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Alendronate Sodium

ALENDRONATE SODIUM TABLETS, USP

FULL PRESCRIBING INFORMATION: CONTENTS*

ALENDRONATE SODIUM DESCRIPTION
CLINICAL PHARMACOLOGY
ANIMAL PHARMACOLOGY
ALENDRONATE SODIUM INDICATIONS AND USAGE
ALENDRONATE SODIUM CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ALENDRONATE SODIUM ADVERSE REACTIONS
- Clinical Studies
- Post-Marketing Experience
OVERDOSAGE
ALENDRONATE SODIUM DOSAGE AND ADMINISTRATION
HOW SUPPLIED
- Storage
SUPPLEMENTAL PATIENT MATERIAL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

ALENDRONATE SODIUM DESCRIPTION

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.

Each tablet, for oral administration, contains 45.68 mg, 52.21 mg or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 35 mg, 40 mg and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 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 0.64% 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.

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 alendronate sodium (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:

Alendronate is not indicated for use in children. Due to Merck’s marketing exclusivity rights, this generic drug product is not approved with descriptive pharmacokinetic information in pediatric patients. Merck’s alendronate sodium tablets and oral solution are approved with that descriptive pharmacokinetic information.

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). Alendronate sodium 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 alendronate sodium 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type I 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 alendronate sodium 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 alendronate sodium. In osteoporosis treatment studies alendronate sodium 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 alendronate sodium 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 alendronate sodium 70 mg for the treatment of osteoporosis and once weekly alendronate sodium 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 alendronate sodium. 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 alendronate sodium 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 alendronate sodium 5 mg/day. In one-year studies with once weekly alendronate sodium 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 alendronate sodium but also a decrease in renal phosphate reabsorption.

Osteoporosis in men

Treatment of men with osteoporosis with alendronate sodium 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 alendronate sodium 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, alendronate sodium 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, alendronate sodium 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.

Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate sodium 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, alendronate sodium 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 alendronate sodium 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 alendronate sodium 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: Alendronate Sodium 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 alendronate sodium 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 alendronate sodium 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. Alendronate sodium 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 alendronate sodium 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 Alendronate Sodium 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline

In patients with postmenopausal osteoporosis treated with alendronate sodium 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 alendronate sodium is required to maintain the effect of the drug.

The therapeutic equivalence of once weekly alendronate sodium 70 mg (n=519) and alendronate sodium 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 alendronate sodium 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 alendronate sodium 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 alendronate sodium (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 alendronate sodium 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 alendronate sodium 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 (alendronate sodium, n=1022; placebo, n=1005) demonstrated that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at three years as shown in the table below.

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

Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate sodium 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 alendronate sodium, p=0.047. The figure below displays the cumulative incidence of hip fractures in this study.

Alendronate Sodium

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 (alendronate sodium, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to alendronate sodium. 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 Alendronate Sodium on Fracture Incidence in OsteoporoticBaseline femoral neck BMD at least 2 SD below the mean for young adult women Patients in the Four-Year Study of FIT (patients without vertebral fracture at baseline)
	Percent of Patients
	Alendronate Sodium (n=1545)	Placebo (n=1521)	Absolute Reduction in Fracture Incidence	Relative Reduction in Fracture Risk (%)
Patients with:
Vertebral fractures (diagnosed by X-ray)Number evaluable for vertebral fractures: Alendronate sodium, n=1426; placebo, n=1428
≥ 1 new vertebral fracture	2.5	4.8	2.3	48p<0.001
≥ 2 new vertebral fractures	0.1	0.6	0.5	78p=0.035
Clinical (symptomatic) fractures
Any clinical (symptomatic) fracture	12.9	16.2	3.3	22p=0.01
≥ 1 clinical (symptomatic) vertebral fracture	1.0	1.6	0.6	41(NS)Not significant. This study was not powered to detect differences at these sites.
Hip fracture	1.0	1.4	0.4	29 (NS)Not significant. This study was not powered to detect differences at these sites.
Wrist (forearm) fracture	3.9	3.8	-0.1	NSNot significant. This study was not powered to detect differences at these sites.

Fracture results across studies

In the Three-Year Study of FIT, alendronate sodium 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).

Alendronate sodium 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, alendronate sodium reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).

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

Alendronate sodium, 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 alendronate sodium 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 alendronate sodium is of normal quality.

Men

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

A two-year, double-blind, placebo-controlled, multicenter study of alendronate sodium 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 alendronate sodium 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 alendronate sodium also reduced height loss (alendronate sodium, -0.6 mm vs. placebo, -2.4 mm).

A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate sodium 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 alendronate sodium 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 (alendronate sodium 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 (alendronate sodium 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, alendronate sodium 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, alendronate sodium 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Alendronate sodium 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 alendronate sodium 35 mg (n=362) and alendronate sodium 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 alendronate sodium at doses of up to 10 mg/day.

Concomitant use with estrogen/hormone replacement therapy (HRT)

The effects on BMD of treatment with alendronate sodium 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 alendronate sodium alone (both 6.0%).

The effects on BMD when alendronate sodium 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 alendronate sodium 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 alendronate sodium and HRT, 94% on alendronate sodium alone, and 78% on HRT alone. The long-term effects of combined alendronate sodium and HRT on fracture occurrence and fracture healing have not been studied.

Glucocorticoid-induced osteoporosis

The efficacy of alendronate sodium 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 alendronate sodium 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 alendronate sodium 5 mg/day for each study.

Studies in Glucocorticoid-Treated Patients: Increase in BMD: Alendronate Sodium 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 alendronate sodium 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 alendronate sodium 5 mg/day. The increases in BMD with alendronate sodium 10 mg/day were similar to those with alendronate sodium 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate sodium 10 mg/day were greater than those with alendronate sodium 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate sodium was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate sodium 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 alendronate sodium 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 alendronate sodium 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 alendronate sodium 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 alendronate sodium (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 (alendronate sodium 0.7% vs. placebo 6.8%).

Paget's disease of bone

The efficacy of alendronate sodium 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 Alendronate Sodium 40 mg/day Versus Placebo or Etidronate 400 mg/day

At six months the suppression in alkaline phosphatase in patients treated with alendronate sodium 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 alendronate sodium in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Alendronate sodium 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 alendronate sodium 40 mg/day for 6 months. As in patients treated for osteoporosis (see Clinical Studies, Treatment of osteoporosis in postmenopausal women, Bone histology), alendronate sodium did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with alendronate sodium, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with alendronate sodium 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.

ALENDRONATE SODIUM INDICATIONS AND USAGE

Alendronate sodium tablets, USP are indicated for:

Treatment and prevention of osteoporosis in postmenopausal women
- For the treatment of osteoporosis, alendronate sodium tablets, USP increase bone mass and reduce 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, alendronate sodium tablets, USP 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 alendronate sodium tablets, USP 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.

ALENDRONATE SODIUM 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
Hypersensitivity to any component of this product
Hypocalcemia (see PRECAUTIONS, General)

WARNINGS

Alendronate sodium, 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 alendronate sodium. 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 alendronate sodium 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 alendronate sodium and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate sodium 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 alendronate sodium should be used under appropriate supervision.

Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when alendronate sodium 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 alendronate sodium (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 alendronate sodium.

Presumably due to the effects of alendronate sodium 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). This category of drugs includes alendronate sodium. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. 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 alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium 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 should guide the management plan of each patient based on individual benefit/risk assessment.

Renal insufficiency

Alendronate sodium is not recommended for patients with renal insufficiency (creatinine clearance <35 mL/min). (See DOSAGE AND ADMINISTRATION.)

Glucocorticoid-induced osteoporosis

The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established (see INDICATIONS AND USAGE). Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered.

A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.

The efficacy of alendronate sodium for the treatment of glucocorticoid-induced osteoporosis has been shown in patients with a median bone mineral density which was 1.2 standard deviations below the mean for healthy young adults.

The efficacy of alendronate sodium has been established in studies of two years' duration. The greatest increase in bone mineral density occurred in the first year with maintenance or smaller gains during the second year. Efficacy of alendronate sodium beyond two years has not been studied.

The efficacy of alendronate sodium in respect to fracture prevention has been demonstrated for vertebral fractures. However, this finding was based on very few fractures that occurred primarily in postmenopausal women. The efficacy for prevention of non-vertebral fractures has not been demonstrated.

Information for Patients

General

Physicians should instruct their patients to read the patient package insert before starting therapy with alendronate sodium and to reread it each time the prescription is renewed.

Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

Dosing Instructions

Patients should be instructed that the expected benefits of alendronate sodium may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption).

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed to swallow each tablet of alendronate sodium with a full glass of water (6-8 oz). Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take alendronate sodium at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician.

Patients should be instructed that if they miss a dose of once weekly alendronate sodium, they should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.