9655602

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.

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.

* Trademark of MERCK & CO., Inc.

All rights reserved

(alendronate sodium/cholecalciferol) Tablets

2

H

HO

H

H

H

Cholecalciferol is a white, crystalline, odorless powder. Cholecalciferol is practically insoluble in

water, freely soluble in usual organic solvents, and slightly soluble in vegetable oils.

FOSAMAX PLUS D for oral administration contains 91.37 mg of alendronate monosodium salt

trihydrate, the molar equivalent of 70 mg of free acid, and 70 mcg of cholecalciferol equivalent to 2800

International Units (IU) vitamin D. Each tablet contains the following inactive ingredients: microcrystalline

cellulose, lactose anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose,

colloidal silicon dioxide, magnesium stearate, butylated hydroxytoluene, modified food starch, and sodium

aluminum silicate.

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

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.

increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal

calcium and phosphate excretion, bone formation and bone resorption.

Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight

exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance,

increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases,

deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness,

bone pain and osteomalacia.

(alendronate sodium/cholecalciferol) Tablets

3

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.

tablet is 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%.

Following administration of FOSAMAX PLUS D after an overnight fast and two hours before a

Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following

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%.

There is no evidence that alendronate is metabolized in animals or humans.

glucuronidation prior to elimination.

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

(alendronate sodium/cholecalciferol) Tablets

4

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.

excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion

of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted

radioactivity was almost exclusively as metabolites of the parent. The mean half-life of baseline adjusted

men and women.

Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly and younger

patients. No dosage adjustment of alendronate is necessary (see DOSAGE AND ADMINISTRATION).

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

Patients with renal insufficiency will have decreased ability to form the active 1,25-dihydroxyvitamin

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.

bile production.

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

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.

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair

the absorption of vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the catabolism of

vitamin D.

(alendronate sodium/cholecalciferol) Tablets

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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 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. 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. 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.

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. In one-year studies with once weekly FOSAMAX

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.

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.

Vitamin D is required for normal bone formation. Vitamin D insufficiency is associated with negative

calcium balance, leading to increased parathyroid hormone levels and worsening of bone loss associated

with osteoporosis. When taken without vitamin D, alendronate is also associated with a reduction in

serum calcium concentrations and increased parathyroid hormone levels. In a 15-week trial,

(alendronate sodium/cholecalciferol) Tablets

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717 postmenopausal women and men, mean age 67 years, with osteoporosis (lumbar spine bone

mineral density [BMD] of at least 2.5 standard deviations below the premenopausal mean) were

randomized to receive either weekly FOSAMAX PLUS D 70 mg/2800 IU vitamin D or weekly

FOSAMAX 70 mg alone with no vitamin D supplementation. Patients who were vitamin D deficient

(25-hydroxyvitamin D <9 ng/mL) at baseline were excluded. Treatment with FOSAMAX PLUS D

70 mg/2800 IU resulted in a smaller reduction in serum calcium levels (-0.9%) when compared to

FOSAMAX 70 mg alone (-1.4%). As well, treatment with FOSAMAX PLUS D 70 mg/2800 IU resulted in a

significantly smaller increase in parathyroid hormone levels when compared to FOSAMAX 70 mg alone

(14% and 24%, respectively).

The sufficiency of patients’ vitamin D status is best assessed by measuring 25-hydroxyvitamin D

levels. In the 15-week trial mentioned above, baseline 25-hydroxyvitamin D levels were 22.2 ng/mL in the

FOSAMAX PLUS D group and 22.1 ng/mL in the FOSAMAX only group. After 15 weeks of treatment, the

mean levels were 23.1 ng/mL and 18.4 ng/mL in the FOSAMAX PLUS D and FOSAMAX only groups,

respectively. The final levels of 25-hydroxyvitamin D at week 15 are summarized in the table below.

25-hydroxyvitamin D Levels after Treatment with FOSAMAX PLUS D and FOSAMAX 70 mg at Week 15*

Number (%) of Patients

25-hydroxyvitamin D Ranges

(ng / mL)

FOSAMAX PLUS D

(N=357)

4 (1.1) 37 (10.4) 87 (24.4) 84 (23.5) 82

(23.0)

63 (17.7)

FOSAMAX 70 mg

(N=351)

46 (13.1) 66 (18.8) 108

(30.8)

58 (16.5) 37

(10.5)

36 (10.3)

* Patients who were vitamin D deficient (25-hydroxyvitamin D <9 ng/mL) at baseline were excluded.

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.

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

(alendronate sodium/cholecalciferol) Tablets

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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.

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.

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,

(alendronate sodium/cholecalciferol) Tablets

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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.

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

FOSAMA

X

(n=1022)

Placebo

(n=1005)

Absolute

Reduction

in Fracture

Incidence

Relative

Reduction

in Fracture

Risk %

Patients with:

Clinical (symptomatic) fractures

fracture

2.3 5.0 2.7 54**

Hip fracture 1.1 2.2 1.1 51*

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)

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

(alendronate sodium/cholecalciferol) Tablets

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thus this study included both osteoporotic and non-osteoporotic women. The results are shown in the

table below for the patients with osteoporosis.

Study of FIT

(patients without vertebral fracture at baseline)

Percent of Patients

FOSAMA

X

(n=1545)

Placebo

(n=1521)

Absolute

Reduction

in Fracture

Incidence

Relative

Reduction

in Fracture

Risk (%)

Patients with:

Vertebral fractures (diagnosed by

Clinical (symptomatic) fractures

Any clinical (symptomatic) fracture 12.9 16.2 3.3 22**

fracture

*p=0.035, ** p=0.01, ***p<0.001

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 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.

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:

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).

(alendronate sodium/cholecalciferol) Tablets

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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)

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.

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, placebocontrolled

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 ฑ 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.

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.

FOSAMAX PLUS D is indicated for:

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

(alendronate sodium/cholecalciferol) Tablets

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FOSAMAX PLUS D, like other bisphosphonate-containing products, 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. 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 PLUS D 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 PLUS D and/or who fail to swallow it with a full glass (6-8 oz) of water, and/or who

continue to take FOSAMAX PLUS D 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 PLUS D should be used under appropriate supervision.

Because of possible irritant effects of alendronate on the upper gastrointestinal mucosa and a

potential for worsening of the underlying disease, caution should be used when FOSAMAX PLUS D 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 with alendronate, some

severe and with complications, although no increased risk was observed in controlled clinical trials.

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

considered.

Hypocalcemia must be corrected before initiating therapy with FOSAMAX PLUS D (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 PLUS D.

Presumably due to the effects of alendronate on increasing bone mineral, small, asymptomatic

decreases in serum calcium and phosphate may occur.

FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency (commonly defined as 25-

hydroxyvitamin D level below 9 ng/mL). Patients at increased risk for vitamin D insufficiency (e.g., those

who are nursing home bound, chronically ill, over the age of 70 years) should receive vitamin D

supplementation in addition to that provided in FOSAMAX PLUS D. Patients with gastrointestinal

malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of

25-hydroxyvitamin D should be considered.

patients with diseases associated with unregulated overproduction of 1,25 dihydroxyvitamin D (e.g.,

leukemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.

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.

(alendronate sodium/cholecalciferol) Tablets

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In placebo-controlled clinical studies of FOSAMAX, the percentages of patients with these symptoms

were similar in the FOSAMAX and placebo groups.

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.

FOSAMAX PLUS D is not recommended for patients with renal insufficiency (creatinine clearance

<35 mL/min). (See DOSAGE AND ADMINISTRATION.)

Physicians should instruct their patients to read the patient package insert before starting therapy

with FOSAMAX PLUS D and to reread it each time the prescription is renewed.

Patients should be instructed to take supplemental calcium if intake is inadequate. Patients at

increased risk for Vitamin D insufficiency (e.g., those who are nursing home bound, chronically ill, over

the age of 70 years) should be instructed to take additional vitamin D. Patients with gastrointestinal

malabsorption syndromes should be informed that they may require additional vitamin D

supplementation. 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.

Patients should be instructed that the expected benefits of FOSAMAX PLUS D 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

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients

should be instructed to swallow each tablet of FOSAMAX PLUS D with a full glass of water (6-8 oz) and

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 FOSAMAX PLUS D 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 FOSAMAX PLUS D

and consult their physician.

Patients should be instructed that if they miss a dose of FOSAMAX PLUS D, they should take one

tablet on the morning after they remember. They should not take two tablets on the same day but should

return to taking one tablet once a week, as originally scheduled on their chosen day.

of one or two years’ duration in postmenopausal osteoporotic women. In these studies, the safety and

tolerability profile of the combination was consistent with those of the individual treatments; however, the

degree of suppression of bone turnover (as assessed by mineralizing surface) was significantly greater

with the combination than with either component alone. The long-term effects of combined FOSAMAX

(alendronate sodium/cholecalciferol) Tablets

13

It is likely that calcium supplements, antacids, and some oral medications will interfere with

absorption of alendronate. Therefore, patients must wait at least one-half hour after taking FOSAMAX

PLUS D before taking any other oral medications.

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients

receiving concomitant therapy with daily doses of FOSAMAX greater than 10 mg and aspirin-containing

products.

FOSAMAX PLUS D may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical

study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper

gastrointestinal adverse events was similar in patients taking FOSAMAX 5 or 10 mg/day compared to

those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution

should be used during concomitant use with FOSAMAX PLUS D.

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair

the absorption of vitamin D.

Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.

The following data are based on findings for the individual components of FOSAMAX PLUS D.

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose

female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and

10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.12

to 1.2 times a maximum recommended daily dose of 40 mg (Paget’s disease) based on surface area,

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year

oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 0.26

humans is unknown.

aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day

the hormonal metabolite of cholecalciferol, was not genotoxic in the Ames microbial mutagenesis assay

resulted in altered estrous cycle and inhibition of pregnancy in rats. The potential effect of cholecalciferol

on male fertility is unknown in rats.

Reproduction studies in rats showed decreased postimplantation survival at 2 mg/kg/day and

decreased body weight gain in normal pups at 1 mg/kg/day. Sites of incomplete fetal ossification were

statistically significantly increased in rats beginning at 10 mg/kg/day in vertebral (cervical, thoracic, and

lumbar), skull, and sternebral bones. The above doses ranged from 0.26 times (1 mg/kg) to 2.6 times

(alendronate sodium/cholecalciferol) Tablets

14

(10 mg/kg) a maximum recommended daily dose of 40 mg (Paget’s disease) based on surface area,

Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day (3.9 times a 40 mg human

parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day (0.13 times a

through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with

15 mg/kg/day for varying periods of time ranging from treatment only during pre-mating to treatment only

during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of

treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the

hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; calcium

supplementation IV prevented maternal, but not fetal deaths.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over

a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount

available for release back into the systemic circulation, is directly related to the dose and duration of

bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of

fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of

bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate

therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous

versus oral) on the risk has not been studied.

neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

There are no studies in pregnant women. FOSAMAX PLUS D should be used during pregnancy only

if the potential benefit justifies the potential risk to the mother and fetus.

Cholecalciferol and some of its active metabolites pass into breast milk. It is not known whether

alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should

be exercised when FOSAMAX PLUS D is administered to nursing women.

Safety and effectiveness in pediatric patients have not been established.

Of the patients receiving FOSAMAX in the Fracture Intervention Trial (FIT), 71% (n=2302) were

United States and Multinational osteoporosis treatment studies in women, and osteoporosis studies in

65 years of age or over. No overall differences in efficacy or safety were observed between these

patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies of up to five years in duration adverse experiences associated with FOSAMAX

usually were mild, and generally did not require discontinuation of therapy.

FOSAMAX has been evaluated for safety in approximately 8000 postmenopausal women in clinical

studies.

In two identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United

States and Multinational; n=994), discontinuation of therapy due to any clinical adverse experience

(alendronate sodium/cholecalciferol) Tablets

15

occurred in 4.1% of 196 patients treated with FOSAMAX 10 mg/day and 6.0% of 397 patients treated with

placebo. In the Fracture Intervention Trial (n=6459), discontinuation of therapy due to any clinical adverse

experience occurred in 9.1% of 3236 patients treated with FOSAMAX 5 mg/day for 2 years and

10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo.

Discontinuations due to upper gastrointestinal adverse experiences were: FOSAMAX, 3.2%; placebo,

2.7%. In these study populations, 49-54% had a history of gastrointestinal disorders at baseline and 54-

89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. Adverse

experiences from these studies considered by the investigators as possibly, probably, or definitely drug

Osteoporosis Treatment Studies in Postmenopausal Women

Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and

United States/Multinational Studies Fracture Intervention Trial

FOSAMAX*

%

(n=196)

Placebo

%

(n=397)

FOSAMAX**

%

(n=3236)

Placebo

%

(n=3223)

abdominal pain

nausea

dyspepsia

constipation

diarrhea

flatulence

acid regurgitation

esophageal ulcer

vomiting

dysphagia

abdominal distention

gastritis

6.6

3.6

3.6

3.1

3.1

2.6

2.0

1.5

1.0

1.0

1.0

0.5

4.8

4.0

3.5

1.8

1.8

0.5

4.3

0.0

1.5

0.0

0.8

1.3

1.5

1.1

1.1

0.0

0.6

0.2

1.1

0.1

0.2

0.1

0.0

0.6

1.5

1.5

1.2

0.2

0.3

0.3

0.9

0.1

0.3

0.1

0.0

0.7

musculoskeletal (bone,

muscle or joint) pain

muscle cramp

4.1

0.0

2.5

1.0

0.4

0.2

0.3

0.1

headache

dizziness

2.6

0.0

1.5

1.0

0.2

0.0

0.2

0.1

taste perversion

0.5

1.0

0.1

0.0

* 10 mg/day for three years

** 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years

Rarely, rash and erythema have occurred.

One patient treated with FOSAMAX (10 mg/day), who had a history of peptic ulcer disease and

gastrectomy and who was taking concomitant aspirin developed an anastomotic ulcer with mild

hemorrhage, which was considered drug related. Aspirin and FOSAMAX were discontinued and the

patient recovered.

The adverse experience profile was similar for the 401 patients treated with either 5 or 20 mg doses

of FOSAMAX in the United States and Multinational studies. The adverse experience profile for the

296 patients who received continued treatment with either 5 or 10 mg doses of FOSAMAX in the two-year

extension of these studies (treatment years 4 and 5) was similar to that observed during the three-year

placebo-controlled period. During the extension period, of the 151 patients treated with

FOSAMAX 10 mg/day, the proportion of patients who discontinued therapy due to any clinical adverse

experience was similar to that during the first three years of the study.

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once

weekly FOSAMAX 70 mg and FOSAMAX 10 mg daily were similar. The adverse experiences considered

group are presented in the following table.

(alendronate sodium/cholecalciferol) Tablets

16

Osteoporosis Treatment Studies in Postmenopausal Women

Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related

Once Weekly FOSAMAX

70 mg

%

(n=519)

FOSAMAX

10 mg/day

%

(n=370)

abdominal pain

dyspepsia

acid regurgitation

nausea

abdominal distention

constipation

flatulence

gastritis

gastric ulcer

3.7

2.7

1.9

1.9

1.0

0.8

0.4

0.2

0.0

3.0

2.2

2.4

2.4

1.4

1.6

1.6

1.1

1.1

musculoskeletal (bone, muscle,

joint) pain

muscle cramp

2.9

0.2

3.2

1.1

In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX

10 mg/day and a one-year study of once weekly FOSAMAX 70 mg) the rates of discontinuation of

therapy due to any clinical adverse experience were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for

placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for placebo. The adverse experiences

with either FOSAMAX or placebo are presented in the following table.

Osteoporosis Studies in Men

Adverse Experiences Considered Possibly, Probably, or

Definitely Drug Related by the Investigators and

Two-year Study One-year Study

FOSAMAX

10 mg/day

%

(n=146)

Placebo

%

(n=95)

Once Weekly

FOSAMAX 70 mg

%

(n=109)

Placebo

%

(n=58)

acid regurgitation

flatulence

gastroesophageal

reflux disease

dyspepsia

diarrhea

abdominal pain

nausea

4.1

4.1

0.7

3.4

1.4

2.1

2.1

3.2

1.1

3.2

0.0

1.1

1.1

0.0

0.0

0.0

2.8

2.8

2.8

0.9

0.0

0.0

0.0

0.0

1.7

0.0

3.4

0.0

In two studies (of one and two years’ duration) of postmenopausal osteoporotic women (total: n=853),

progestin (n=354) was consistent with those of the individual treatments.

The safety of FOSAMAX 5 mg/day in postmenopausal women 40-60 years of age has been

evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to

receive FOSAMAX for either two or three years. In these studies the overall safety profiles of FOSAMAX

5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience

occurred in 7.5% of 642 patients treated with FOSAMAX 5 mg/day and 5.7% of 648 patients treated with

placebo.

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once

weekly FOSAMAX 35 mg and FOSAMAX 5 mg daily were similar.

(alendronate sodium/cholecalciferol) Tablets

17

The adverse experiences from these studies considered by the investigators as possibly, probably, or

FOSAMAX 5 mg/day or placebo are presented in the following table.

Osteoporosis Prevention Studies in Postmenopausal Women

Adverse Experiences Considered Possibly, Probably, or

Definitely Drug Related by the Investigators and

Two/Three-Year Studies One-Year Study

FOSAMA

X

5 mg/day

%

(n=642)

Placebo

%

(n=648)

FOSAMAX

5 mg/day

%

(n=361)

Once Weekly

FOSAMAX

35 mg

%

(n=362)

dyspepsia

abdominal pain

acid regurgitation

nausea

diarrhea

constipation

abdominal distention

1.9

1.7

1.4

1.4

1.1

0.9

0.2

1.4

3.4

2.5

1.4

1.7

0.5

0.3

2.2

4.2

4.2

2.5

1.1

1.7

1.4

1.7

2.2

4.7

1.4

0.6

0.3

1.1

musculoskeletal (bone,

muscle or joint)

pain

0.8

0.9

1.9

2.2

In two, one-year, placebo-controlled, double-blind, multicenter studies in patients receiving

glucocorticoid treatment, the overall safety and tolerability profiles of FOSAMAX 5 and 10 mg/day were

generally similar to that of placebo. The adverse experiences considered by the investigators as possibly,

placebo are presented in the following table.

One-Year Studies in Glucocorticoid-Treated Patients

Adverse Experiences Considered Possibly, Probably, or

Definitely Drug Related by the Investigators and

FOSAMAX

10 mg/day

%

(n=157)

FOSAMAX

5 mg/day

%

(n=161)

Placebo

%

(n=159)

abdominal pain

acid regurgitation

constipation

melena

nausea

diarrhea

headache

3.2

2.5

1.3

1.3

0.6

0.0

0.6

1.9

1.9

0.6

0.0

1.2

0.0

0.0

0.0

1.3

0.0

0.0

0.6

1.3

1.3

The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that

continued therapy for the second year of the studies (FOSAMAX: n=147) was consistent with that

observed in the first year.

In clinical studies (osteoporosis and Paget's disease), adverse experiences reported in 175 patients

taking FOSAMAX 40 mg/day for 3-12 months were similar to those in postmenopausal women treated

with FOSAMAX 10 mg/day. However, there was an apparent increased incidence of upper

gastrointestinal adverse experiences in patients taking FOSAMAX 40 mg/day (17.7% FOSAMAX vs.

10.2% placebo). One case of esophagitis and two cases of gastritis resulted in discontinuation of

treatment.

Additionally, musculoskeletal (bone, muscle or joint) pain, which has been described in patients with

Paget's disease treated with other bisphosphonates, was considered by the investigators as possibly,

probably, or definitely drug related in approximately 6% of patients treated with FOSAMAX 40 mg/day

(alendronate sodium/cholecalciferol) Tablets

18

versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of

therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 6.4% of patients

with Paget's disease treated with FOSAMAX 40 mg/day and 2.4% of patients treated with placebo.

In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum

calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking

FOSAMAX versus approximately 12% and 3% of those taking placebo. However, the incidences of

were similar in both treatment groups.

In a fifteen week double-blind, multinational study in osteoporotic postmenopausal women (n=682)

and men (n=35), the safety profile of FOSAMAX PLUS D was similar to that of FOSAMAX once weekly

70 mg.

The following adverse reactions have been reported in post-marketing use with alendronate:

symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically

in association with initiation of treatment. Rarely, symptomatic hypocalcemia has occurred, generally in

association with predisposing conditions. Rarely, peripheral edema.

perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with

DOSAGE AND ADMINISTRATION).

Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection,

Stevens-Johnson syndrome and toxic epidermal necrolysis.

Significant lethality after single oral doses with alendronate was seen in female rats and mice at

higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg

No specific information is available on the treatment of overdosage with alendronate. Hypocalcemia,

hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn,

esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind

alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient

should remain fully upright.

Dialysis would not be beneficial.

Significant lethality occurred in mice treated with a single high oral dose of calcitriol (4 mg/kg), the

hormonal metabolite of cholecalciferol.

There is limited information regarding doses of cholecalciferol associated with acute toxicity, although

been given without reports of toxicity. Signs and symptoms of vitamin D toxicity include hypercalcemia,

hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy. Serum and

urine calcium levels should be monitored in patients with suspected vitamin D toxicity. Standard therapy

includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe

hypercalcemia.

(alendronate sodium/cholecalciferol) Tablets

19

Dialysis to remove vitamin D would not be beneficial.

beverages (including mineral water), food, and some medications are likely to reduce the absorption of

PLUS D with food, beverages (other than plain water) or other medications will lessen the effect of

alendronate by decreasing its absorption into the body.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation,

FOSAMAX PLUS D should only be swallowed upon arising for the day with a full glass of water (6-8 oz)

and patients should not lie down for at least 30 minutes and until after their first food of the day.

FOSAMAX PLUS D should not be taken at bedtime or before arising for the day. Failure to follow these

instructions may increase the risk of esophageal adverse experiences (see WARNINGS,

Patients should receive supplemental calcium if dietary intake is inadequate (see PRECAUTIONS,

chronically ill, over the age of 70 years) should receive vitamin D supplementation in addition to that

provided in FOSAMAX PLUS D. Patients with gastrointestinal malabsorption syndromes may require

higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be

considered.

The recommended intake of vitamin D is 400 IU-800 IU daily. FOSAMAX PLUS D is intended to

provide seven days’ worth of 400 IU daily vitamin D in a single, once-weekly dose.

No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal

insufficiency (creatinine clearance 35 to 60 mL/min). FOSAMAX PLUS D is not recommended for patients

with more severe renal insufficiency (creatinine clearance <35 m