Long-term treatment of osteoporosis with Fosamax 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received Fosamax 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with Fosamax. In osteoporosis treatment studies Fosamax 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies Fosamax 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly Fosamax 70 mg for the treatment of osteoporosis and once weekly Fosamax 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with Fosamax. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of Fosamax 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. Similar reductions were observed with Fosamax 5 mg/day. In one-year studies with once weekly Fosamax 35 and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to Fosamax but also a decrease in renal phosphate reabsorption.

Osteoporosis in men

Treatment of men with osteoporosis with Fosamax 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly Fosamax 70 mg.

Glucocorticoid-induced Osteoporosis

Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation.

In clinical studies of up to two years' duration, Fosamax 5 and 10 mg/day reduced cross-linked N-telopeptides of type I collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition of bone resorption, Fosamax 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).

Paget's disease of bone

Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

Fosamax decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, Fosamax 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, Fosamax induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

Clinical Studies

Treatment of Osteoporosis

Postmenopausal women

Effect on bone mineral density

The efficacy of Fosamax 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years' duration. These included two three-year, multicenter studies of virtually identical design, one performed in the United States (U.S.) and the other in 15 different countries (Multinational), which enrolled 478 and 516 patients, respectively. The following graph shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving Fosamax 10 mg/day relative to placebo-treated patients at three years for each of these studies.

Osteoporosis Treatment Studies in Postmenopausal Women: Increase in BMD: Fosamax 10mg/day at Three Years

At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received Fosamax 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See figures below for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with Fosamax 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Fosamax was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean). Thus, overall Fosamax reverses the loss of bone mineral density, a central factor in the progression of osteoporosis.

Osteoporosis Treatment Studies in Postmenopausal Women: Time Course of Effect of Fosamax 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline

In patients with postmenopausal osteoporosis treated with Fosamax 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. These data indicate that continued treatment with Fosamax is required to maintain the effect of the drug.

The therapeutic equivalence of once weekly Fosamax 70 mg (n=519) and Fosamax 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70-mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10-mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.

Effect on fracture incidence

Data on the effects of Fosamax on fracture incidence are derived from three clinical studies: 1) U.S. and Multinational combined: a study of patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture, 2) Three-Year Study of the Fracture Intervention Trial (FIT): a study of patients with at least one baseline vertebral fracture, and 3) Four-Year Study of FIT: a study of patients with low bone mass but without a baseline vertebral fracture.

To assess the effects of Fosamax on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of Fosamax (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with Fosamax experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received Fosamax had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).

The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion.

Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture)

This randomized, double-blind, placebo-controlled, 2027-patient study (Fosamax, n=1022; placebo, n=1005) demonstrated that treatment with Fosamax resulted in statistically significant reductions in fracture incidence at three years as shown in the table below.

Effect of Fosamax on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral fracture at baseline)
Percent of Patients
Fosamax
(n=1022)
Placebo
(n=1005)
Absolute
Reduction
in Fracture
Incidence
Relative
Reduction in Fracture
Risk %
*
Number evaluable for vertebral fractures: Fosamax, n=984; placebo, n=966
p<0.001
p=0.007
§
p<0.01
p<0.05
Patients with:
Vertebral fractures (diagnosed by X-ray)*
     ≥ 1 new vertebral fracture 7.9 15.0 7.1 47
     ≥ 2 new vertebral fractures 0.5 4.9 4.4 90
Clinical (symptomatic) fractures
     Any clinical (symptomatic) fracture 13.8 18.1 4.3 26
     ≥ 1 clinical (symptomatic) vertebral fracture 2.3 5.0 2.7 54§
Hip fracture 1.1 2.2 1.1 51
Wrist (forearm) fracture 2.2 4.1 1.9 48

Furthermore, in this population of patients with baseline vertebral fracture, treatment with Fosamax significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%).

In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on Fosamax, p=0.047. The figure below displays the cumulative incidence of hip fractures in this study.

Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT (patients with radiographic vertebral fracture at baseline)

Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture)

This randomized, double-blind, placebo-controlled, 4432-patient study (Fosamax, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to Fosamax. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in the table below for the patients with osteoporosis.

Effect of Fosamax on Fracture Incidence in Osteoporotic* Patients in the Four-Year Study of FIT (patients without vertebral fracture at baseline)
Percent of Patients
Fosamax
(n=1545)
Placebo
(n=1521)
Absolute
Reduction
in Fracture
Incidence
Relative
Reduction in Fracture Risk (%)
*
Baseline femoral neck BMD at least 2 SD below the mean for young adult women
Number evaluable for vertebral fractures: Fosamax, n=1426; placebo, n=1428
p<0.001
§
p=0.035
p=0.01
#
Not significant. This study was not powered to detect differences at these sites.
Patients with:
Vertebral fractures (diagnosed by X-ray)
     ≥ 1 new vertebral fracture 2.5 4.8 2.3 48
     ≥ 2 new vertebral fractures 0.1 0.6 0.5 78§
Clinical (symptomatic) fractures
     Any clinical (symptomatic) fracture 12.9 16.2 3.3 22
     ≥ 1 clinical (symptomatic) vertebral fracture 1.0 1.6 0.6 41(NS)#
Hip fracture 1.0 1.4 0.4 29 (NS)#
Wrist (forearm) fracture 3.9 3.8 -0.1 NS#

Fracture results across studies

In the Three-Year Study of FIT, Fosamax reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034).

Fosamax reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, Fosamax reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).

Thus, Fosamax reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.

Fosamax, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.

Bone histology

Bone histology in 270 postmenopausal patients with osteoporosis treated with Fosamax at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with Fosamax is of normal quality.

Men

The efficacy of Fosamax in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

A two-year, double-blind, placebo-controlled, multicenter study of Fosamax 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either: 1) a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, or 2) a baseline osteoporotic fracture and a BMD T-score ≤-1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving Fosamax 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with Fosamax also reduced height loss (Fosamax, -0.6 mm vs. placebo, -2.4 mm).

A one-year, double-blind, placebo-controlled, multicenter study of once weekly Fosamax 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either: 1) a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, 2) a BMD T-score ≤-2 at the lumbar spine and ≤-1 at the femoral neck, or 3) a baseline osteoporotic fracture and a BMD T-score ≤-1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving Fosamax 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study.

In both studies, BMD responses were similar regardless of age (≥65 years vs. <65 years), gonadal function (baseline testosterone <9 ng/dL vs. ≥9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score ≤-2.5 vs. >-2.5).

Prevention of osteoporosis in postmenopausal women

Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40-60 years of age. One thousand six hundred nine patients (Fosamax 5 mg/day; n=498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (Fosamax 5 mg/day; n=88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, Fosamax 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see figures below). In addition, Fosamax 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Fosamax 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.

Osteoporosis Prevention Studies in Postmenopausal Women

The therapeutic equivalence of once weekly Fosamax 35 mg (n=362) and Fosamax 5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2% (2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.

Bone histology

Bone histology was normal in the 28 patients biopsied at the end of three years who received Fosamax at doses of up to 10 mg/day.

Concomitant use with estrogen/hormone replacement therapy (HRT)

The effects on BMD of treatment with Fosamax 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or Fosamax alone (both 6.0%).

The effects on BMD when Fosamax was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of Fosamax 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).

In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.

Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with Fosamax and HRT, 94% on Fosamax alone, and 78% on HRT alone. The long-term effects of combined Fosamax and HRT on fracture occurrence and fracture healing have not been studied.

Glucocorticoid-induced osteoporosis

The efficacy of Fosamax 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational [which also included Fosamax 2.5 mg/day]). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. The following figure shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving Fosamax 5 mg/day for each study.

Studies in Glucocorticoid-Treated Patients: Increase in BMD: Fosamax 5 mg/day at One Year

After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received Fosamax 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with Fosamax 5 mg/day. The increases in BMD with Fosamax 10 mg/day were similar to those with Fosamax 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with Fosamax 10 mg/day were greater than those with Fosamax 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Fosamax was effective regardless of dose or duration of glucocorticoid use. In addition, Fosamax was similarly effective regardless of age (<65 vs. ≥65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications.

Bone histology was normal in the 49 patients biopsied at the end of one year who received Fosamax at doses of up to 10 mg/day.

Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with Fosamax 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body.

After one year, 2.3% of patients treated with Fosamax 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with Fosamax (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (Fosamax 0.7% vs. placebo 6.8%).

Paget's disease of bone

The efficacy of Fosamax 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget's disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. The following figure shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.

Studies in Paget's Disease of Bone: Effect on Serum Alkaline Phosphatase of Fosamax 40 mg/day Versus Placebo or Etidronate 400 mg/day

At six months the suppression in alkaline phosphatase in patients treated with Fosamax was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline ≥60%) occurred in approximately 85% of patients treated with Fosamax in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Fosamax was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).

Bone histology was evaluated in 33 patients with Paget's disease treated with Fosamax 40 mg/day for 6 months. As in patients treated for osteoporosis (see Clinical Studies, Treatment of osteoporosis in postmenopausal women, Bone histology), Fosamax did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with Fosamax, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with Fosamax is of normal quality.

Animal Pharmacology

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

Indications and Usage for Fosamax

Fosamax is indicated for:

  • Treatment and prevention of osteoporosis in postmenopausal women

    • For the treatment of osteoporosis, Fosamax increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). Osteoporosis may be confirmed by the finding of low bone mass (for example, at least 2 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture. (See CLINICAL PHARMACOLOGY, Pharmacodynamics.)

    • For the prevention of osteoporosis, Fosamax may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture.

      Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass (for example, at least 1 standard deviation below the mean for healthy young adult women); thin body build; Caucasian or Asian race; and family history of osteoporosis. The presence of such risk factors may be important when considering the use of Fosamax for prevention of osteoporosis.

  • Treatment to increase bone mass in men with osteoporosis

  • Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density (see PRECAUTIONS, Glucocorticoid-induced osteoporosis). Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

  • Treatment of Paget's disease of bone in men and women

    • Treatment is indicated in patients with Paget's disease of bone having alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease.

Contraindications

  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
  • Inability to stand or sit upright for at least 30 minutes
  • Patients at increased risk of aspiration should not receive Fosamax oral solution.
  • Hypersensitivity to any component of this product
  • Hypocalcemia (see PRECAUTIONS, General)

Warnings

Fosamax, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with Fosamax. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Fosamax and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking Fosamax and/or who fail to swallow it with the recommended amount of water, and/or who continue to take Fosamax after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with dosing instructions due to mental disability, therapy with Fosamax should be used under appropriate supervision.

Because of possible irritant effects of Fosamax on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when Fosamax is given to patients with active upper gastrointestinal problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).

There have been post-marketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in controlled clinical trials.

Precautions

General

Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be considered.

Hypocalcemia must be corrected before initiating therapy with Fosamax (see CONTRAINDICATIONS). Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with Fosamax.

Presumably due to the effects of Fosamax on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.

Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids.

Musculoskeletal Pain

In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see ADVERSE REACTIONS). However, such reports have been infrequent. This category of drugs includes Fosamax (alendronate). Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

In placebo-controlled clinical studies of Fosamax, the percentages of patients with these symptoms were similar in the Fosamax and placebo groups.

Dental

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often with delayed healing, has been reported in patients taking bisphosphonates. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates, but some have occurred in patients with postmenopausal osteoporosis. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., pre-existing dental disease, anemia, coagulopathy, infection).

Patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy should receive care by an oral surgeon. Dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk for ONJ. Clinical judgment of the treating physician shoul

Recent Drug Updates at DrugIndexOnline:





Acetaminophen/Phenylephrine Drops Acetaminophen/Phenylephrine Drops
Generic Name: Acetaminophen/Phenylephrine Drops (a-SEET-a-MIN-oh-fen/FEN-il-EF-rin) Brand Name: Tylenol Infants Plus ColdAcetaminophen/Phenylephrine Drops is used for:Relieving symptoms such as pain and sinus congestion due to colds, upper respiratory infections, and allergies. It may also used more...

Alumina, Magnesia, and Simethicone Alumina, Magnesia, and Simethicone
Some commonly used brand names are: In the U.S.— Advanced Formula Di-Gel 29 Alamag 2 Alamag Plus 9 Alenic Alka 15 Alenic Alka Extra Strength 18 Alka-Mints 27 Alkets 27 Alkets Extra Strength 27 Almacone 9 Almacone II 9 AlternaGEL 21 Alu-Cap 25 Aludrox 9 Alu-Tab 25 Amitone 27 Amphojel 25 An more...

ascorbic acid ascorbic acid
Generic Name: ascorbic acid (vitamin C) (ah SCORE bik AH sid) Brand Names: Ascot, C/Rose Hips, Cecon, Cemill 1000, Cemill 500, Centrum Singles-Vitamin C, Cevi-Bid, N Ice with Vitamin C, Sunkist Vitamin C, Vicks Vitamin C Drops What is ascorbic acid? Ascorbic acid is found in citrus fruit more...

Capen Capen
Some commonly used brand names are: In the U.S.— Thiola Capen Captimer Epatiol Mucolysin Sutilan Thiosol Tioglis Vincol † Not commercially available in Canada. Category Antiurolithic, cystine calculi Description Tiopronin (tye-oh-PRO-nin) is used to prevent kidney stones more...

Cisplatin Cisplatin
Generic Name: Cisplatin (sis-PLA-tin) Brand Name: Platinol AQCisplatin can cause severe kidney problems or allergic reactions. Hearing loss (more common in children), bleeding problems, a decrease in your body's ability to fight infection (weakened immune system), or severe nausea and vomiting more...

Measles And Rubella Virus Vaccine Live Measles And Rubella Virus Vaccine Live
Some commonly used brand names are: In the U.S.— M-R-VAX II Generic name product may be available in Canada. † Not commercially available in Canada. Category Immunizing agent, active Description Measles and rubella (MEE-zills and rue-BELL-a)virus vaccine live is an active more...

Prevacid IV Prevacid IV
Generic Name: Lansoprazole Injection (lan-SOE-pra-zole) Brand Name: Prevacid I.V.Prevacid IV is used for:Short-term treatment of irritation of the esophagus when medicine cannot be taken by mouth. It may also be used for other conditions as determined by your doctor. Prevacid IV is a proton pu more...

PreviDent 5000 Sensitive PreviDent 5000 Sensitive
Generic Name: Sodium Fluoride/Potassium Nitrate (SOE-dee-um FLUR-ide/po-TAS-ee-um NYE-trate) Brand Name: PreviDent 5000 SensitivePreviDent 5000 Sensitive is used for:Preventing tooth decay. It is also used to help reduce painful sensitivity of the teeth to touch; sweets; or hot, cold, or acidic more...