Fosamax^®

(Alendronate Sodium Tablets)

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DESCRIPTION
CLINICAL PHARMACOLOGY
ANIMAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

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Description

FOSAMAX (alendronate sodium) is an
aminobisphosphonate that acts as a specific inhibitor of
osteoclast-mediated bone resorption. Bisphosphonates are
synthetic analogs of pyrophosphate that bind to the
hydroxyapatite found in bone.

Alendronate sodium is chemically
described as (4-amino-1-hydroxybutylidene) bisphosphonic
acid monosodium salt trihydrate.

The empirical formula of alendronate
sodium is C₄H₁₂NNaO₇P₂•3H₂O and its formula weight is 325.12. The
structural formula is:

Alendronate sodium is a white,
crystalline, nonhygroscopic powder. It is soluble in
water, very slightly soluble in alcohol, and practically
insoluble in chloroform.

Tablets FOSAMAX for oral administration
contain 6.53, 13.05 or 52.21 mg of alendronate
monosodium salt trihydrate, which is the molar equivalent
of 5.0, 10.0 and 40.0 mg, respectively, of free
acid, and the following inactive ingredients:
microcrystalline cellulose, anhydrous lactose,
croscarmellose sodium, and magnesium stearate.

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Clinical Pharmacology

Mechanism
of Action

Animal studies have indicated the
following mode of action. At the cellular level,
alendronate shows preferential localization to sites of
bone resorption, specifically under osteoclasts. The
osteoclasts adhere normally to the bone surface but lack
the ruffled border that is indicative of active
resorption. Alendronate does not interfere with
osteoclast recruitment or attachment, but it does inhibit
osteoclast activity. Studies in mice on the localization
of radioactive [3H]alendronate in bone showed about 10-fold
higher uptake on osteoclast surfaces than on osteoblast
surfaces. Bones examined 6 and 49 days after [3H]alendronate
administration in rats and mice, respectively, showed
that normal bone was formed on top of the alendronate,
which was incorporated inside the matrix. While
incorporated in bone matrix, alendronate is not
pharmacologically active. Thus, alendronate must be
continuously administered to suppress osteoclasts on
newly formed resorption surfaces. Histomorphometry in
baboons and rats showed that alendronate treatment
reduces bone turnover (i.e., the number of sites at which
bone is remodeled). In addition, bone formation exceeds
bone resorption at these remodeling sites, leading to
progressive gains in bone mass.

Pharmacokinetics
Absorption

Relative to an intravenous (IV)
reference dose, the mean oral bioavailability of
alendronate in women was 0.7% for doses ranging from 5 to
40 mg when administered after an overnight fast and
two hours before a standardized breakfast. Oral
bioavailability of the 10 mg tablet in men (0.59%)
was similar to that in women (0.78%) when administered
after an overnight fast and 2 hours before
breakfast.

A study examining the effect of timing
of a meal on the bioavailability of alendronate was
performed in 49 postmenopausal women.
Bioavailability was decreased (by approximately 40%) when
10 mg alendronate was administered either 0.5 or
1 hour before a standardized breakfast, when
compared to dosing 2 hours before eating. 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, and systemic clearance
did not exceed 200 mL/min. Plasma concentrations
fell by more than 95% within 6 hours following IV
administration. The terminal half-life in humans is
estimated to exceed 10 years, probably reflecting
release of alendronate from the skeleton. Based on the
above, it is estimated that after 10 years of oral
treatment with FOSAMAX (10 mg daily) the amount of
alendronate released daily from the skeleton is
approximately 25% of that absorbed from the
gastrointestinal tract.

Special Populations

Pediatric: Alendronate
pharmacokinetics have not been investigated in patients
<18 years of age.

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 (³65 years
of age) and younger patients. No dosage adjustment is
necessary (see DOSAGE AND ADMINISTRATION).

Race: Pharmacokinetic
differences due to race have not been studied.

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

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

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; no other specific drug
interaction studies were performed.

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

Summary of Pharmacokinetic
Parameters in the Normal Population

	Mean	90% Confidence Interval
Absolute bioavailability of 5 mg tablet, taken 2 hours before first meal of the day	0.63% (females)	(0.48, 0.83)
Absolute bioavailability of 10 mg tablet, taken 2 hours before first meal of the day	0.78% (females)	(0.61, 1.04)
	0.59% (males)	(0.43, 0.81)
Absolute bioavailability of 40 mg tablet, taken 2 hours before first meal of the day	0.60% (females)	(0.46, 0.78)
Renal Clearance (mL/min) (n=6)	71	(64, 78)

Pharmacodynamics
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.

Alendronate is an aminobisphosphonate
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. Alendronate thus
reduces the elevated rate of bone turnover observed in
postmenopausal women to approximate more closely that in
premenopausal women. Alendronate is not an estrogen and
does not have the benefits and risks of estrogen
replacement therapy.

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.

In long-term (two- or three-year)
osteoporosis treatment studies, FOSAMAX 10 mg/day
reduced urinary excretion of markers of bone resorption,
including deoxypyridinoline and cross-linked
N-telopeptides of type l collagen, by approximately
50-60% to reach levels similar to those seen in healthy
premenopausal women. Similar decreases were seen in
patients in osteoporosis prevention studies who received
FOSAMAX 5 mg/day. The decrease in the rate of bone
resorption indicated by these markers was evident as
early as one month and at three to six months reached a
plateau that was maintained for the entire duration of
treatment with FOSAMAX. In osteoporosis treatment studies
FOSAMAX 10 mg/day decreased the markers of bone
formation, osteocalcin and total serum alkaline
phosphatase, by approximately 50% and 25-30%,
respectively, to reach a plateau after 6 to 12 months. In
osteoporosis prevention studies FOSAMAX 5 mg/day
decreased these markers by approximately 40% and 15%,
respectively. 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, but no further decreases were observed for
the three-year duration of the studies. Similar
reductions were observed with FOSAMAX 5 mg/day. 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.

Paget’s disease of bone

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

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

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

Clinical
Studies
Treatment of osteoporosis in postmenopausal women
Effect on bone mineral density

The efficacy of FOSAMAX 10 mg once
daily in postmenopausal women, 44 to 84 years of age,
with osteoporosis (lumbar spine bone mineral density
[BMD] of at least 2 standard deviations below the
premenopausal mean) was demonstrated in four
double-blind, placebo-controlled clinical studies of two
or three years’ duration. These included two large
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.

Highly significant
increases in BMD, relative both to baseline and placebo,
were seen at each measurement site in each study in
patients who received FOSAMAX 10 mg/day. Total body
BMD also increased significantly in each study,
suggesting that the increases in bone mass of the spine
and hip did not occur at the expense of other skeletal
sites. Increases in BMD were evident as early as three
months and continued throughout the three years of
treatment. (See figures below for lumbar spine results.)
Thus, FOSAMAX appears to reverse the progression of
osteoporosis. 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).

In patients with
postmenopausal osteoporosis treated with FOSAMAX 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 continuous daily treatment with FOSAMAX is
required to maintain the effect of the drug.

Effect on fracture incidence

To assess the effects of FOSAMAX on
vertebral fracture incidence, 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
significant 48% 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 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 statistically
significant smaller loss in stature than those who
received placebo (–3.0 mm vs.
–4.6 mm). Furthermore, of patients who
sustained any vertebral fracture, those treated with
FOSAMAX experienced less height loss (5.9 mm vs.
23.3 mm) due to a reduction in both the number and
severity of fractures.

The Vertebral Fracture
Study of the Fracture Intervention Trial (FIT) included
results from 2027 patients who had at least one baseline
vertebral (compression) fracture. The results of this
study demonstrated the reduction in fracture incidence
due to FOSAMAX. In this three-year,
randomized, double-blind, placebo-controlled study, 1022
patients received FOSAMAX and 1005 patients received
placebo. Treatment with FOSAMAX resulted in statistically
significant and clinically meaningful reductions in the
proportion of patients experiencing fractures as shown in
the table below.

Effect of FOSAMAX on Fracture Incidence Over Three Years in the Vertebral Fracture Study of FIT
	% of Patients		Reduction (%) in
	FOSAMAX	Placebo	Fracture Incidence
Patients with:
> 1 new vertebral fracture	8.0	15.0	47
> 2 new vertebral fractures	0.5	4.9	90
> 1 painful vertebral fracture	2.3	5.0	55
Hip fractures	1.1	2.2	51
Wrist (forearm) fracture	2.2	4.1	48

Furthermore, treatment with
FOSAMAX significantly reduced the incidence of total
hospitalizations (24.9% vs. 30.4%).

The reduction in the incidence of
vertebral fractures (FOSAMAX versus placebo) in the
Vertebral Fracture Study of FIT (in which all women had
at least one baseline vertebral fracture) was consistent
with that in the combined U.S. and Multinational
(U.S./Mult) treatment studies (see above), in which 80%
of the women did not have a vertebral fracture at
baseline. During these three-year studies, treatment with
FOSAMAX reduced the proportion of women experiencing at
least one new vertebral fracture in both study
populations by approximately 50% (FIT: 47% reduction,
p<0.001; U.S./Mult: 48% reduction,
p = 0.034). Similarly, FOSAMAX reduced the
proportion of women experiencing multiple (two or more)
new vertebral fractures by approximately 90% in both
studies (p<0.001). Thus, FOSAMAX reduces the incidence
of fractures whether or not patients have experienced a
previous vertebral fracture.

The two figures below display the
cumulative incidence of patients with hip and wrist
fractures over 3 years in the Vertebral Fracture Study of
FIT. In both figures, the cumulative incidence of
patients with these types of fracture is lower with
FOSAMAX compared with placebo at all time points. FOSAMAX
reduced the proportion of women experiencing hip fracture
by 51% and wrist fracture by 48%. Proportionately similar
reductions of hip and wrist fractures were seen in pooled
earlier osteoporosis treatment studies.

Overall, these results
demonstrate the efficacy of FOSAMAX to reduce the
incidence of fractures at the spine, hip and wrist, which
are the three most common sites of osteoporotic fracture.

Bone histology

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

Prevention of osteoporosis in
postmenopausal women

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

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

Paget’s disease of bone

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

At six months the
suppression in alkaline phosphatase in patients treated
with FOSAMAX was significantly greater than that achieved
with etidronate and contrasted with the complete lack of
response in placebo-treated patients. Response (defined
as either normalization of serum alkaline phosphatase or
decrease from baseline ³60%) occurred in
approximately 85% of patients treated with FOSAMAX in the
combined studies vs. 30% in the etidronate group and 0%
in the placebo group. FOSAMAX was similarly effective
irrespective of age, gender, race, prior use of other
bisphosphonates, or baseline alkaline phosphatase within
the range studied (at least twice the upper limit of
normal).

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

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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.

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Indicatons and Usage

FOSAMAX is
indicated for the treatment and prevention of
osteoporosis in postmenopausal women.

• For the treatment of osteoporosis,
  FOSAMAX increases bone mass and prevents
  fractures, including those of the hip, wrist, and
  spine (vertebral compression fractures).
  Osteoporosis may be confirmed by the finding of
  low bone mass (for example, at least 2 standard
  deviations below the premenopausal mean) or by
  the presence or history of osteoporotic fracture.
  (See CLINICAL PHARMACOLOGY, Pharmacodynamics.)
• For the prevention of
  osteoporosis, FOSAMAX may be considered in
  postmenopausal women who are at risk of
  developing osteoporosis and for whom the desired
  clinical outcome is to maintain bone mass and to
  reduce the risk of future fracture.

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

FOSAMAX is indicated for the treatment
of Paget’s disease of bone.

• 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.

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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)

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Warnings

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

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

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down
after taking FOSAMAX and/or who fail to swallow it with a full glass (6-8 oz) of water, and/or
who continue to take FOSAMAX after developing symptoms suggestive of esophageal irritation.
Therefore, it is very important that the full dosing instructions are provided to, and understood by,
the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with
dosing instructions due to mental disability, therapy with FOSAMAX should be used under
appropriate supervision.

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

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Precautions

General

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

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

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

Hypocalcemia must be corrected before
initiating therapy with FOSAMAX (see CONTRAINDICATIONS).
Other disturbances of mineral metabolism (such as
vitamin D deficiency) should also be effectively
treated. Presumably due to the effects of FOSAMAX on
increasing bone mineral, small, asymptomatic decreases in
serum calcium and phosphate may occur, especially in
patients with Paget’s disease, in whom the
pretreatment rate of bone turnover may be greatly
elevated. Adequate calcium and vitamin D intake
should be ensured to provide for these enhanced needs.

Information
for Patients

Patients should be instructed that the
expected benefits of FOSAMAX may only be obtained when
each tablet is swallowed 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 FOSAMAX (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 FOSAMAX 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 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 and consult their physician.

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 excessive cigarette smoking,
and/or alcohol consumption, if these factors exist.

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

Drug
Interactions (also see
CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug
Interactions)

Estrogen

The safety and effectiveness of the
concomitant use of hormone replacement therapy and
FOSAMAX in postmenopausal women has not been established.

Calcium Supplements/Antacids

It is likely that calcium supplements,
antacids, and some oral medications will interfere with
absorption of FOSAMAX. Therefore, patients must wait at
least one-half hour after taking FOSAMAX before taking
any other drug.

Aspirin

In clinical studies, the incidence of
upper gastrointestinal adverse events was increased in
patients receiving concomitant therapy with doses of
FOSAMAX greater than 10 mg/day and
aspirin-containing compounds.

Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)

FOSAMAX 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 compared to those taking
placebo. However, since NSAID use is associated with
gastrointestinal irritation, caution should be used
during concomitant use with FOSAMAX.

Carcinogenesis, Mutagenesis,
Impairment of Fertility

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
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
0.5 to 4 times the 10 mg human dose based on surface
area, mg/m2.

Parafollicular cell (thyroid) adenomas
were increased in high-dose male rats (p=0.003) in a
2-year carcinogenicity study at doses of 1 and
3.75 mg/kg body weight. These doses are equivalent
to 1 and 3 times the 10 mg human dose based on
surface area.

Alendronate was not genotoxic in the in
vitro microbial mutagenesis assay with and without
metabolic activation, in an in vitro
mammalian cell mutagenesis assay, in an in vitro
alkaline elution assay in rat hepatocytes, and in an in
vivo chromosomal aberration assay in mice. In an in
vitro chromosomal aberration assay in Chinese
hamster ovary cells, however, alendronate was weakly
positive at concentrations ³5 mM in the
presence of cytotoxicity.

Alendronate had no effect on fertility
(male or female) in rats at oral doses up to
5 mg/kg/day (four times the 10 mg human dose
based on surface area).

Pregnancy
Pregnancy Category C:

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 1 times (1 mg/kg) to 9 times
(10 mg/kg) the 10 mg human dose based on
surface area, mg/m2. No similar fetal effects were seen when
pregnant rabbits were treated at doses up to
35 mg/kg/day (50 times the 10 mg human dose
based on surface area, mg/m2).

Both total and ionized calcium
decreased in pregnant rats at 15 mg/kg/day (13 times
the 10 mg human dose based on surface area)
resulting in delays and failures of delivery. Protracted
parturition due to maternal hypocalcemia occurred in rats
at doses as low as 0.5 mg/kg/day (0.5 times the
recommended human dose) when rats were treated from
before mating 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.

There are no studies in pregnant women.
FOSAMAX should be used during pregnancy only if the
potential benefit justifies the potential risk to the
mother and fetus.

Nursing Mothers

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
is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric
patients have not been established.

Use in the Elderly

Of the patients receiving FOSAMAX in
the two large osteoporosis treatment studies and
Paget’s disease studies (see CLINICAL PHARMACOLOGY, Clinical
Studies), 45% and 70%, respectively, were 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.

Use in Men

Safety and effectiveness in male
osteoporosis have not been established.

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Adverse Reactions

ADVERSE REACTIONS

Clinical Studies

In clinical studies adverse experiences associated
with FOSAMAX usually were mild, and generally did not require discontinuation of therapy

FOSAMAX has been evaluated for safety in approximately 3800
postmenopausal women in clinical studies.

Treatment of osteoporosis

In two large, three-year, placebo-controlled,
double-blind, multicenter studies (United States and Multinational), discontinuation of
therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated
with FOSAMAX 10 mg/day and 6.0% of 397 patients treated with placebo. Adverse
experiences reported by the investigators as possibly, probably, or definitely drug
related in ³1% of patients treated with either FOSAMAX
10 mg/day or placebo are presented in the following table.

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.

In the Vertebral Fracture Study of the Fracture Intervention Trial,
discontinuation of therapy due to any clinical adverse experience occurred in 7.6% of 1022
patients treated with FOSAMAX 5 mg/day for 2 years and 10 mg/day for the third year
and 9.4% of 1005 patients treated with placebo. Similarly, discontinuations due to upper
gastrointestinal adverse experiences were comparable: FOSAMAX, 2.6%; placebo, 2.6%. The
overall adverse experience profile was similar to that seen in other studies with FOSAMAX
5 or 10 mg/day.

Prevention of osteoporosis

The safety of FOSAMAX 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. The adverse experiences reported by the investigators as possibly, probably
or definitely drug related in ³1% of patients treated with
either FOSAMAX 5 mg/day or placebo are presented in the following table.

Paget’s disease of bone

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 reported by the investigators as possibly, probably, or definitely
drug related in approximately 6% of patients treated with FOSAMAX 40 mg/day 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.

Laboratory Test Findings

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 decreases in
serum calcium to <8.0 mg/dL (2.0 mM) and serum phosphate to £2.0 mg/dL (0.65 mM) were similar in both treatment
groups.

Post-Marketing Experience

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

Body as a Whole: hypersensitivity reactions including urticaria
and rarely angioedema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal
ulcers and oropharyngeal ulceration. Rarely, gastric or duodenal ulcers, some severe and
with complications have been reported (see WARNINGS, PRECAUTIONS, General and Information
for Patients, and DOSAGE AND ADMINISTRATION).

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Overdosage

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg
(3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly
higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to
200 mg/kg (4000 mg/m2).

No specific information is available on the treatment of overdosage with FOSAMAX.
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.

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Dosage and Administration

FOSAMAX
must be taken at least one-half hour before the
first food, beverage, or medication of the day with plain
water only (see PRECAUTIONS, Information for Patients).
Other beverages (including mineral water), food, and some
medications are likely to reduce the absorption of
FOSAMAX (see PRECAUTIONS, Drug Interactions).
Waiting less than 30 minutes, or taking FOSAMAX with
food, beverages (other than plain water) or other
medications will lessen the effect of FOSAMAX by
decreasing its absorption into the body.

To facilitate delivery to the stomach
and thus reduce the potential for esophageal irritation,
FOSAMAX 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 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 and vitamin D, if dietary intake is
inadequate (see PRECAUTIONS, General).

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 is not recommended for patients
with more severe renal insufficiency (creatinine
clearance <35 mL/min) due to lack of experience.

Treatment of osteoporosis in
postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is 10 mg
once a day.

Prevention of osteoporosis in
postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is 5 mg
once a day.

Safety of treatment or prevention of
osteoporosis with FOSAMAX for longer than four years has
not been studied; extension studies are ongoing.

Paget’s disease of bone

The recommended treatment regimen is
40 mg once a day for six months.

Retreatment of Paget’s disease

In clinical studies in which patients
were followed every six months, relapses during the 12
months following therapy occurred in 9% (3 out of 32) of
patients who responded to treatment with FOSAMAX.
Specific retreatment data are not available, although
responses to FOSAMAX were similar in patients who had
received prior bisphosphonate therapy and those who had
not. Retreatment with FOSAMAX may be considered,
following a six-month post-treatment evaluation period in
patients who have relapsed, based on increases in serum
alkaline phosphatase, which should be measured
periodically. Retreatment may also be considered in those
who failed to normalize their serum alkaline phosphatase.

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How Supplied

No. 3759 — Tablets FOSAMAX, 5 mg,
are white, round, uncoated tablets with an outline of a
bone image on one side and code MRK 925 on the other.
They are supplied as follows:

NDC 0006-0925-31 unit-of-use
bottles of 30

NDC 0006-0925-58 unit-of-use
bottles of 100.

No. 3600 — Tablets FOSAMAX,
10 mg, are white, round, uncoated tablets with a
bone image and code MRK 936 on one side and a bone
image and FOSAMAX on the other. They are supplied as
follows:

NDC 0006-0936-31 unit-of-use
bottles of 30

(6505-01-424-1106, 10 mg 30’s)

NDC 0006-0936-58 unit-of-use
bottles of 100

NDC 0006-0936-28 unit dose
packages of 100

(6505-01-424-1113, 10 mg 100’s)

NDC 0006-0936-82 bottles of
1000.

NDC 0006-0936-72 carton of 25
UNIBLISTER™ cards of 31 tablets each.

No. 3592 — Tablets FOSAMAX,
40 mg, are white, triangular-shaped, uncoated
tablets with code MRK 212 on one side and FOSAMAX on
the other. They are supplied as follows:

NDC 0006-0212-31 unit-of-use
bottles of 30

(6505-01-424-1111, 40 mg 30’s).

Storage

Store in a well-closed container at
room temperature, 15-30°C (59-86°F).

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Issued July 1997

FOSAMAX is a registered trademark of Merck & Co., Inc.