Business Editors/Health & Pharmaceutical Writers
NEW ORLEANS--(BUSINESS WIRE)--April 28, 2003--
Two-Fold Greater Increases in Bone Mineral Density Shown at 12 Months
Postmenopausal women with osteoporosis had significantly greater increases in bone mineral density (BMD) of the lumbar spine and total hip after one year of treatment with FOSAMAX(R) (alendronate sodium) 70 mg once-weekly compared to women treated with Evista (raloxifene) 60 mg once-daily, according to preliminary results from the Efficacy of FOSAMAX vs. Evista Comparison Trial (EFFECT).
The study results are from the first head-to-head trial comparing raloxifene with once-weekly alendronate and were presented at the 51st Annual Meeting of the American College of Obstetricians and Gynecologists (ACOG) by Risa Kagan, M.D., co-medical director, FORE-Foundation for Osteoporosis Research and Education, Oakland, CA.
FOSAMAX is a prescription medicine from Merck & Co., Inc. and is available in a once-weekly dosing regimen for the treatment (70 mg) and prevention (35 mg) of postmenopausal osteoporosis. FOSAMAX is also available in once daily dosing for the treatment (10 mg) and prevention (5 mg) of postmenopausal osteoporosis.
The standard dosing regimen for FOSAMAX in the United States includes swallowing the tablet with six to eight ounces of plain water the first thing upon arising for the day and at least 30 minutes before the first food, beverage or medication of the day. After swallowing FOSAMAX, patients should not lie down for at least 30 minutes and not until after consuming their first food of the day.
EFFECT preliminary results
Results showed that for the primary endpoint (percent change in BMD at the lumbar spine after one year), there was more than a two-fold increase in BMD at the lumbar spine in patients receiving FOSAMAX once-weekly as compared to patients receiving Evista (4.4 percent and 1.9 percent, respectively; p less than 0.001).
FOSAMAX also significantly increased BMD at the hip (secondary endpoint) to a greater degree than Evista. Total hip BMD increased 2.0 percent for patients taking FOSAMAX versus 1.0 percent for patients on Evista at 12 months; p less than 0.001. Bone mineral density at the hip trochanter, a specific region of the hip, significantly increased 3.2 percent for patients treated with FOSAMAX versus 1.8 percent for patients on Evista at 12 months; p less than 0.001.
Significant increases in BMD with FOSAMAX at the lumbar spine and total hip were also seen at the six month data point. FOSAMAX increased BMD at the lumbar spine 3.1 percent compared to 1.7 percent for Evista at six months; p less than 0.001. Total hip BMD increased 1.3 percent for patients taking FOSAMAX versus 0.6 percent for patients on Evista at six months; p less than 0.013.
The percentage of patients either maintaining or increasing bone mineral density at the lumbar spine was 94% for FOSAMAX compared to 75% for Evista at 12 months. Also, there were greater reductions in bone turnover (the rate at which bone is lost and replaced) markers at six and 12 months with FOSAMAX than with Evista.
Preliminary safety data showed that discontinuations due to clinical adverse events were similar between the two treatment groups.
Study design
In this double-blind, randomized, one year study across 52 sites in the U.S., 456 women with osteoporosis received either FOSAMAX 70 mg once-weekly (N=223) or Evista 60 mg once-daily (N=233) and, in addition, calcium 500 mg and vitamin D 400 mg daily. All patients in the study had osteoporosis as defined by a BMD score of 2.0 standard deviations or greater below young normal mean bone mass for either the lumbar spine or total hip. BMD was measured in both groups at enrollment and again at six and 12 months of treatment. All BMD measures were validated by a quality assurance center and laboratory tests were performed by a central testing facility.
All patients were at least 40 years of age or older and at least six months postmenopausal, except for patients who were menopausal due to surgical removal of the ovaries, which required that they be at least 25 years of age. Patients with a history of breast or uterine cancer, or who used medicines that included a bisphosphonate, a parathyroid hormone (PTH), estrogen, estrogen analogues, or selective estrogen receptor modulators (SERMS) within one year of the study were excluded from enrollment.
The primary efficacy analysis was intention-to-treat. In addition to the primary endpoint (mean percentage change of BMD at the lumbar spine after one-year), the secondary endpoints included mean percentage change in BMD in the total hip and the hip trochanter. Other secondary endpoints included mean percent change in bone turnover markers (indicators of the rate of bone resorption (breakdown) and formation) and percentage of patients who maintained or increased BMD at the lumbar spine.
Important information about FOSAMAX
FOSAMAX, like other bisphosphonates, should be used with caution in people with certain stomach or digestive problems. FOSAMAX should not be used if the patient has certain disorders of the esophagus that delay emptying or if the patient is unable to stand or sit upright for at least 30 minutes. In addition, FOSAMAX should not be used in patients with severe kidney disease or low levels of calcium in their blood, in patients who are allergic to FOSAMAX or in patients who are pregnant or nursing.
Some patients may develop severe digestive reactions including irritation, inflammation or ulceration of the esophagus. The risk of severe esophageal experiences appears to be greater in patients who fail to follow dosing instructions (see prescribing information for more details). Patients who experience heartburn, difficulty or pain when swallowing or chest pain should stop taking the drug and consult their doctor.
The most commonly reported side effects with FOSAMAX have been abdominal pain, musculoskeletal pain, indigestion, regurgitation and nausea.
FOSAMAX is a medicine from Merck & Co., Inc.
Introduced in 1995 for the treatment of postmenopausal osteoporosis, FOSAMAX is also approved for: the treatment of Paget's disease of bone (40 mg once daily); the prevention of osteoporosis in postmenopausal women at risk of osteoporosis (5 mg once daily, 35 mg once weekly); the treatment of postmenopausal osteoporosis and the reduction in the incidence of hip and spine fractures in postmenopausal women who have osteoporosis (10 mg once daily, 70 mg once weekly).
In addition, FOSAMAX is approved for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density (5 mg once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is 10 mg once daily); and for the treatment to increase bone mass in men with osteoporosis (10 mg once daily; alternatively, 70 mg once weekly may be considered).
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.
FORWARD LOOKING STATEMENT:
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties which may cause results to differ materially from those set forth in the statements. The forward-looking statements include statements regarding product development and product potential. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect the company's businesses, particularly those mentioned in the cautionary statements in Item 1 of our Form 10-K for the year ended Dec. 31, 2002, and in our periodic reports on Form 10-Q and Form 8-K (if any) which we incorporate by reference.
FOSAMAX(R) (alendronate sodium) is a registered trademark of Merck & Co., Inc.
Full prescribing and patient product information for FOSAMAX (R) is attached.
7957021
FOSAMAX(R)
(ALENDRONATE SODIUM TABLETS)
DESCRIPTION
FOSAMAX(a)(alendronate sodium) is a bisphosphonate that acts as a
specific inhibitor of osteoclast-mediated bone resorption.
Bisphosphonates are synthetic analogs of pyrophosphate that bind to
the hydroxyapatite found in bone.
Alendronate sodium is chemically described as
(4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt
trihydrate.
The empirical formula of alendronate sodium is C4H12NNaO7P2o3H2O
and its formula weight is 325.12. The structural formula is:
(GRAPHIC OMITTED)
Alendronate sodium is a white, crystalline, nonhygroscopic powder.
It is soluble in water, very slightly soluble in alcohol, and
practically insoluble in chloroform.
Tablets FOSAMAX for oral administration contain 6.53, 13.05,
45.68, 52.21 or 91.37 mg of alendronate monosodium salt trihydrate,
which is the molar equivalent of 5, 10, 35, 40 and 70 mg,
respectively, of free acid, and the following inactive ingredients:
microcrystalline cellulose, anhydrous lactose, croscarmellose sodium,
and magnesium stearate. Tablets FOSAMAX 10 mg also contain carnauba
wax.
CLINICAL PHARMACOLOGY
Mechanism of Action
Animal studies have indicated the following mode of action. At the
cellular level, alendronate shows preferential localization to sites
of bone resorption, specifically under osteoclasts. The osteoclasts
adhere normally to the bone surface but lack the ruffled border that
is indicative of active resorption. Alendronate does not interfere
with osteoclast recruitment or attachment, but it does inhibit
osteoclast activity. Studies in mice on the localization of
radioactive (3H)alendronate in bone showed about 10-fold higher uptake
on osteoclast surfaces than on osteoblast surfaces. Bones examined 6
and 49 days after (3H)alendronate administration in rats and mice,
respectively, showed that normal bone was formed on top of the
alendronate, which was incorporated inside the matrix. While
incorporated in bone matrix, alendronate is not pharmacologically
active. Thus, alendronate must be continuously administered to
suppress osteoclasts on newly formed resorption surfaces.
Histomorphometry in baboons and rats showed that alendronate treatment
reduces bone turnover (i.e., the number of sites at which bone is
remodeled). In addition, bone formation exceeds bone resorption at
these remodeling sites, leading to progressive gains in bone mass.
Pharmacokinetics
Absorption
Relative to an intravenous (IV) reference dose, the mean oral
bioavailability of alendronate in women was 0.64% for doses ranging
from 5 to 70 mg when administered after an overnight fast and two
hours before a standardized breakfast. Oral bioavailability of the 10
mg tablet in men (0.59%) was similar to that in women when
administered after an overnight fast and 2 hours before breakfast.
A study examining the effect of timing of a meal on the
bioavailability of alendronate was performed in 49 postmenopausal
women. Bioavailability was decreased (by approximately 40%) when 10 mg
alendronate was administered either 0.5 or 1 hour before a
standardized breakfast, when compared to dosing 2 hours before eating.
In studies of treatment and prevention of osteoporosis, alendronate
was effective when administered at least 30 minutes before breakfast.
Bioavailability was negligible whether alendronate was
administered with or up to two hours after a standardized breakfast.
Concomitant administration of alendronate with coffee or orange juice
reduced bioavailability by approximately 60%.
Distribution
Preclinical studies (in male rats) show that alendronate
transiently distributes to soft tissues following 1 mg/kg IV
administration but is then rapidly redistributed to bone or excreted
in the urine. The mean steady-state volume of distribution, exclusive
of bone, is at least 28 L in humans. Concentrations of drug in plasma
following therapeutic oral doses are too low (less than 5 ng/mL) for
analytical detection. Protein binding in human plasma is approximately
78%.
Metabolism
There is no evidence that alendronate is metabolized in animals or
humans.
Excretion
Following a single IV dose of (14C)alendronate, approximately 50%
of the radioactivity was excreted in the urine within 72 hours and
little or no radioactivity was recovered in the feces. Following a
single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min
(64, 78; 90% confidence interval (CI)), and systemic clearance did not
exceed 200 mL/min. Plasma concentrations fell by more than 95% within
6 hours following IV administration. The terminal half-life in humans
is estimated to exceed 10 years, probably reflecting release of
alendronate from the skeleton. Based on the above, it is estimated
that after 10 years of oral treatment with 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 (less than) 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 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 (less than) 35 mL/min) due
to lack of experience with alendronate in renal failure.
Hepatic Insufficiency: As there is evidence that alendronate is
not metabolized or excreted in the bile, no studies were conducted in
patients with hepatic insufficiency. No dosage adjustment is
necessary.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Intravenous ranitidine was shown to double the bioavailability of
oral alendronate. The clinical significance of this increased
bioavailability and whether similar increases will occur in patients
given oral H2-antagonists is unknown.
In healthy subjects, oral prednisone (20 mg three times daily for
five days) did not produce a clinically meaningful change in the oral
bioavailability of alendronate (a mean increase ranging from 20 to
44%).
Products containing calcium and other multivalent cations are
likely to interfere with absorption of alendronate.
Pharmacodynamics
Alendronate is a bisphosphonate that binds to bone hydroxyapatite
and specifically inhibits the activity of osteoclasts, the
bone-resorbing cells. Alendronate reduces bone resorption with no
direct effect on bone formation, although the latter process is
ultimately reduced because bone resorption and formation are coupled
during bone turnover.
Osteoporosis in postmenopausal women
Osteoporosis is characterized by low bone mass that leads to an
increased risk of fracture. The diagnosis can be confirmed by the
finding of low bone mass, evidence of fracture on x-ray, a history of
osteoporotic fracture, or height loss or kyphosis, indicative of
vertebral (spinal) fracture. Osteoporosis occurs in both males and
females but is most common among women following the menopause, when
bone turnover increases and the rate of bone resorption exceeds that
of bone formation. These changes result in progressive bone loss and
lead to osteoporosis in a significant proportion of women over age 50.
Fractures, usually of the spine, hip, and wrist, are the common
consequences. From age 50 to age 90, the risk of hip fracture in white
women increases 50-fold and the risk of vertebral fracture 15- to
30-fold. It is estimated that approximately 40% of 50-year-old women
will sustain one or more osteoporosis-related fractures of the spine,
hip, or wrist during their remaining lifetimes. Hip fractures, in
particular, are associated with substantial morbidity, disability, and
mortality.
Daily oral doses of alendronate (5, 20, and 40 mg for six weeks)
in postmenopausal women produced biochemical changes indicative of
dose-dependent inhibition of bone resorption, including decreases in
urinary calcium and urinary markers of bone collagen degradation (such
as deoxypyridinoline and cross-linked N-telopeptides of type I
collagen). These biochemical changes tended to return toward baseline
values as early as 3 weeks following the discontinuation of therapy
with alendronate and did not differ from placebo after 7 months.
Long-term treatment of osteoporosis with FOSAMAX 10 mg/day (for up
to five years) reduced urinary excretion of markers of bone
resorption, deoxypyridinoline and cross-linked N-telopeptides of type
l collagen, by approximately 50% and 70%, respectively, to reach
levels similar to those seen in healthy premenopausal women. Similar
decreases were seen in patients in osteoporosis prevention studies who
received FOSAMAX 5 mg/day. The decrease in the rate of bone resorption
indicated by these markers was evident as early as one month and at
three to six months reached a plateau that was maintained for the
entire duration of treatment with FOSAMAX. In osteoporosis treatment
studies FOSAMAX 10 mg/day decreased the markers of bone formation,
osteocalcin and bone specific alkaline phosphatase by approximately
50%, and total serum alkaline phosphatase, by approximately 25 to 30%
to reach a plateau after 6 to 12 months. In osteoporosis prevention
studies FOSAMAX 5 mg/day decreased osteocalcin and total serum
alkaline phosphatase by approximately 40% and 15%, respectively.
Similar reductions in the rate of bone turnover were observed in
postmenopausal women during one-year studies with once weekly FOSAMAX
70 mg for the treatment of osteoporosis and once weekly FOSAMAX 35 mg
for the prevention of osteoporosis. These data indicate that the rate
of bone turnover reached a new steady-state, despite the progressive
increase in the total amount of alendronate deposited within bone.
As a result of inhibition of bone resorption, asymptomatic
reductions in serum calcium and phosphate concentrations were also
observed following treatment with FOSAMAX. In the long-term studies,
reductions from baseline in serum calcium (approximately 2%) and
phosphate (approximately 4 to 6%) were evident the first month after
the initiation of FOSAMAX 10 mg. No further decreases in serum calcium
were observed for the five-year duration of treatment, however, serum
phosphate returned toward prestudy levels during years three through
five. Similar reductions were observed with FOSAMAX 5 mg/day. In
one-year studies with once weekly FOSAMAX 35 and 70 mg, similar
reductions were observed at 6 and 12 months. The reduction in serum
phosphate may reflect not only the positive bone mineral balance due
to FOSAMAX but also a decrease in renal phosphate reabsorption.
Osteoporosis in men
Treatment of men with osteoporosis with FOSAMAX 10 mg/day for two
years reduced urinary excretion of cross-linked N-telopeptides of type
I collagen by approximately 60% and bone-specific alkaline phosphatase
by approximately 40%.
Glucocorticoid-induced Osteoporosis
Sustained use of glucocorticoids is commonly associated with
development of osteoporosis and resulting fractures (especially
vertebral, hip, and rib). It occurs both in males and females of all
ages. Osteoporosis occurs as a result of inhibited bone formation and
increased bone resorption resulting in net bone loss. Alendronate
decreases bone resorption without directly inhibiting bone formation.
In clinical studies of up to two years' duration, FOSAMAX 5 and 10
mg/day reduced cross-linked N-telopeptides of type I collagen (a
marker of bone resorption) by approximately 60% and reduced
bone-specific alkaline phosphatase and total serum alkaline
phosphatase (markers of bone formation) by approximately 15 to 30% and
8 to 18%, respectively. As a result of inhibition of bone resorption,
FOSAMAX 5 and 10 mg/day induced asymptomatic decreases in serum
calcium (approximately 1 to 2%) and serum phosphate (approximately 1
to 8%).
Paget's disease of bone
Paget's disease of bone is a chronic, focal skeletal disorder
characterized by greatly increased and disorderly bone remodeling.
Excessive osteoclastic bone resorption is followed by osteoblastic new
bone formation, leading to the replacement of the normal bone
architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms
to severe morbidity due to bone pain, bone deformity, pathological
fractures, and neurological and other complications. Serum alkaline
phosphatase, the most frequently used biochemical index of disease
activity, provides an objective measure of disease severity and
response to therapy.
FOSAMAX decreases the rate of bone resorption directly, which
leads to an indirect decrease in bone formation. In clinical trials,
FOSAMAX 40 mg once daily for six months produced significant decreases
in serum alkaline phosphatase as well as in urinary markers of bone
collagen degradation. As a result of the inhibition of bone
resorption, FOSAMAX induced generally mild, transient, and
asymptomatic decreases in serum calcium and phosphate.
Clinical Studies
Treatment of osteoporosis
Postmenopausal women
Effect on bone mineral density
The efficacy of FOSAMAX 10 mg once daily in postmenopausal women,
44 to 84 years of age, with osteoporosis (lumbar spine bone mineral
density (BMD) of at least 2 standard deviations below the
premenopausal mean) was demonstrated in four double-blind,
placebo-controlled clinical studies of two or three years' duration.
These included two three-year, multicenter studies of virtually
identical design, one performed in the United States (U.S.) and the
other in 15 different countries (Multinational), which enrolled 478
and 516 patients, respectively. The following graph shows the mean
increases in BMD of the lumbar spine, femoral neck, and trochanter in
patients receiving FOSAMAX 10 mg/day relative to placebo-treated
patients at three years for each of these studies.
(GRAPHIC OMITTED)
At three years significant increases in BMD, relative both to
baseline and placebo, were seen at each measurement site in each study
in patients who received FOSAMAX 10 mg/day. Total body BMD also
increased significantly in each study, suggesting that the increases
in bone mass of the spine and hip did not occur at the expense of
other skeletal sites. Increases in BMD were evident as early as three
months and continued throughout the three years of treatment. (See
figures below for lumbar spine results.) In the two-year extension of
these studies, treatment of 147 patients with FOSAMAX 10 mg/day
resulted in continued increases in BMD at the lumbar spine and
trochanter (absolute additional increases between years 3 and 5:
lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck,
forearm and total body were maintained. FOSAMAX was similarly
effective regardless of age, race, baseline rate of bone turnover, and
baseline BMD in the range studied (at least 2 standard deviations
below the premenopausal mean). Thus, overall FOSAMAX reverses the loss
of bone mineral density, a central factor in the progression of
osteoporosis.
(GRAPHIC OMITTED)
In patients with postmenopausal osteoporosis treated with FOSAMAX
10 mg/day for one or two years, the effects of treatment withdrawal
were assessed. Following discontinuation, there were no further
increases in bone mass and the rates of bone loss were similar to
those of the placebo groups. These data indicate that continued
treatment with FOSAMAX is required to maintain the effect of the drug.
The therapeutic equivalence of once weekly FOSAMAX 70 mg (n=519)
and FOSAMAX 10 mg daily (n=370) was demonstrated in a one-year,
double-blind, multicenter study of postmenopausal women with
osteoporosis. In the primary analysis of completers, the mean
increases from baseline in lumbar spine BMD at one year were 5.1%
(4.8, 5.4%; 95% CI) in the 70-mg once-weekly group (n=440) and 5.4%
(5.0, 5.8%; 95% CI) in the 10-mg daily group (n=330). The two
treatment groups were also similar with regard to BMD increases at
other skeletal sites. The results of the intention-to-treat analysis
were consistent with the primary analysis of completers.
Effect on fracture incidence
Data on the effects of FOSAMAX on fracture incidence are derived
from three clinical studies: 1) U.S. and Multinational combined: a
study of patients with a BMD T-score at or below minus 2.5 with or
without a prior vertebral fracture, 2) Three-Year Study of the
Fracture Intervention Trial (FIT): a study of patients with at least
one baseline vertebral fracture, and 3) Four-Year Study of FIT: a
study of patients with low bone mass but without a baseline vertebral
fracture.
To assess the effects of FOSAMAX on the incidence of vertebral
fractures (detected by digitized radiography; approximately one third
of these were clinically symptomatic), the U.S. and Multinational
studies were combined in an analysis that compared placebo to the
pooled dosage groups of FOSAMAX (5 or 10 mg for three years or 20 mg
for two years followed by 5 mg for one year). There was a
statistically significant reduction in the proportion of patients
treated with FOSAMAX experiencing one or more new vertebral fractures
relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative
risk reduction). A reduction in the total number of new vertebral
fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the
pooled analysis, patients who received FOSAMAX had a loss in stature
that was statistically significantly less than was observed in those
who received placebo (-3.0 mm vs. -4.6 mm).
The Fracture Intervention Trial (FIT) consisted of two studies in
postmenopausal women: the Three-Year Study of patients who had at
least one baseline radiographic vertebral fracture and the Four-Year
Study of patients with low bone mass but without a baseline vertebral
fracture. In both studies of FIT, 96% of randomized patients completed
the studies (i.e. had a closeout visit at the scheduled end of the
study); approximately 80% of patients were still taking study
medication upon completion.
Fracture Intervention Trial: Three-Year Study (patients with at
least one baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 2027-patient
study (FOSAMAX, n=1022; placebo, n=1005) demonstrated that treatment
with FOSAMAX resulted in statistically significant reductions in
fracture incidence at three years as shown in the table below.
----------------------------------------------------------------------
Effect of FOSAMAX on Fracture Incidence in the Three-Year
Study of FIT
(patients with vertebral fracture at baseline)
----------------------------------------------------------------------
Percent of Patients
Absolute Relative
Reduction Reduction
FOSAMAX Placebo in in
(n=1022) (n=1005) Fracture Fracture
Incidence Risk %
------------------------ ---------- --------- ---------- ---------
Patients with:
Vertebral fractures
(diagnosed by X-ray)(a)
(greater than or
equal to) 1 new
vertebral fracture 7.9 15.0 7.1 47(d)
(greater than or
equal to) 2 new
vertebral fractures 0.5 4.9 4.4 90(d)
Clinical (symptomatic)
fractures
Any clinical
(symptomatic)
fracture 13.8 18.1 4.3 26(e)
(greater than or
equal to) 1
clinical (symptomatic)
vertebral fracture 2.3 5.0 2.7 54(c)
Hip fracture 1.1 2.2 1.1 51(b)
Wrist (forearm) fracture 2.2 4.1 1.9 48(b)
------------------------ ---------- --------- ---------- ---------
(a) Number evaluable for vertebral fractures: FOSAMAX, n=984; placebo,
n=966
(b) p(less than)0.05
(c) p(less than)0.01
(d) p(less than)0.001
(e) p=0.007
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.
(GRAPHIC OMITTED)
Fracture Intervention Trial: Four-Year Study (patients with low
bone mass but without a baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 4432-patient
study (FOSAMAX, n=2214; placebo, n=2218) further investigated the
reduction in fracture incidence due to FOSAMAX. The intent of the
study was to recruit women with osteoporosis, defined as a baseline
femoral neck BMD at least two standard deviations below the mean for
young adult women. However, due to subsequent revisions to the
normative values for femoral neck BMD, 31% of patients were found not
to meet this entry criterion and thus this study included both
osteoporotic and non-osteoporotic women. The results are shown in the
table below for the patients with osteoporosis.
----------------------------------------------------------------------
Effect of FOSAMAX on Fracture Incidence in Osteoporotic(a)
Patients in the Four-Year
Study of FIT
(patients without vertebral fracture at baseline)
----------------------------------------------------------------------
Percent of Patients
Absolute Relative
Reduction Reduction
FOSAMAX Placebo in in
(n=1545) (n=1521) Fracture Fracture
Incidence Risk (%)
------------------------ ---------- --------- ---------- -----------
Patients with:
Vertebral fractures
(diagnosed by X-ray)(b)
(greater than or
equal to) 1 new
vertebral fracture 2.5 4.8 2.3 48(f)
(greater than or
equal to) 2 new
vertebral fractures 0.1 0.6 0.5 78(d)
Clinical (symptomatic)
fractures
Any clinical
(symptomatic) fracture 12.9 16.2 3.3 22(e)
(greater than or
equal to) 1 clinical
(symptomatic)
vertebral fracture 1.0 1.6 0.6 41(NS)(c)
Hip fracture 1.0 1.4 0.4 29(NS)(c)
Wrist (forearm) fracture 3.9 3.8 -0.1 NS(c)
------------------------ ---------- --------- ---------- -----------
(a) Baseline femoral neck BMD at least 2 SD below the mean for young
adult women
(b) Number evaluable for vertebral fractures: FOSAMAX, n=1426;
placebo, n=1428
(c) Not significant. This study was not powered to detect differences
at these sites.
(d) p=0.035
(e) p=0.01
(f) p(less than)0.001
Fracture results across studies
In the Three-Year Study of FIT, FOSAMAX reduced the percentage of
women experiencing at least one new radiographic vertebral fracture
from 15.0% to 7.9% (47% relative risk reduction, p(less than)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(less than)0.001) in the combined U.S./Multinational
studies and from 4.9% to 0.5% (90% relative risk reduction, p(less
than)0.001) in the Three-Year Study of FIT. In the Four-Year Study of
FIT, FOSAMAX reduced the percentage of osteoporotic women experiencing
multiple vertebral fractures from 0.6% to 0.1% (78% relative risk
reduction, p=0.035).
Thus, FOSAMAX reduced the incidence of radiographic vertebral
fractures in osteoporotic women whether or not they had a previous
radiographic vertebral fracture.
FOSAMAX, over a three- or four-year period, was associated with
statistically significant reductions in loss of height vs. placebo in
patients with and without baseline radiographic vertebral fractures.
At the end of the FIT studies the between-treatment group differences
were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
Bone histology
Bone histology in 270 postmenopausal patients with osteoporosis
treated with FOSAMAX at doses ranging from 1 to 20 mg/day for one,
two, or three years revealed normal mineralization and structure, as
well as the expected decrease in bone turnover relative to placebo.
These data, together with the normal bone histology and increased bone
strength observed in rats and baboons exposed to long-term alendronate
treatment, support the conclusion that bone formed during therapy with
FOSAMAX is of normal quality.
Men
The efficacy of FOSAMAX 10 mg once daily in men with osteoporosis
was demonstrated in a two-year, double-blind, placebo-controlled,
multicenter study, which enrolled a total of 241 men between the ages
of 31 and 87 (mean, 63). All patients in the trial had either: 1) a
BMD T-score (less than or equal to) -2 at the femoral neck and (less
than or equal to) -1 at the lumbar spine, or 2) a baseline
osteoporotic fracture and a BMD T-score (less than or equal to) -1 at
the femoral neck. At two years, the mean increases relative to placebo
in BMD in men receiving FOSAMAX 10 mg/day were significant at the
following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter,
3.1%; and total body, 1.6%. BMD responses were similar regardless of
age ((greater than or equal to) 65 years vs. (less than) 65 years),
gonadal function (baseline testosterone (less than) 9 ng/dL vs.
(greater than or equal to) 9 ng/dL), or baseline BMD (femoral neck and
lumbar spine T-score (less than or equal to) -2.5 vs. (greater than)
-2.5). Treatment with FOSAMAX also reduced height loss (FOSAMAX, -0.6
mm vs. placebo, -2.4 mm).
The safety and efficacy of once weekly FOSAMAX 70 mg in men with
osteoporosis are currently being studied, but data are not yet
available.
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.
(GRAPHIC OMITTED)
The therapeutic equivalence of once weekly FOSAMAX 35 mg (n=362)
and FOSAMAX 5 mg daily (n=361) was demonstrated in a one-year,
double-blind, multicenter study of postmenopausal women without
osteoporosis. In the primary analysis of completers, the mean
increases from baseline in lumbar spine BMD at one year were 2.9%
(2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2%
(2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment
groups were also similar with regard to BMD increases at other
skeletal sites. The results of the intention-to-treat analysis were
consistent with the primary analysis of completers.
Bone histology
Bone histology was normal in the 28 patients biopsied at the end
of three years who received FOSAMAX at doses of up to 10 mg/day.
Concomitant use with estrogen/hormone replacement therapy (HRT)
The effects on BMD of treatment with FOSAMAX 10 mg once daily and
conjugated estrogen (0.625 mg/day) either alone or in combination were
assessed in a two-year, double-blind, placebo-controlled study of
hysterectomized postmenopausal osteoporotic women (n=425). At two
years, the increases in lumbar spine BMD from baseline were
significantly greater with the combination (8.3%) than with either
estrogen or FOSAMAX alone (both 6.0%).
The effects on BMD when FOSAMAX was added to stable doses (for at
least one year) of HRT (estrogen +/- progestin) were assessed in a
one-year, double-blind, placebo-controlled study in postmenopausal
osteoporotic women (n=428). The addition of FOSAMAX 10 mg once daily
to HRT produced, at one year, significantly greater increases in
lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
In these studies, significant increases or favorable trends in BMD
for combined therapy compared with HRT alone were seen at the total
hip, femoral neck, and trochanter. No significant effect was seen for
total body BMD.
Histomorphometric studies of transiliac biopsies in 92 subjects
showed normal bone architecture. Compared to placebo there was a 98%
suppression of bone turnover (as assessed by mineralizing surface)
after 18 months of combined treatment with FOSAMAX and HRT, 94% on
FOSAMAX alone, and 78% on HRT alone. The long-term effects of combined
FOSAMAX and HRT on fracture occurrence and fracture healing have not
been studied.
Glucocorticoid-induced osteoporosis
The efficacy of FOSAMAX 5 and 10 mg once daily in men and women
receiving glucocorticoids (at least 7.5 mg/day of prednisone or
equivalent) was demonstrated in two, one-year, double-blind,
randomized, placebo-controlled, multicenter studies of virtually
identical design, one performed in the United States and the other in
15 different countries (Multinational (which also included FOSAMAX 2.5
mg/day)). These studies enrolled 232 and 328 patients, respectively,
between the ages of 17 and 83 with a variety of
glucocorticoid-requiring diseases. Patients received supplemental
calcium and vitamin D. The following figure shows the mean increases
relative to placebo in BMD of the lumbar spine, femoral neck, and
trochanter in patients receiving FOSAMAX 5 mg/day for each study.
(GRAPHIC OMITTED)
After one year, significant increases relative to placebo in BMD
were seen in the combined studies at each of these sites in patients
who received FOSAMAX 5 mg/day. In the placebo-treated patients, a
significant decrease in BMD occurred at the femoral neck (-1.2%), and
smaller decreases were seen at the lumbar spine and trochanter. Total
body BMD was maintained with FOSAMAX 5 mg/day. The increases in BMD
with FOSAMAX 10 mg/day were similar to those with FOSAMAX 5 mg/day in
all patients except for postmenopausal women not receiving estrogen
therapy. In these women, the increases (relative to placebo) with
FOSAMAX 10 mg/day were greater than those with FOSAMAX 5 mg/day at the
lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not
at other sites. FOSAMAX was effective regardless of dose or duration
of glucocorticoid use. In addition, FOSAMAX was similarly effective
regardless of age ((less than) 65 vs. (greater than or equal to) 65
years), race (Caucasian vs. other races), gender, underlying disease,
baseline BMD, baseline bone turnover, and use with a variety of common
medications.
Bone histology was normal in the 49 patients biopsied at the end
of one year who received FOSAMAX at doses of up to 10 mg/day.
Of the original 560 patients in these studies, 208 patients who
remained on at least 7.5 mg/day of prednisone or equivalent continued
into a one-year double-blind extension. After two years of treatment,
spine BMD increased by 3.7% and 5.0% relative to placebo with FOSAMAX
5 and 10 mg/day, respectively. Significant increases in BMD (relative
to placebo) were also observed at the femoral neck, trochanter, and
total body.
After one year, 2.3% of patients treated with FOSAMAX 5 or 10
mg/day (pooled) vs. 3.7% of those treated with placebo experienced a
new vertebral fracture (not significant). However, in the population
studied for two years, treatment with FOSAMAX (pooled dosage groups: 5
or 10 mg for two years or 2.5 mg for one year followed by 10 mg for
one year) significantly reduced the incidence of patients with a new
vertebral fracture (FOSAMAX 0.7% vs. placebo 6.8%).
Paget's disease of bone
The efficacy of FOSAMAX 40 mg once daily for six months was
demonstrated in two double-blind clinical studies of male and female
patients with moderate to severe Paget's disease (alkaline phosphatase
at least twice the upper limit of normal): a placebo-controlled,
multinational study and a U.S. comparative study with etidronate
disodium 400 mg/day. The following figure shows the mean percent
changes from baseline in serum alkaline phosphatase for up to six
months of randomized treatment.
(GRAPHIC OMITTED)
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 (greater than or
equal to) 60%) occurred in approximately 85% of patients treated with
FOSAMAX in the combined studies vs. 30% in the etidronate group and 0%
in the placebo group. FOSAMAX was similarly effective regardless of
age, gender, race, prior use of other bisphosphonates, or baseline
alkaline phosphatase within the range studied (at least twice the
upper limit of normal).
Bone histology was evaluated in 33 patients with Paget's disease
treated with FOSAMAX 40 mg/day for 6 months. As in patients treated
for osteoporosis (see Clinical Studies, Treatment of osteoporosis in
postmenopausal women, Bone histology), FOSAMAX did not impair
mineralization, and the expected decrease in the rate of bone turnover
was observed. Normal lamellar bone was produced during treatment with
FOSAMAX, even where preexisting bone was woven and disorganized.
Overall, bone histology data support the conclusion that bone formed
during treatment with FOSAMAX is of normal quality.
ANIMAL PHARMACOLOGY
The relative inhibitory activities on bone resorption and
mineralization of alendronate and etidronate were compared in the
Schenk assay, which is based on histological examination of the
epiphyses of growing rats. In this assay, the lowest dose of
alendronate that interfered with bone mineralization (leading to
osteomalacia) was 6000-fold the antiresorptive dose. The corresponding
ratio for etidronate was one to one. These data suggest that
alendronate administered in therapeutic doses is highly unlikely to
induce osteomalacia.
INDICATIONS AND USAGE
FOSAMAX is indicated for:
-- Treatment and prevention of osteoporosis in postmenopausal
women
-- For the treatment of osteoporosis, FOSAMAX increases bone
mass and reduces the incidence of fractures, including
those of the hip and spine (vertebral compression
fractures). Osteoporosis may be confirmed by the finding
of low bone mass (for example, at least 2 standard
deviations below the premenopausal mean) or by the
presence or history of osteoporotic fracture. (See
CLINICAL PHARMACOLOGY, Pharmacodynamics.)
-- For the prevention of osteoporosis, FOSAMAX may be
considered in postmenopausal women who are at risk of
developing osteoporosis and for whom the desired clinical
outcome is to maintain bone mass and to reduce the risk of
future fracture.
-- Bone loss is particularly rapid in postmenopausal women
younger than age 60. Risk factors often associated with
the development of postmenopausal osteoporosis include
early menopause; moderately low bone mass (for example, at
least 1 standard deviation below the mean for healthy
young adult women); thin body build; Caucasian or Asian
race; and family history of osteoporosis. The presence of
such risk factors may be important when considering the
use of FOSAMAX for prevention of osteoporosis.
-- Treatment to increase bone mass in men with osteoporosis
-- Treatment of glucocorticoid-induced osteoporosis in men and
women receiving glucocorticoids in a daily dosage equivalent
to 7.5 mg or greater of prednisone and who have low bone
mineral density (see PRECAUTIONS, Glucocorticoid-induced
osteoporosis). Patients treated with glucocorticoids should
receive adequate amounts of calcium and vitamin D.
-- Treatment of Paget's disease of bone in men and women
-- Treatment is indicated in patients with Paget's disease of
bone having alkaline phosphatase at least two times the
upper limit of normal, or those who are symptomatic, or
those at risk for future complications from their disease.
CONTRAINDICATIONS
-- Abnormalities of the esophagus which delay esophageal emptying
such as stricture or achalasia
-- Inability to stand or sit upright for at least 30 minutes
-- Hypersensitivity to any component of this product
-- Hypocalcemia (see PRECAUTIONS, General)
WARNINGS
FOSAMAX, like other bisphosphonates, may cause local irritation of
the upper gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal
ulcers and esophageal erosions, occasionally with bleeding and rarely
followed by esophageal stricture or perforation, have been reported in
patients receiving treatment with FOSAMAX. In some cases these have
been severe and required hospitalization. Physicians should therefore
be alert to any signs or symptoms signaling a possible esophageal
reaction and patients should be instructed to discontinue FOSAMAX and
seek medical attention if they develop dysphagia, odynophagia,
retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be
greater in patients who lie down after taking FOSAMAX and/or who fail
to swallow it with 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).
There have been post-marketing reports of gastric and duodenal
ulcers, some severe and with complications, although no increased risk
was observed in controlled clinical trials.
PRECAUTIONS
General
Causes of osteoporosis other than estrogen deficiency, aging, and
glucocorticoid use should be considered.
Hypocalcemia must be corrected before initiating therapy with
FOSAMAX (see CONTRAINDICATIONS). Other 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 and in
patients receiving glucocorticoids, in whom calcium absorption may be
decreased.
Ensuring adequate calcium and vitamin D intake is especially
important in patients with Paget's disease of bone and in patients
receiving glucocorticoids.
Renal insufficiency
FOSAMAX is not recommended for patients with renal insufficiency
(creatinine clearance (less than) 35 mL/min). (See DOSAGE AND
ADMINISTRATION.)
Glucocorticoid-induced osteoporosis
The risk versus benefit of FOSAMAX for treatment at daily dosages
of glucocorticoids less than 7.5 mg of prednisone or equivalent has
not been established (see INDICATIONS AND USAGE). Before initiating
treatment, the hormonal status of both men and women should be
ascertained and appropriate replacement considered.
A bone mineral density measurement should be made at the
initiation of therapy and repeated after 6 to 12 months of combined
FOSAMAX and glucocorticoid treatment.
The efficacy of FOSAMAX for the treatment of
glucocorticoid-induced osteoporosis has been shown in patients with a
median bone mineral density which was 1.2 standard deviations below
the mean for healthy young adults.
The efficacy of FOSAMAX has been established in studies of two
years' duration. The greatest increase in bone mineral density
occurred in the first year with maintenance or smaller gains during
the second year. Efficacy of FOSAMAX beyond two years has not been
studied.
The efficacy of FOSAMAX in respect to fracture prevention has been
demonstrated for vertebral fractures. However, this finding was based
on very few fractures that occurred primarily in postmenopausal women.
The efficacy for prevention of non-vertebral fractures has not been
demonstrated.
Information for Patients
General
Physicians should instruct their patients to read the patient
package insert before starting therapy with FOSAMAX and to reread it
each time the prescription is renewed.
Patients should be instructed to take supplemental calcium and
vitamin D, if daily dietary intake is inadequate. Weight-bearing
exercise should be considered along with the modification of certain
behavioral factors, such as cigarette smoking and/or excessive alcohol
consumption, if these factors exist.
Dosing Instructions
Patients should be instructed that the expected benefits of
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 that if they miss a dose of once
weekly FOSAMAX, 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.
Drug Interactions (also see CLINICAL PHARMACOLOGY,
Pharmacokinetics, Drug Interactions)
Estrogen/hormone replacement therapy (HRT)
Concomitant use of HRT (estrogen +/- progestin) and FOSAMAX was
assessed in two clinical studies 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 and HRT on fracture occurrence
have not been studied (see CLINICAL PHARMACOLOGY, Clinical Studies,
Concomitant use with estrogen/hormone replacement therapy (HRT) and
ADVERSE REACTIONS, Clinical Studies, Concomitant use with
estrogen/hormone replacement therapy).
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 oral medications.
Aspirin
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.
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/day 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 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, mg/m2. The
relevance of this finding to humans is unknown.
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 and 1
times a 40 mg human daily dose based on surface area, mg/m2. The
relevance of this finding to humans is unknown.
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 gave equivocal
results.
Alendronate had no effect on fertility (male or female) in rats at
oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based
on surface area, mg/m2).
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 0.26 times (1 mg/kg) to
2.6 times (10 mg/kg) a maximum recommended daily dose of 40 mg
(Paget's disease) 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 (10.3 times a 40 mg human daily dose based on surface area,
mg/m2).
Both total and ionized calcium decreased in pregnant rats at 15
mg/kg/day (3.9 times a 40 mg human daily dose based on surface area,
mg/m2) 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 (0.13 times a 40 mg human daily dose based on
surface area, mg/m2) 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.
Geriatric Use
Of the patients receiving FOSAMAX in the Fracture Intervention
Trial (FIT), 71% (n=2302) were (greater than or equal to) 65 years of
age and 17% (n=550) were (greater than or equal to) 75 years of age.
Of the patients receiving FOSAMAX in the United States and
Multinational osteoporosis treatment studies in women, the
osteoporosis study in men, glucocorticoid-induced osteoporosis
studies, and Paget's disease studies (see CLINICAL PHARMACOLOGY,
Clinical Studies), 45%, 50%, 37%, 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.
ADVERSE REACTIONS
Clinical Studies
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.
Treatment of osteoporosis
Postmenopausal women
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 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 related
in (greater than or equal to) 1% of patients treated with either
FOSAMAX or placebo are presented in the following table.
----------------------------------------------------------------------
Osteoporosis Treatment Studies in Postmenopausal Women
Adverse Experiences Considered Possibly, Probably,
or Definitely Drug Related by the Investigators and
Reported in (greater than or equal to) 1% of Patients
----------------------------------------------------------------------
United States/ Fracture Intervention
Multinational Studies Trial
------------------------------ -----------------------
FOSAMAX(a) Placebo FOSAMAX(b) Placebo
% % % %
(n=196) (n=397) (n=3236) (n=3223)
------------------------------ -----------------------
Gastrointestinal
abdominal pain 6.6 4.8 1.5 1.5
nausea 3.6 4.0 1.1 1.5
dyspepsia 3.6 3.5 1.1 1.2
constipation 3.1 1.8 0.0 0.2
diarrhea 3.1 1.8 0.6 0.3
flatulence 2.6 0.5 0.2 0.3
acid regurgitation 2.0 4.3 1.1 0.9
esophageal ulcer 1.5 0.0 0.1 0.1
vomiting 1.0 1.5 0.2 0.3
dysphagia 1.0 0.0 0.1 0.1
abdominal
distention 1.0 0.8 0.0 0.0
gastritis 0.5 1.3 0.6 0.7
Musculoskeletal
musculoskeletal
(bone, muscle
or joint) pain 4.1 2.5 0.4 0.3
muscle cramp 0.0 1.0 0.2 0.1
Nervous System/
Psychiatric
headache 2.6 1.5 0.2 0.2
dizziness 0.0 1.0 0.0 0.1
Special Senses
taste perversion 0.5 1.0 0.1 0.0
----------------------------------------------------------------------
(a) 10 mg/day for three years
(b) 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 by the
investigators as possibly, probably, or definitely drug related in
(greater than or equal to) 1% of patients in either treatment group
are presented in the following table.
----------------------------------------------------------------------
Osteoporosis Treatment Studies in Postmenopausal Women
Adverse Experiences Considered Possibly, Probably,
or Definitely Drug Related by the Investigators
and Reported in (greater than or equal to) 1% of Patients
----------------------------------------------------------------------
Once Weekly FOSAMAX FOSAMAX
70 mg 10 mg/day
% %
(n=519) (n=370)
---------------------------- ---------------------
Gastrointestinal
abdominal pain 3.7 3.0
dyspepsia 2.7 2.2
acid regurgitation 1.9 2.4
nausea 1.9 2.4
abdominal distention 1.0 1.4
constipation 0.8 1.6
flatulence 0.4 1.6
gastritis 0.2 1.1
gastric ulcer 0.0 1.1
Musculoskeletal
musculoskeletal (bone,
muscle, joint) pain 2.9 3.2
muscle cramp 0.2 1.1
----------------------------------------------------------------------
Men
In a two-year, placebo-controlled, double-blind, multicenter
study, discontinuation of therapy due to any clinical adverse
experience occurred in 2.7% of men treated with FOSAMAX 10 mg/day and
10.5% of men treated with placebo. The adverse experiences considered
by the investigators as possibly, probably, or definitely drug related
in (greater than or equal to) 2% of patients treated with either
FOSAMAX 10 mg/day or placebo are presented in the following table.
----------------------------------------------------------------------
Osteoporosis Study in Men
Adverse Experiences Considered Possibly, Probably, or
Definitely Drug Related by the Investigators and
Reported in (greater than or equal to) 2% of Patients
----------------------------------------------------------------------
FOSAMAX Placebo
10 mg/day
% %
(n=146) (n=95)
------- ------
Gastrointestinal
acid regurgitation 4.1 3.2
flatulence 4.1 1.1
dyspepsia 3.4 0.0
abdominal pain 2.1 1.1
nausea 2.1 0.0
----------------------------------------------------------------------
Prevention of osteoporosis in postmenopausal women
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.
The adverse experiences from these studies considered by the
investigators as possibly, probably, or definitely drug related in
(greater than or equal to) 1% of patients treated with either once
weekly FOSAMAX 35 mg, 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
Reported in (greater than or equal to) 1% of Patients
----------------------------------------------------------------------
Two/Three-Year Studies One-Year Study
---------------------- --------------
Once Weekly
FOSAMAX Placebo FOSAMAX FOSAMAX
5 mg/day 5 mg/day 35 mg
% % % %
(n=642) (n=648) (n=361) (n=362)
------- ------- ------- -------
Gastrointestinal
dyspepsia 1.9 1.4 2.2 1.7
abdominal pain 1.7 3.4 4.2 2.2
acid regurgitation 1.4 2.5 4.2 4.7
nausea 1.4 1.4 2.5 1.4
diarrhea 1.1 1.7 1.1 0.6
constipation 0.9 0.5 1.7 0.3
abdominal distension 0.2 0.3 1.4 1.1
Musculoskeletal
musculoskeletal
(bone, muscle or
joint) pain 0.8 0.9 1.9 2.2
----------------------------------------------------------------------
Concomitant use with estrogen/hormone replacement therapy
In two studies (of one and two years' duration) of postmenopausal
osteoporotic women (total: n=853), the safety and tolerability profile
of combined treatment with FOSAMAX 10 mg once daily and estrogen +/-
progestin (n=354) was consistent with those of the individual
treatments.
Treatment of glucocorticoid-induced osteoporosis
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, probably, or definitely
drug related in (greater than or equal to) 1% of patients treated with
either FOSAMAX 5 or 10 mg/day or 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
Reported in (greater than or equal to) 1% of Patients
----------------------------------------------------------------------
FOSAMAX FOSAMAX Placebo
10 mg/day 5 mg/day
% % %
(n=157) (n=161) (n=159)
------- ------- -------
Gastrointestinal
abdominal pain 3.2 1.9 0.0
acid regurgitation 2.5 1.9 1.3
constipation 1.3 0.6 0.0
melena 1.3 0.0 0.0
nausea 0.6 1.2 0.6
diarrhea 0.0 0.0 1.3
Nervous System/Psychiatric
headache 0.6 0.0 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.
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 considered 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
(less than) 8.0 mg/dL (2.0 mM) and serum phosphate to (less than or
equal 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. As with other bisphosphonates, transient
symptoms as in an acute-phase response (myalgia, malaise and rarely,
fever) have been reported with FOSAMAX, typically in association with
initiation of treatment.
Gastrointestinal: esophagitis, esophageal erosions, esophageal
ulcers, rarely esophageal stricture or perforation, and oropharyngeal
ulceration. Gastric or duodenal ulcers, some severe and with
complications have also been reported (see WARNINGS, PRECAUTIONS,
Information for Patients, and DOSAGE AND ADMINISTRATION).
Skin: rash (occasionally with photosensitivity), pruritus.
Special Senses: rarely uveitis, rarely scleritis.
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.
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,
PRECAUTIONS, Information for Patients).
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 (less than) 35 mL/min) due
to lack of experience.
Treatment of osteoporosis in postmenopausal women (see INDICATIONS
AND USAGE)
The recommended dosage is:
-- one 70 mg tablet once weekly
or
-- one 10 mg tablet once daily
Treatment to increase bone mass in men with osteoporosis
The recommended dosage is one 10 mg tablet once daily.
Alternatively, one 70 mg tablet once weekly may be considered.
Prevention of osteoporosis in postmenopausal women (see
INDICATIONS AND USAGE)
The recommended dosage is:
-- one 35 mg tablet once weekly
or
-- one 5 mg tablet once daily
The safety of treatment and prevention of osteoporosis with
FOSAMAX has been studied for up to 7 years.
Treatment of glucocorticoid-induced osteoporosis in men and women
The recommended dosage is one 5 mg tablet once daily, except for
postmenopausal women not receiving estrogen, for whom the recommended
dosage is one 10 mg tablet once daily.
Paget's disease of bone in men and women
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.
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. 3797 -- Tablets FOSAMAX, 10 mg, are white, oval, wax-polished
tablets with code MRK on one side and 936 on the other. They are
supplied as follows:
NDC 0006-0936-31 unit-of-use bottles of 30
NDC 0006-0936-58 unit-of-use bottles of 100
NDC 0006-0936-28 unit dose packages of 100
NDC 0006-0936-82 bottles of 1,000
NDC 0006-0936-72 carton of 25 UNIBLISTER(TM) cards of 31 tablets
each.
No. 3813 -- Tablets FOSAMAX, 35 mg, are white, oval, uncoated
tablets with code 77 on one side and a bone image on the other. They
are supplied as follows:
NDC 0006-0077-44 unit-of-use blister package of 4
NDC 0006-0077-21 unit dose packages of 20.
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.
No. 3814 -- Tablets FOSAMAX, 70 mg, are white, oval, uncoated
tablets with code 31 on one side and an outline of a bone image on the
other. They are supplied as follows:
NDC 0006-0031-44 unit-of-use blister package of 4
NDC 0006-0031-21 unit dose packages of 20.
Storage
Store in a well-closed container at room temperature, 15-30
(degrees)C (59-86 (degrees)F).
----------------------------------------------------------------------
Issued January 2003
Printed in USA
(a) Registered trademark of MERCK & CO., Inc.
COPYRIGHT(c)MERCK & CO., Inc., 1995, 1997, 2000
All rights reserved.
Once Weekly FOSAMAX(R) (Alendronate Sodium Tablets)
Patient Information about
Once Weekly FOSAMAX(R) (FOSS-ah-max) for Osteoporosis
Generic name: alendronate sodium (a-LEN-dro-nate)
Please read this information before you start taking once weekly FOSAMAX(a). Also, read the leaflet each time you renew your prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss FOSAMAX when you start taking your medication and at regular checkups.
How should I take once weekly FOSAMAX?
These are the important things you must do to help make sure you will benefit from FOSAMAX:
1. Choose the day of the week that best fits your schedule. Every
week, take one FOSAMAX tablet on your chosen day.
2. After getting up for the day and before taking your first food,
beverage, or other medication, swallow your FOSAMAX tablet with
a full glass (6-8 oz) of plain water only.
Not mineral water
Not coffee or tea
Not juice
Do not chew or suck on a tablet of FOSAMAX.
3. After swallowing your FOSAMAX tablet do not lie down - stay
fully upright (sitting, standing or walking) for at least 30
minutes and do not lie down until after your first food of the
day. This will help the FOSAMAX tablet reach your stomach
quickly and help reduce the potential for irritation of your
esophagus (the tube that connects your mouth with your
stomach).
4. After swallowing your FOSAMAX tablet, wait at least 30 minutes
before taking your first food, beverage, or other medication of
the day, including antacids, calcium supplements and vitamins.
FOSAMAX is effective only if taken when your stomach is empty.
5. Do not take FOSAMAX at bedtime or before getting up for the
day.
6. If you have difficulty or pain upon swallowing, chest pain, or
new or worsening heartburn, stop taking FOSAMAX and call your
doctor.
7. If you miss a dose, take only one FOSAMAX tablet on the morning
after you remember. Do not take two tablets on the same day.
Return to taking one tablet once a week, as originally
scheduled on your chosen day.
8. It is important that you continue taking FOSAMAX for as long as
your doctor prescribes it. FOSAMAX can treat your osteoporosis
or help you from getting osteoporosis only if you continue to
take it.
What is FOSAMAX?
FOSAMAX is for:
| -- | The treatment or prevention of osteoporosis (thinning of bone) in women after menopause. It reduces the chance of having a hip or spinal fracture. |
| -- | Treatment to increase bone mass in men with osteoporosis. |
You will find more information about osteoporosis at the end of this leaflet.
How does FOSAMAX work?
FOSAMAX works by:
-- Reducing the activity of the cells that cause bone loss
-- Decreasing the faster rate of bone loss that occurs after
menopause
-- Increasing the amount of bone in most patients
These effects are seen as soon as three months after therapy with FOSAMAX has begun. These effects continue as long as you keep taking FOSAMAX. The density of bone is maintained or increased and the bone is less likely to fracture.
Who should not take FOSAMAX?
Patients with:
-- Certain disorders of the esophagus (the tube that connects your
mouth with your stomach)
-- Inability to stand or sit upright for at least 30 minutes
-- Low levels of calcium in their blood
-- Severe kidney disease
-- Allergy to FOSAMAX
Patients who are:
-- Pregnant or Nursing
If you are pregnant or nursing, you should not be taking FOSAMAX.
Talk to your doctor.
What other medical problems should I discuss with my doctor?
Talk to your doctor about any:
-- Problems with swallowing
-- Stomach or digestive problems
-- Other medical problems you have or have had in the past
What are the possible side effects of FOSAMAX?
Some patients may develop severe digestive reactions including irritation, inflammation or ulceration (occasionally severe and/or with bleeding) of the esophagus (the tube that connects your mouth with your stomach). These reactions can cause chest pain, heartburn or difficulty or pain upon swallowing. This may occur especially if patients do not drink a full glass of water with FOSAMAX and/or if they lie down in less than 30 minutes or before their first food of the day. Esophageal reactions may worsen if patients continue to take FOSAMAX after developing symptoms suggesting irritation of the esophagus.
Like all prescription drugs, FOSAMAX may cause side effects. Side effects usually have been mild. They generally have not caused patients to stop taking FOSAMAX. Some patients treated with FOSAMAX experienced abdominal (stomach) pain. This is the most commonly reported side effect. Less frequently reported side effects are:
Nausea, heartburn, irritation or pain of the esophagus (the
tube that connects your mouth with your stomach), vomiting,
difficulty swallowing, a full or bloated feeling in the
stomach, constipation, diarrhea, black and/or bloody stools,
stomach or other peptic ulcers (some severe), and gas.
Bone, muscle or joint pain (rarely, with flu-like symptoms or fever), headache, or an altered sense of taste were also experienced by some patients. Rarely, a rash (occasionally made worse by sunlight), itching, or eye pain have occurred. Allergic reactions such as hives or, rarely, swelling of the face, lips, tongue and/or throat which may cause difficulty in breathing or swallowing have also been reported. Mouth ulcers have occurred when the tablet was chewed or dissolved in the mouth.
Anytime you have a medical problem you think may be related to FOSAMAX, talk to your doctor.
What should I know about osteoporosis?
Normally your bones are being rebuilt all the time. First, old bone is removed (resorbed). Then a similar amount of new bone is formed. This balanced process keeps your skeleton healthy and strong.
Osteoporosis is a thinning and weakening of the bones. It is common in women after menopause and may also occur in men. Osteoporosis often occurs in women several years after the menopause, which happens when the ovaries stop producing the female hormone, estrogen, or are removed (which may occur, for example, at the time of a hysterectomy). Osteoporosis can also occur in men due to several causes, including aging and/or a low level of the male hormone, testosterone. In all instances of osteoporosis bone is removed faster than it is formed, so bone loss occurs and bones become weaker. Therefore, maintaining bone mass is important to keep your bones healthy. At the start osteoporosis usually has no symptoms, but it can result in fractures (broken bones). Fractures usually cause pain. Fractures of the bones of the spine may not be painful, but over time they cause height loss. Eventually the spine becomes curved and the body becomes bent over. Fractures may happen during normal, everyday activity, such as lifting, or from minor injury that would normally not cause bone to break. Fractures most often occur at the hip, spine, or wrist. This can lead to pain, severe disability, or loss of mobility.
How can osteoporosis be treated or prevented?
-- Medication.
Your doctor has prescribed FOSAMAX. FOSAMAX acts specifically on
your bones. FOSAMAX is not a hormone and does not have the
benefits and risks of estrogen (hormone replacement therapy used
in postmenopausal women) elsewhere in your body.
-- Lifestyle changes.
In addition to FOSAMAX, your doctor may recommend one or more of the following lifestyle changes:
-- Stop smoking. Smoking appears to increase the risk of
osteoporosis.
-- Reduce the use of alcohol. Too much alcohol appears to increase
the risk of osteoporosis and injuries that may cause fractures.
-- Exercise regularly. Like muscles, bones need exercise to stay
strong and healthy. Exercise must be safe to prevent injuries
including fractures. You should consult your doctor before you
begin any exercise program.
-- Eat a balanced diet. Adequate dietary calcium is important.
Your doctor can advise you whether you need to change your diet
or take any dietary supplements such as calcium or vitamin D.
This medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others. Keep FOSAMAX and all medicines out of the reach of children. If you suspect that more than the prescribed dose of this medicine has been taken, drink a full glass of milk and contact your local poison control center or emergency room immediately. Do not induce vomiting. Do not lie down.
This leaflet provides a summary of information about FOSAMAX. If you have any questions or concerns about either FOSAMAX or osteoporosis, talk to your doctor. In addition, talk to your pharmacist or other health care provider.
Issued January 2003
(a) Registered trademark of MERCK & CO., Inc.
COPYRIGHT(c)MERCK & CO., Inc., 2000
All rights reserved.
