Higher Persistency Rates Seen with FOSAMAX(R) Once Weekly Therapies Compared to Other Weekly and Monthly Oral Bisphosphonates, According to Two New Outcomes Studies.PHILADELPHIA -- Higher persistency rates were seen among osteoporosis patients taking FOSAMAX(R) Once Weekly (alendronate alendronate /alen·dro·nate/ (ah-len´dro-nat) a bisphosphonate bisphosphonate /bis·phos·pho·nate/ (bis-fos´fo-nat) diphosphonate. calcium-regulating agent used in the form of the sodium salt to inhibit the resorption of bone in the treatment of osteitis deformans, osteoporosis, and hypercalcemia related to malignancy.) therapies than were seen among patients taking ibandronate once monthly or once weekly risedronate therapies, according to results from two new outcomes studies conducted by Merck & Co., Inc. that compared persistency rates of weekly versus monthly oral bisphosophate dosing frequency. Both studies were based on a review of two prescription drug databases containing prescription records from a total of over 300,000 patients in the U.S. These data were presented yesterday at the 28th Annual Meeting of the American Society for Bone Mineral Research (ASBMR ASBMR - American Society for Bone and Mineral Research). "The results from both studies are noteworthy because they suggest that persistency rates are not higher with monthly dosing of oral bisphosphonates versus weekly dosing," said Thomas W. Weiss, Dr PH, senior manager, Outcomes Research, Merck & Co., Inc. and lead study author. "Another recent study showed patients placed a higher importance on a drug's proven ability to reduce the risk of bones breaking versus other attributes of osteoporosis therapy - including dosing frequency." (Current Medical Research and Opinion, May, 2006). Monthly versus weekly persistency study This first study evaluated whether monthly dosing of oral bisphosphonates improved treatment persistency compared to weekly dosing. The study included 272,232 women aged 50 or older who had filled a new (index) prescription for weekly alendronate or alendronate/cholecalciferol (n=157,692), weekly risedronate or risedronate with calcium (Actonel or Actonel with Calcium; n=98,496), or monthly ibandronate (Boniva; n=16,044) from April 2005 to July 2005 and who had no prescriptions for the newly prescribed bisphosphonate during the 12 months prior to the date of their initial prescription fill. All patients were followed for 365 days after the date of the initial prescription fill (the follow-up period). --At 91-120 days, persistency rates were 50.0 percent (alendronate or alendronate/cholecalciferol), 47.4 percent (risedronate or risedronate with calcium) and 42.1 percent (ibandronate) --At 181-210 days, persistency rates were 36.0 percent (alendronate or alendronate/cholecalciferol), 33.8 percent (risedronate or risedronate with calcium ) and 29.5 percent (ibandronate) --At 271-300 days, persistency rates were 26.7 percent (alendronate or alendronate/cholecalciferol), 24.8 percent (risedronate or risedronate with calcium) and 21.7 percent (ibandronate) --At greater than 360 days, persistency rates were 18.9 percent (alendronate or alendronate/cholecalciferol), 17.4 percent (risedronate or risedronate with calcium) and 15.6 percent (ibandronate) These results are statistically significant (p< 0.0001) across the three bisphosphonates for each time point. In this study, persistency rate was defined as the percent of patients who refilled their prescription within a 60-day period following the last supply day of the previous dispensing. Second persistency study This study included 44,635 women over the age of 50 who had a bisphosphonate prescription (index) filled between December 30, 2004 and May 31, 2005 and who had no prescriptions for the newly prescribed bisphosphonate during the 12 months prior to the date of their initial prescription fill. Data for these patients were reviewed for at least five months, from their initial fill date to November 2, 2005 (the follow-up period), and evaluated to see if they stayed on treatment. Results showed that patients on Fosamax Once-Weekly had higher persistency rates (35.1 percent; n=8,837) than those patients on Boniva Once-Monthly (30.4 percent; n=225) or Actonel Once-Weekly (32.5 percent; n=6,066) during the follow up period. In this study, the persistency rate was defined as the percent of patients who refilled their prescription within a 45-day period following the last supply day of the previous dispensing and who did not change to another therapy during the follow-up period. About FOSAMAX FOSAMAX is the only bisphosphonate that is indicated to significantly reduce the risk of both osteoporotic hip and spine fractures. The sustained efficacy of FOSAMAX for the treatment of osteoporosis in postmenopausal women was demonstrated in a trial that found in over 10 years of therapy FOSAMAX 10 mg once daily maintained or continued to help build bone. About Osteoporosis Osteoporosis can lead to bone loss and an increased risk of fractures. Osteoporosis is especially common in women after menopause, but also occurs in men. Most often, it is due to an increase in the rate of resorption (breakdown) of bone tissue that is not matched by the rate of bone formation. Important information about FOSAMAX and FOSAMAX PLUS D(TM) (alendronate/cholecalciferol) Patients should talk to their doctor if they have or have had problems with swallowing. In addition, patients should talk to their doctor if they have conditions which may cause an overproduction of vitamin D (e.g., sarcoidosis, leukemia, lymphoma). Patients should tell their doctor about all medicines they are taking, including prescription and non-prescription medicines, vitamins and herbal supplements. 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 new or worsening heartburn, difficulty or pain when swallowing or chest pain should stop taking the drug and call their doctor right away. Patients who develop severe bone, joint and/or muscle pain at any time should contact their doctor. The most commonly reported side effects with FOSAMAX in clinical studies have been abdominal pain (3.7 percent), musculoskeletal pain (2.9 percent), indigestion (2.7 percent), regurgitation (1.9 percent) and nausea (1.9 percent). The standard dosing regimen for FOSAMAX and FOSAMAX PLUS D(TM) 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 or FOSAMAX PLUS D, patients should not lie down for at least 30 minutes and not until after consuming their first food of the day. Patients should not chew or suck on a tablet of FOSAMAX or FOSAMAX PLUS D. About Merck Merck & Co., Inc., is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com. 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 are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. 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 Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference. Full prescribing information and patient prescribing information for FOSAMAX(R) and FOSAMAX PLUS D(TM) is attached. FOSAMAX(R) is a registered trademark of Merck & Co., Inc. FOSAMAX PLUS D(TM) is a trademark of Merck & Co., Inc. All other brands are trademarks of their respective owners and are not trademarks of Merck & Co., Inc.
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FOSAMAX(R)
(ALENDRONATE SODIUM) TABLETS AND ORAL SOLUTION
DESCRIPTION
FOSAMAX*(C) (alendronate sodium) is a bisphosphonate that acts as
a specific inhibitor of osteoclast-mediated bone resorption.
Bisphosphonates are synthetic analogs of pyrophosphate that bind to
the hydroxyapatite found in bone.
Alendronate sodium is chemically described as
(4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt
trihydrate.
The empirical formula of alendronate sodium is C4H12NNaO7P2--3H2O
and its formula weight is 325.12. The structural formula is:
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.
Each bottle of the oral solution contains 91.35 mg of alendronate
monosodium salt trihydrate, which is the molar equivalent to 70 mg of
free acid. Each bottle also contains the following inactive
ingredients: sodium citrate dihydrate and citric acid anhydrous as
buffering agents, sodium saccharin, artificial raspberry flavor, and
purified water. Added as preservatives are sodium propylparaben
0.0225% and sodium butylparaben 0.0075%.
CLINICAL PHARMACOLOGY
Mechanism of Action
Animal studies have indicated the following mode of action. At the
cellular level, alendronate shows preferential localization to sites
of bone resorption, specifically under osteoclasts. The osteoclasts
adhere normally to the bone surface but lack the ruffled border that
is indicative of active resorption. Alendronate does not interfere
with osteoclast recruitment or attachment, but it does inhibit
osteoclast activity. Studies in mice on the localization of
radioactive (3H)alendronate in bone showed about 10-fold higher uptake
on osteoclast surfaces than on osteoblast surfaces. Bones examined 6
and 49 days after (3H)alendronate administration in rats and mice,
respectively, showed that normal bone was formed on top of the
alendronate, which was incorporated inside the matrix. While
incorporated in bone matrix, alendronate is not pharmacologically
active. Thus, alendronate must be continuously administered to
suppress osteoclasts on newly formed resorption surfaces.
Histomorphometry in baboons and rats showed that alendronate treatment
reduces bone turnover (i.e., the number of sites at which bone is
remodeled). In addition, bone formation exceeds bone resorption at
these remodeling sites, leading to progressive gains in bone mass.
Pharmacokinetics
Absorption
Relative to an intravenous (IV) reference dose, the mean oral
bioavailability of alendronate in women was 0.64% for doses ranging
from 5 to 70 mg when administered after an overnight fast and two
hours before a standardized breakfast. Oral bioavailability of the 10
mg tablet in men (0.59%) was similar to that in women when
administered after an overnight fast and 2 hours before breakfast.
FOSAMAX 70 mg oral solution and FOSAMAX 70 mg tablet are equally
bioavailable.
A study examining the effect of timing of a meal on the
bioavailability of alendronate was performed in 49 postmenopausal
women. Bioavailability was decreased (by approximately 40%) when 10 mg
alendronate was administered either 0.5 or 1 hour before a
standardized breakfast, when compared to dosing 2 hours before eating.
In studies of treatment and prevention of osteoporosis, alendronate
was effective when administered at least 30 minutes before breakfast.
Bioavailability was negligible whether alendronate was
administered with or up to two hours after a standardized breakfast.
Concomitant administration of alendronate with coffee or orange juice
reduced bioavailability by approximately 60%.
Distribution
Preclinical studies (in male rats) show that alendronate
transiently distributes to soft tissues following 1 mg/kg IV
administration but is then rapidly redistributed to bone or excreted
in the urine. The mean steady-state volume of distribution, exclusive
of bone, is at least 28 L in humans. Concentrations of drug in plasma
following therapeutic oral doses are too low (less than 5 ng/mL) for
analytical detection. Protein binding in human plasma is approximately
78%.
Metabolism
There is no evidence that alendronate is metabolized in animals or
humans.
Excretion
Following a single IV dose of (14C)alendronate, approximately 50%
of the radioactivity was excreted in the urine within 72 hours and
little or no radioactivity was recovered in the feces. Following a
single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min
(64, 78; 90% confidence interval (CI)), and systemic clearance did not
exceed 200 mL/min. Plasma concentrations fell by more than 95% within
6 hours following IV administration. The terminal half-life in humans
is estimated to exceed 10 years, probably reflecting release of
alendronate from the skeleton. Based on the above, it is estimated
that after 10 years of oral treatment with FOSAMAX (10 mg daily) the
amount of alendronate released daily from the skeleton is
approximately 25% of that absorbed from the gastrointestinal tract.
Special Populations
Pediatric: The oral bioavailability in children was similar to
that observed in adults; however, FOSAMAX is not indicated for use in
children (see PRECAUTIONS, Pediatric Use).
Gender: Bioavailability and the fraction of an IV dose excreted in
urine were similar in men and women.
Geriatric: Bioavailability and disposition (urinary excretion)
were similar in elderly and younger patients. No dosage adjustment is
necessary (see DOSAGE AND ADMINISTRATION).
Race: Pharmacokinetic differences due to race have not been
studied.
Renal Insufficiency: Preclinical studies show that, in rats with
kidney failure, increasing amounts of drug are present in plasma,
kidney, spleen, and tibia. In healthy controls, drug that is not
deposited in bone is rapidly excreted in the urine. No evidence of
saturation of bone uptake was found after 3 weeks dosing with
cumulative IV doses of 35 mg/kg in young male rats. Although no
clinical information is available, it is likely that, as in animals,
elimination of alendronate via the kidney will be reduced in patients
with impaired renal function. Therefore, somewhat greater accumulation
of alendronate in bone might be expected in patients with impaired
renal function.
No dosage adjustment is necessary for patients with
mild-to-moderate renal insufficiency (creatinine clearance 35 to 60
mL/min). FOSAMAX is not recommended for patients with more severe
renal insufficiency (creatinine clearance <35 mL/min) due to lack of
experience with alendronate in renal failure.
Hepatic Insufficiency: As there is evidence that alendronate is
not metabolized or excreted in the bile, no studies were conducted in
patients with hepatic insufficiency. No dosage adjustment is
necessary.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Intravenous ranitidine was shown to double the bioavailability of
oral alendronate. The clinical significance of this increased
bioavailability and whether similar increases will occur in patients
given oral H2-antagonists is unknown.
In healthy subjects, oral prednisone (20 mg three times daily for
five days) did not produce a clinically meaningful change in the oral
bioavailability of alendronate (a mean increase ranging from 20 to
44%).
Products containing calcium and other multivalent cations are
likely to interfere with absorption of alendronate.
Pharmacodynamics
Alendronate is a bisphosphonate that binds to bone hydroxyapatite
and specifically inhibits the activity of osteoclasts, the
bone-resorbing cells. Alendronate reduces bone resorption with no
direct effect on bone formation, although the latter process is
ultimately reduced because bone resorption and formation are coupled
during bone turnover.
Osteoporosis in postmenopausal women
Osteoporosis is characterized by low bone mass that leads to an
increased risk of fracture. The diagnosis can be confirmed by the
finding of low bone mass, evidence of fracture on x-ray, a history of
osteoporotic fracture, or height loss or kyphosis, indicative of
vertebral (spinal) fracture. Osteoporosis occurs in both males and
females but is most common among women following the menopause, when
bone turnover increases and the rate of bone resorption exceeds that
of bone formation. These changes result in progressive bone loss and
lead to osteoporosis in a significant proportion of women over age 50.
Fractures, usually of the spine, hip, and wrist, are the common
consequences. From age 50 to age 90, the risk of hip fracture in white
women increases 50-fold and the risk of vertebral fracture 15- to
30-fold. It is estimated that approximately 40% of 50-year-old women
will sustain one or more osteoporosis-related fractures of the spine,
hip, or wrist during their remaining lifetimes. Hip fractures, in
particular, are associated with substantial morbidity, disability, and
mortality.
Daily oral doses of alendronate (5, 20, and 40 mg for six weeks)
in postmenopausal women produced biochemical changes indicative of
dose-dependent inhibition of bone resorption, including decreases in
urinary calcium and urinary markers of bone collagen degradation (such
as deoxypyridinoline and cross-linked N-telopeptides of type I
collagen). These biochemical changes tended to return toward baseline
values as early as 3 weeks following the discontinuation of therapy
with alendronate and did not differ from placebo after 7 months.
Long-term treatment of osteoporosis with FOSAMAX 10 mg/day (for up
to five years) reduced urinary excretion of markers of bone
resorption, deoxypyridinoline and cross-linked N-telopeptides of type
l collagen, by approximately 50% and 70%, respectively, to reach
levels similar to those seen in healthy premenopausal women. Similar
decreases were seen in patients in osteoporosis prevention studies who
received FOSAMAX 5 mg/day. The decrease in the rate of bone resorption
indicated by these markers was evident as early as one month and at
three to six months reached a plateau that was maintained for the
entire duration of treatment with FOSAMAX. In osteoporosis treatment
studies FOSAMAX 10 mg/day decreased the markers of bone formation,
osteocalcin and bone specific alkaline phosphatase by approximately
50%, and total serum alkaline phosphatase by approximately 25 to 30%
to reach a plateau after 6 to 12 months. In osteoporosis prevention
studies FOSAMAX 5 mg/day decreased osteocalcin and total serum
alkaline phosphatase by approximately 40% and 15%, respectively.
Similar reductions in the rate of bone turnover were observed in
postmenopausal women during one-year studies with once weekly FOSAMAX
70 mg for the treatment of osteoporosis and once weekly FOSAMAX 35 mg
for the prevention of osteoporosis. These data indicate that the rate
of bone turnover reached a new steady-state, despite the progressive
increase in the total amount of alendronate deposited within bone.
As a result of inhibition of bone resorption, asymptomatic
reductions in serum calcium and phosphate concentrations were also
observed following treatment with FOSAMAX. In the long-term studies,
reductions from baseline in serum calcium (approximately 2%) and
phosphate (approximately 4 to 6%) were evident the first month after
the initiation of FOSAMAX 10 mg. No further decreases in serum calcium
were observed for the five-year duration of treatment; however, serum
phosphate returned toward prestudy levels during years three through
five. Similar reductions were observed with FOSAMAX 5 mg/day. In
one-year studies with once weekly FOSAMAX 35 and 70 mg, similar
reductions were observed at 6 and 12 months. The reduction in serum
phosphate may reflect not only the positive bone mineral balance due
to FOSAMAX but also a decrease in renal phosphate reabsorption.
Osteoporosis in men
Treatment of men with osteoporosis with FOSAMAX 10 mg/day for two
years reduced urinary excretion of cross-linked N-telopeptides of type
I collagen by approximately 60% and bone-specific alkaline phosphatase
by approximately 40%. Similar reductions were observed in a one-year
study in men with osteoporosis receiving once weekly FOSAMAX 70 mg.
Glucocorticoid-induced Osteoporosis
Sustained use of glucocorticoids is commonly associated with
development of osteoporosis and resulting fractures (especially
vertebral, hip, and rib). It occurs both in males and females of all
ages. Osteoporosis occurs as a result of inhibited bone formation and
increased bone resorption resulting in net bone loss. Alendronate
decreases bone resorption without directly inhibiting bone formation.
In clinical studies of up to two years' duration, FOSAMAX 5 and 10
mg/day reduced cross-linked N-telopeptides of type I collagen (a
marker of bone resorption) by approximately 60% and reduced
bone-specific alkaline phosphatase and total serum alkaline
phosphatase (markers of bone formation) by approximately 15 to 30% and
8 to 18%, respectively. As a result of inhibition of bone resorption,
FOSAMAX 5 and 10 mg/day induced asymptomatic decreases in serum
calcium (approximately 1 to 2%) and serum phosphate (approximately 1
to 8%).
Paget's disease of bone
Paget's disease of bone is a chronic, focal skeletal disorder
characterized by greatly increased and disorderly bone remodeling.
Excessive osteoclastic bone resorption is followed by osteoblastic new
bone formation, leading to the replacement of the normal bone
architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms
to severe morbidity due to bone pain, bone deformity, pathological
fractures, and neurological and other complications. Serum alkaline
phosphatase, the most frequently used biochemical index of disease
activity, provides an objective measure of disease severity and
response to therapy.
FOSAMAX decreases the rate of bone resorption directly, which
leads to an indirect decrease in bone formation. In clinical trials,
FOSAMAX 40 mg once daily for six months produced significant decreases
in serum alkaline phosphatase as well as in urinary markers of bone
collagen degradation. As a result of the inhibition of bone
resorption, FOSAMAX induced generally mild, transient, and
asymptomatic decreases in serum calcium and phosphate.
Clinical Studies
Treatment of osteoporosis
Postmenopausal women
Effect on bone mineral density
The efficacy of FOSAMAX 10 mg once daily in postmenopausal women,
44 to 84 years of age, with osteoporosis (lumbar spine bone mineral
density (BMD) of at least 2 standard deviations below the
premenopausal mean) was demonstrated in four double-blind,
placebo-controlled clinical studies of two or three years' duration.
These included two three-year, multicenter studies of virtually
identical design, one performed in the United States (U.S.) and the
other in 15 different countries (Multinational), which enrolled 478
and 516 patients, respectively. The following graph shows the mean
increases in BMD of the lumbar spine, femoral neck, and trochanter in
patients receiving FOSAMAX 10 mg/day relative to placebo-treated
patients at three years for each of these studies.
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
ReductionReduction
FOSAMAX Placebo in in
(n=1022)(n=1005) Fracture Fracture
Incidence Risk %
-------------------------------------------------------------
Patients with:
Vertebral fractures
(diagnosed by X-ray)+
(greater than=) 1 new 47***
vertebral fracture 7.9 15.0 7.1
(greater than=) 2 new 90***
vertebral fractures 0.5 4.9 4.4
Clinical (symptomatic)
fractures
Any clinical 26|
(symptomatic)
fracture 13.8 18.1 4.3
(greater than=) 1 54**
clinical (symptomatic)
vertebral
fracture 2.3 5.0 2.7
Hip fracture 1.1 2.2 1.1 51*
Wrist (forearm) fracture 2.2 4.1 1.9 48*
-------------------------------------------------------------
+Number evaluable for vertebral fractures: FOSAMAX, n=984;
placebo, n=966
*p<0.05, **p<0.01, ***p<0.001, |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.
Cumulative Incidence of Hip Fractures in the
Three-Year Study of FIT
(patients with radiographic vertebral fracture at baseline)
GRAPHIC OMMITTED
Fracture Intervention Trial: Four-Year Study (patients with low
bone mass but without a baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 4432-patient
study (FOSAMAX, n=2214; placebo, n=2218) further investigated the
reduction in fracture incidence due to FOSAMAX. The intent of the
study was to recruit women with osteoporosis, defined as a baseline
femoral neck BMD at least two standard deviations below the mean for
young adult women. However, due to subsequent revisions to the
normative values for femoral neck BMD, 31% of patients were found not
to meet this entry criterion and thus this study included both
osteoporotic and non-osteoporotic women. The results are shown in the
table below for the patients with osteoporosis.
Effect of FOSAMAX on Fracture Incidence in Osteoporotic+
Patients in the Four-Year
Study of FIT
(patients without vertebral fracture at baseline)
--------------------------------------------------------------
Percent of Patients
Absolute Relative
ReductionReduction
FOSAMAX Placebo in in
(n=1545)(n=1521) Fracture Fracture
Incidence Risk (%)
--------------------------------------------------------------
Patients with:
Vertebral fractures
(diagnosed by X-ray)++
(greater than=) 1 new 48***
vertebral fracture 2.5 4.8 2.3
(greater than=) 2 new 78*
vertebral fractures 0.1 0.6 0.5
Clinical (symptomatic)
fractures
Any clinical 22**
(symptomatic) fracture 12.9 16.2 3.3 41 (NS)+++
(greater than=) 1
clinical (symptomatic)
vertebral
fracture 1.0 1.6 0.6
Hip fracture 1.0 1.4 0.4 29 (NS)+++
Wrist (forearm) fracture 3.9 3.8 -0.1 NS+++
---------------------------------------------------------------------
+Baseline femoral neck BMD at least 2 SD below the mean for young
adult women
++Number evaluable for vertebral fractures: FOSAMAX, n=1426;
placebo, n=1428
+++Not significant. This study was not powered to detect
differences at these sites.
*p=0.035, ** p=0.01, ***p<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<0.001); in the
Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1%
(44% relative risk reduction, p=0.001); and in the combined
U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk
reduction, p=0.034).
FOSAMAX reduced the percentage of women experiencing multiple (two
or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk
reduction, p<0.001) in the combined U.S./Multinational studies and
from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the
Three-Year Study of FIT. In the Four-Year Study of FIT, FOSAMAX
reduced the percentage of osteoporotic women experiencing multiple
vertebral fractures from 0.6% to 0.1% (78% relative risk reduction,
p=0.035).
Thus, FOSAMAX reduced the incidence of radiographic vertebral
fractures in osteoporotic women whether or not they had a previous
radiographic vertebral fracture.
FOSAMAX, over a three- or four-year period, was associated with
statistically significant reductions in loss of height vs. placebo in
patients with and without baseline radiographic vertebral fractures.
At the end of the FIT studies the between-treatment group differences
were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
Bone histology
Bone histology in 270 postmenopausal patients with osteoporosis
treated with FOSAMAX at doses ranging from 1 to 20 mg/day for one,
two, or three years revealed normal mineralization and structure, as
well as the expected decrease in bone turnover relative to placebo.
These data, together with the normal bone histology and increased bone
strength observed in rats and baboons exposed to long-term alendronate
treatment, support the conclusion that bone formed during therapy with
FOSAMAX is of normal quality.
Men
The efficacy of FOSAMAX in men with hypogonadal or idiopathic
osteoporosis was demonstrated in two clinical studies.
A two-year, double-blind, placebo-controlled, multicenter study of
FOSAMAX 10 mg once daily enrolled a total of 241 men between the ages
of 31 and 87 (mean, 63). All patients in the trial had either: 1) a
BMD T-score (<=)-2 at the femoral neck and (<=)-1 at the lumbar spine,
or 2) a baseline osteoporotic fracture and a BMD T-score (<=)-1 at the
femoral neck. At two years, the mean increases relative to placebo in
BMD in men receiving FOSAMAX 10 mg/day were significant at the
following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter,
3.1%; and total body, 1.6%. Treatment with FOSAMAX also reduced height
loss (FOSAMAX, -0.6 mm vs. placebo, -2.4 mm).
A one-year, double-blind, placebo-controlled, multicenter study of
once weekly FOSAMAX 70 mg enrolled a total of 167 men between the ages
of 38 and 91 (mean, 66). Patients in the study had either: 1) a BMD
T-score <=-2 at the femoral neck and <=-1 at the lumbar spine, 2) a
BMD T-score <=-2 at the lumbar spine and <=-1 at the femoral neck, or
3) a baseline osteoporotic fracture and a BMD T-score <=-1 at the
femoral neck. At one year, the mean increases relative to placebo in
BMD in men receiving FOSAMAX 70 mg once weekly were significant at the
following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter,
2.0%; and total body, 1.2%. These increases in BMD were similar to
those seen at one year in the 10 mg once-daily study.
In both studies, BMD responses were similar regardless of age
(=>65 years vs. <65 years), gonadal function (baseline testosterone <9
ng/dL vs. =>9 ng/dL), or baseline BMD (femoral neck and lumbar spine
T-score <=-2.5 vs. >-2.5).
Prevention of osteoporosis in postmenopausal women
Prevention of bone loss was demonstrated in two double-blind,
placebo-controlled studies of postmenopausal women 40-60 years of age.
One thousand six hundred nine patients (FOSAMAX 5 mg/day; n=498) who
were at least six months postmenopausal were entered into a two-year
study without regard to their baseline BMD. In the other study, 447
patients (FOSAMAX 5 mg/day; n=88), who were between six months and
three years postmenopause, were treated for up to three years. In the
placebo-treated patients BMD losses of approximately 1% per year were
seen at the spine, hip (femoral neck and trochanter) and total body.
In contrast, FOSAMAX 5 mg/day prevented bone loss in the majority of
patients and induced significant increases in mean bone mass at each
of these sites (see figures below). In addition, FOSAMAX 5 mg/day
reduced the rate of bone loss at the forearm by approximately half
relative to placebo. FOSAMAX 5 mg/day was similarly effective in this
population regardless of age, time since menopause, race and baseline
rate of bone turnover.
GRAPHIC OMMITTED
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 OMMITTED
After one year, significant increases relative to placebo in BMD
were seen in the combined studies at each of these sites in patients
who received FOSAMAX 5 mg/day. In the placebo-treated patients, a
significant decrease in BMD occurred at the femoral neck (-1.2%), and
smaller decreases were seen at the lumbar spine and trochanter. Total
body BMD was maintained with FOSAMAX 5 mg/day. The increases in BMD
with FOSAMAX 10 mg/day were similar to those with FOSAMAX 5 mg/day in
all patients except for postmenopausal women not receiving estrogen
therapy. In these women, the increases (relative to placebo) with
FOSAMAX 10 mg/day were greater than those with FOSAMAX 5 mg/day at the
lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not
at other sites. FOSAMAX was effective regardless of dose or duration
of glucocorticoid use. In addition, FOSAMAX was similarly effective
regardless of age (<65 vs. (>=)65 years), race (Caucasian vs. other
races), gender, underlying disease, baseline BMD, baseline bone
turnover, and use with a variety of common medications.
Bone histology was normal in the 49 patients biopsied at the end
of one year who received FOSAMAX at doses of up to 10 mg/day.
Of the original 560 patients in these studies, 208 patients who
remained on at least 7.5 mg/day of prednisone or equivalent continued
into a one-year double-blind extension. After two years of treatment,
spine BMD increased by 3.7% and 5.0% relative to placebo with FOSAMAX
5 and 10 mg/day, respectively. Significant increases in BMD (relative
to placebo) were also observed at the femoral neck, trochanter, and
total body.
After one year, 2.3% of patients treated with FOSAMAX 5 or 10
mg/day (pooled) vs. 3.7% of those treated with placebo experienced a
new vertebral fracture (not significant). However, in the population
studied for two years, treatment with FOSAMAX (pooled dosage groups: 5
or 10 mg for two years or 2.5 mg for one year followed by 10 mg for
one year) significantly reduced the incidence of patients with a new
vertebral fracture (FOSAMAX 0.7% vs. placebo 6.8%).
Paget's disease of bone
The efficacy of FOSAMAX 40 mg once daily for six months was
demonstrated in two double-blind clinical studies of male and female
patients with moderate to severe Paget's disease (alkaline phosphatase
at least twice the upper limit of normal): a placebo-controlled,
multinational study and a U.S. comparative study with etidronate
disodium 400 mg/day. The following figure shows the mean percent
changes from baseline in serum alkaline phosphatase for up to six
months of randomized treatment.
GRAPHIC OMMITTED
At six months the suppression in alkaline phosphatase in patients
treated with FOSAMAX was significantly greater than that achieved with
etidronate and contrasted with the complete lack of response in
placebo-treated patients. Response (defined as either normalization of
serum alkaline phosphatase or decrease from baseline (>=)60%) occurred
in approximately 85% of patients treated with FOSAMAX in the combined
studies vs. 30% in the etidronate group and 0% in the placebo group.
FOSAMAX was similarly effective regardless of age, gender, race, prior
use of other bisphosphonates, or baseline alkaline phosphatase within
the range studied (at least twice the upper limit of normal).
Bone histology was evaluated in 33 patients with Paget's disease
treated with FOSAMAX 40 mg/day for 6 months. As in patients treated
for osteoporosis (see Clinical Studies, Treatment of osteoporosis in
postmenopausal women, Bone histology), FOSAMAX did not impair
mineralization, and the expected decrease in the rate of bone turnover
was observed. Normal lamellar bone was produced during treatment with
FOSAMAX, even where preexisting bone was woven and disorganized.
Overall, bone histology data support the conclusion that bone formed
during treatment with FOSAMAX is of normal quality.
ANIMAL PHARMACOLOGY
The relative inhibitory activities on bone resorption and
mineralization of alendronate and etidronate were compared in the
Schenk assay, which is based on histological examination of the
epiphyses of growing rats. In this assay, the lowest dose of
alendronate that interfered with bone mineralization (leading to
osteomalacia) was 6000-fold the antiresorptive dose. The corresponding
ratio for etidronate was one to one. These data suggest that
alendronate administered in therapeutic doses is highly unlikely to
induce osteomalacia.
INDICATIONS AND USAGE
FOSAMAX is indicated for:
-- Treatment and prevention of osteoporosis in postmenopausal
women
-- For the treatment of osteoporosis, FOSAMAX increases
bone mass and reduces the incidence of fractures,
including those of the hip and spine (vertebral
compression fractures). Osteoporosis may be confirmed
by the finding of low bone mass (for example, at least
2 standard deviations below the premenopausal mean) or
by the presence or history of osteoporotic fracture.
(See CLINICAL PHARMACOLOGY, Pharmacodynamics.)
-- For the prevention of osteoporosis, FOSAMAX may be
considered in postmenopausal women who are at risk of
developing osteoporosis and for whom the desired
clinical outcome is to maintain bone mass and to
reduce the risk of future fracture.
Bone loss is particularly rapid in postmenopausal women younger
than age 60. Risk factors often associated with the development of
postmenopausal osteoporosis include early menopause; moderately low
bone mass (for example, at least 1 standard deviation below the mean
for healthy young adult women); thin body build; Caucasian or Asian
race; and family history of osteoporosis. The presence of such risk
factors may be important when considering the use of FOSAMAX for
prevention of osteoporosis.
Treatment to increase bone mass in men with osteoporosis
-- Treatment of glucocorticoid-induced osteoporosis in men and
women receiving glucocorticoids in a daily dosage equivalent
to 7.5 mg or greater of prednisone and who have low bone
mineral density (see PRECAUTIONS, Glucocorticoid-induced
osteoporosis). Patients treated with glucocorticoids should
receive adequate amounts of calcium and vitamin D.
-- Treatment of Paget's disease of bone in men and women
Treatment is indicated in patients with Paget's disease of bone
having alkaline phosphatase at least two times the upper limit of
normal, or those who are symptomatic, or those at risk for future
complications from their disease.
CONTRAINDICATIONS
-- Abnormalities of the esophagus which delay esophageal emptying
such as stricture or achalasia
-- Inability to stand or sit upright for at least 30 minutes
-- Patients at increased risk of aspiration should not receive
FOSAMAX oral solution.
-- Hypersensitivity to any component of this product
-- Hypocalcemia (see PRECAUTIONS, General)
WARNINGS
FOSAMAX, like other bisphosphonates, may cause local irritation of
the upper gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal
ulcers and esophageal erosions, occasionally with bleeding and rarely
followed by esophageal stricture or perforation, have been reported in
patients receiving treatment with FOSAMAX. In some cases these have
been severe and required hospitalization. Physicians should therefore
be alert to any signs or symptoms signaling a possible esophageal
reaction and patients should be instructed to discontinue FOSAMAX and
seek medical attention if they develop dysphagia, odynophagia,
retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be
greater in patients who lie down after taking FOSAMAX and/or who fail
to swallow it with the recommended amount of water, and/or who
continue to take FOSAMAX after developing symptoms suggestive of
esophageal irritation. Therefore, it is very important that the full
dosing instructions are provided to, and understood by, the patient
(see DOSAGE AND ADMINISTRATION). In patients who cannot comply with
dosing instructions due to mental disability, therapy with FOSAMAX
should be used under appropriate supervision.
Because of possible irritant effects of FOSAMAX on the upper
gastrointestinal mucosa and a potential for worsening of the
underlying disease, caution should be used when FOSAMAX is given to
patients with active upper gastrointestinal problems (such as
dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).
There have been post-marketing reports of gastric and duodenal
ulcers, some severe and with complications, although no increased risk
was observed in controlled clinical trials.
PRECAUTIONS
General
Causes of osteoporosis other than estrogen deficiency, aging, and
glucocorticoid use should be considered.
Hypocalcemia must be corrected before initiating therapy with
FOSAMAX (see CONTRAINDICATIONS). Other disorders affecting mineral
metabolism (such as vitamin D deficiency) should also be effectively
treated. In patients with these conditions, serum calcium and symptoms
of hypocalcemia should be monitored during therapy with FOSAMAX.
Presumably due to the effects of FOSAMAX on increasing bone
mineral, small, asymptomatic decreases in serum calcium and phosphate
may occur, especially in patients with Paget's disease, in whom the
pretreatment rate of bone turnover may be greatly elevated and in
patients receiving glucocorticoids, in whom calcium absorption may be
decreased.
Ensuring adequate calcium and vitamin D intake is especially
important in patients with Paget's disease of bone and in patients
receiving glucocorticoids.
Musculoskeletal Pain
In post marketing experience, severe and occasionally
incapacitating bone, joint, and/or muscle pain has been reported in
patients taking bisphosphonates that are approved for the prevention
and treatment of osteoporosis (see ADVERSE REACTIONS). However, such
reports have been infrequent. This category of drugs includes FOSAMAX
(alendronate). Most of the patients were postmenopausal women. The
time to onset of symptoms varied from one day to several months after
starting the drug. Most patients had relief of symptoms after
stopping. A subset had recurrence of symptoms when rechallenged with
the same drug or another bisphosphonate.
In placebo-controlled clinical studies of FOSAMAX, the percentages
of patients with these symptoms were similar in the FOSAMAX and
placebo groups.
Dental
Osteonecrosis of the jaw, generally associated with tooth
extraction and/or local infection, often with delayed healing, has
been reported in patients taking bisphosphonates. Most reported cases
of bisphosphonate-associated osteonecrosis have been in cancer
patients treated with intravenous bisphosphonates, but some have
occurred in patients with postmenopausal osteoporosis. Known risk
factors for osteonecrosis include a diagnosis of cancer, concomitant
therapies (e.g., chemotherapy, radiotherapy, corticosteroids), poor
oral hygiene, and co-morbid disorders (e.g., pre-existing dental
disease, anemia, coagulopathy, infection).
Patients who develop osteonecrosis of the jaw (ONJ) while on
bisphosphonate therapy should receive care by an oral surgeon. Dental
surgery may exacerbate the condition. For patients requiring dental
procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk for ONJ.
Clinical judgment of the treating physician should guide the
management plan of each patient based on individual benefit/risk
assessment.
Renal insufficiency
FOSAMAX is not recommended for patients with renal insufficiency
(creatinine clearance <35 mL/min). (See DOSAGE AND ADMINISTRATION.)
Glucocorticoid-induced osteoporosis
The risk versus benefit of 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 it is taken with plain water the
first thing upon arising for the day at least 30 minutes before the
first food, beverage, or medication of the day. Even dosing with
orange juice or coffee has been shown to markedly reduce the
absorption of 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 each tablet of FOSAMAX with a full glass of water (6-8 oz). To
facilitate gastric emptying patients should drink at least 2 oz (a
quarter of a cup) of water after taking FOSAMAX oral solution.
Patients should be instructed not to lie down for at least 30 minutes
and until after their first food of the day. Patients should not chew
or suck on the tablet because of a potential for oropharyngeal
ulceration. Patients should be specifically instructed not to take
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 dose on the morning after they
remember. They should not take two doses on the same day but should
return to taking one dose once a week, as originally scheduled on
their chosen day.
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.
Bisphosphonates are incorporated into the bone matrix, from which
they are gradually released over a period of years. The amount of
bisphosphonate incorporated into adult bone, and hence, the amount
available for release back into the systemic circulation, is directly
related to the dose and duration of bisphosphonate use. There are no
data on fetal risk in humans. However, there is a theoretical risk of
fetal harm, predominantly skeletal, if a woman becomes pregnant after
completing a course of bisphosphonate therapy. The impact of variables
such as time between cessation of bisphosphonate therapy to
conception, the particular bisphosphonate used, and the route of
administration (intravenous versus oral) on the risk has not been
studied.
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
The efficacy and safety of FOSAMAX were examined in a randomized,
double-blind, placebo-controlled two-year study of 139 pediatric
patients, aged 4-18 years, with severe osteogenesis imperfecta.
One-hundred-and-nine patients were randomized to 5 mg FOSAMAX daily
(weight <40 kg) or 10 mg FOSAMAX daily (weight =>40 kg) and 30
patients to placebo. The mean baseline lumbar spine BMD Z-score of the
patients was -4.5. The mean change in lumbar spine BMD Z-score from
baseline to Month 24 was 1.3 in the FOSAMAX-treated patients and 0.1
in the placebo-treated patients. Treatment with FOSAMAX did not reduce
the risk of fracture. Sixteen percent of the FOSAMAX patients who
sustained a radiologically-confirmed fracture by Month 12 of the study
had delayed fracture healing (callus remodeling) or fracture non-union
when assessed radiographically at Month 24 compared with 9% of the
placebo-treated patients. In FOSAMAX-treated patients, bone
histomorphometry data obtained at Month 24 demonstrated decreased bone
turnover and delayed mineralization time; however, there were no
mineralization defects. There were no statistically significant
differences between the FOSAMAX and placebo groups in reduction of
bone pain.
FOSAMAX is not indicated for use in children.
(For clinical adverse experiences in children, see ADVERSE
REACTIONS, Clinical Studies, Osteogenesis Imperfecta.)
Geriatric Use
Of the patients receiving FOSAMAX in the Fracture Intervention
Trial (FIT), 71% (n=2302) were (>=)65 years of age and 17% (n=550)
were (>=)75 years of age. Of the patients receiving FOSAMAX in the
United States and Multinational osteoporosis treatment studies in
women, osteoporosis studies in men, glucocorticoid-induced
osteoporosis studies, and Paget's disease studies (see CLINICAL
PHARMACOLOGY, Clinical Studies), 45%, 54%, 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 (>=)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=)1% of
Patients
----------------------------------------------------------------------
United Fracture Intervention
States/Multinational Trial
Studies
---------------------------------------------------
FOSAMAX* Placebo FOSAMAX** Placebo
% % % %
(n=196) (n=397) (n=3236) (n=3223)
---------------------------------------------------
Gastrointestinal
abdominal pain
nausea 6.6 4.8 1.5 1.5
dyspepsia 3.6 4.0 1.1 1.5
constipation 3.6 3.5 1.1 1.2
diarrhea 3.1 1.8 0.0 0.2
flatulence 3.1 1.8 0.6 0.3
acid regurgitation 2.6 0.5 0.2 0.3
esophageal ulcer 2.0 4.3 1.1 0.9
vomiting 1.5 0.0 0.1 0.1
dysphagia 1.0 1.5 0.2 0.3
abdominal 1.0 0.0 0.1 0.1
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
----------------------------------------------------------------------
* 10 mg/day for three years
** 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional
years
Rarely, rash and erythema have occurred.
One patient treated with FOSAMAX (10 mg/day), who had a history of
peptic ulcer disease and gastrectomy and who was taking concomitant
aspirin developed an anastomotic ulcer with mild hemorrhage, which was
considered drug related. Aspirin and FOSAMAX were discontinued and the
patient recovered.
The adverse experience profile was similar for the 401 patients
treated with either 5 or 20 mg doses of FOSAMAX in the United States
and Multinational studies. The adverse experience profile for the 296
patients who received continued treatment with either 5 or 10 mg doses
of FOSAMAX in the two-year extension of these studies (treatment years
4 and 5) was similar to that observed during the three-year
placebo-controlled period. During the extension period, of the 151
patients treated with FOSAMAX 10 mg/day, the proportion of patients
who discontinued therapy due to any clinical adverse experience was
similar to that during the first three years of the study.
In a one-year, double-blind, multicenter study, the overall safety
and tolerability profiles of once weekly FOSAMAX 70 mg and FOSAMAX 10
mg daily were similar. The adverse experiences considered by the
investigators as possibly, probably, or definitely drug related in
(>=)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=)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, 2.9 3.2
muscle, joint) pain
muscle cramp 0.2 1.1
-----------------------------------------------------------------
Men
In two placebo-controlled, double-blind, multicenter studies in
men (a two-year study of FOSAMAX 10 mg/day and a one-year study of
once weekly FOSAMAX 70 mg) the rates of discontinuation of therapy due
to any clinical adverse experience were 2.7% for FOSAMAX 10 mg/day vs.
10.5% for placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for
placebo. The adverse experiences considered by the investigators as
possibly, probably, or definitely drug related in (>=)2% of patients
treated with either FOSAMAX or placebo are presented in the following
table.
Osteoporosis Studies in Men
Adverse Experiences Considered Possibly, Probably, or
Definitely Drug Related by the Investigators and
Reported in (greater than=)2% of Patients
---------------------------------------------------------------------
Two-year Study One-year Study
-----------------------------------------------------
Once Weekly
FOSAMAX Placebo FOSAMAX 70 Placebo
10 mg/day % mg %
% (n=95) % (n=58)
(n=146) (n=109)
-----------------------------------------------------
Gastrointestinal
acid
regurgitation
flatulence 4.1 3.2 0.0 0.0
gastroesophageal 4.1 1.1 0.0 0.0
reflux 0.7 3.2 2.8 0.0
disease
dyspepsia 3.4 0.0 2.8 1.7
diarrhea 1.4 1.1 2.8 0.0
abdominal pain 2.1 1.1 0.9 3.4
nausea 2.1 0.0 0.0 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
(>=)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=)1% of Patients
-------------------------------------------------------------------
Two/Three-Year One-Year Study
Studies
-------------------------------------------
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 distention 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 (>=)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=)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.
Osteogenesis Imperfecta
FOSAMAX is not indicated for use in children.
The overall safety profile of FOSAMAX in OI patients treated for
up to 24 months was generally similar to that of adults with
osteoporosis treated with FOSAMAX. However, there was an increased
occurrence of vomiting in OI patients treated with FOSAMAX compared to
placebo. During the 24-month treatment period, vomiting was observed
in 32 of 109 (29.4%) patients treated with FOSAMAX and 3 of 30 (10%)
patients treated with placebo.
In a pharmacokinetic study, 6 of 24 pediatric OI patients who
received a single oral dose of FOSAMAX 35 or 70 mg developed fever,
flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours
after administration. These events, lasting no more than 2 to 3 days
and responding to acetaminophen, are consistent with an acute-phase
response that has been reported in patients receiving bisphosphonates,
including FOSAMAX. See ADVERSE REACTIONS, Post-Marketing Experience,
Body as a Whole.
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. Transient symptoms of myalgia, malaise,
asthenia and rarely, fever have been reported with FOSAMAX, typically
in association with initiation of treatment. Rarely, symptomatic
hypocalcemia has occurred, generally in association with predisposing
conditions. Rarely, peripheral edema.
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).
Localized osteonecrosis of the jaw, generally associated with
tooth extraction and/or local infection, often with delayed healing,
has been reported rarely (see PRECAUTIONS, Dental).
Musculoskeletal: bone, joint, and/or muscle pain, occasionally
severe, and rarely incapacitating (see PRECAUTIONS, Musculoskeletal
Pain); joint swelling.
Nervous system: dizziness and vertigo.
Skin: rash (occasionally with photosensitivity), pruritus, rarely
severe skin reactions, including Stevens-Johnson syndrome and toxic
epidermal necrolysis.
Special Senses: rarely uveitis, scleritis or episcleritis.
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.
FOSAMAX should only be taken upon arising for the day. To
facilitate delivery to the stomach and thus reduce the potential for
esophageal irritation, a FOSAMAX tablet should be swallowed with a
full glass of water (6-8 oz). To facilitate gastric emptying FOSAMAX
oral solution should be followed by at least 2 oz (a quarter of a cup)
of water. 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 <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 bottle of 70 mg oral solution once weekly
or
-- one 10 mg tablet once daily
Treatment to increase bone mass in men with osteoporosis
The recommended dosage is:
-- one 70 mg tablet once weekly
or
-- one bottle of 70 mg oral solution once weekly
or
-- one 10 mg tablet once daily
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.
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.
No. 3833 -- Oral Solution FOSAMAX, 70 mg, is a clear, colorless
solution with a raspberry flavor and is supplied as follows:
NDC 0006-3833-34 unit-of-use cartons of 4 single-dose bottles
containing 75 mL each.
Storage
FOSAMAX Tablets:
Store in a well-closed container at room temperature,
15-30(degree)C (59-86(degree)F).
FOSAMAX Oral Solution:
Store at 25(degree)C (77(degree)F), excursions permitted to
15-30(degree)C (59-86(degree)F). (See USP Controlled Room
Temperature.) Do not freeze.
Issued February 2006
Printed in USA
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT 1995, 1997, 2000 MERCK & CO., Inc.
All rights reserved
9635604
Patient Information
Once Weekly FOSAMAX(R) (alendronate sodium)
Tablets and Oral Solution
Read this information before you start taking FOSAMAX*
(FOSS-ah-max). Also, read the leaflet each time you refill your
prescription, just in case anything has changed. This leaflet does not
take the place of discussions with your doctor. You and your doctor
should discuss FOSAMAX when you start taking your medicine and at
regular checkups.
What is the most important information I should know about once
weekly FOSAMAX?
-- You must take once weekly FOSAMAX exactly as directed to help
make sure it works and to help lower the chance of harmful
side effects.
-- Choose the day of the week that best fits your schedule. Every
week, take 1 dose of FOSAMAX (one tablet or one entire bottle
of solution) on your chosen day.
-- After getting up for the day and before taking your first
food, drink, or other medicine, take your FOSAMAX with plain
water only as follows:
-- TABLETS: Swallow one tablet with a full glass (6-8 oz) of
plain water.
-- ORAL SOLUTION: Drink one entire bottle of solution
followed by at least 2 ounces (a quarter of a cup) of
plain water.
Do not take FOSAMAX with:
Mineral water
Coffee or tea
Juice
-- Do not chew or suck on a tablet of FOSAMAX.
-- After taking your FOSAMAX, do not lie down - stay fully
upright (sitting, standing, or walking) for at least 30
minutes. Do not lie down until after your first food of the
day. This will help FOSAMAX reach your stomach quickly and
help reduce the chance that FOSAMAX might irritate your
esophagus, the tube that connects your mouth with your
stomach.
-- After taking your FOSAMAX, wait at least 30 minutes before
taking your first food, drink, or other medicine of the day,
including antacids, calcium, and other supplements and
vitamins. FOSAMAX is effective only if it is taken when your
stomach is empty.
-- Do not take FOSAMAX at bedtime or before getting up for the
day.
-- If you have chest pain, new or worsening heartburn, or have
trouble or pain when you swallow, stop taking FOSAMAX and call
your doctor.
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 (break).
-- Treatment to increase bone mass in men with osteoporosis.
FOSAMAX tablets are for treatment and prevention, and FOSAMAX oral
solution is for treatment of osteoporosis.
Improvement in bone density may be seen as early as 3 months after
you start taking FOSAMAX. For FOSAMAX to continue to work, you need to
keep taking it.
FOSAMAX is not a hormone.
There is more information about osteoporosis at the end of this
leaflet.
Who should not take FOSAMAX?
Do not take FOSAMAX (tablets or oral solution) if you:
-- Have certain problems with your esophagus, the tube that
connects your mouth with your stomach
-- Cannot stand or sit upright for at least 30 minutes
-- Have low levels of calcium in your blood
-- Have severe kidney disease
-- Are allergic to FOSAMAX or any of its ingredients. A list of
ingredients is at the end of this leaflet.
Do not take FOSAMAX oral solution if you have difficulty
swallowing liquids.
If you are pregnant or nursing, talk to your doctor about whether
taking FOSAMAX is right for you based on possible risk to you and your
child.
Talk to your doctor about any:
-- Problems with swallowing
-- Stomach or digestive problems
-- Other medical problems you have or have had in the past
-- Medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements
How should I take once weekly FOSAMAX?
See "What is the most important information I should know about
once weekly FOSAMAX?" for important information about how to take the
medicine and to help make sure it works for you. In addition, follow
these instructions:
-- Take 1 dose of FOSAMAX once a week.
-- Choose the day of the week that best fits your schedule. Every
week take 1 dose of FOSAMAX on your chosen day.
-- After getting up for the day and before taking your first
food, drink, or other medicine, take your FOSAMAX with plain
water only as follows:
-- TABLETS: Swallow one tablet with a full glass (6-8 oz) of
plain water.
-- ORAL SOLUTION: Drink one entire bottle of solution
followed by at least 2 ounces (a quarter of a cup) of
plain water.
-- It is important that you keep taking FOSAMAX for as long as
your doctor says to take it. For FOSAMAX to continue to work,
you need to keep taking it.
-- If you miss a dose, take only 1 dose of FOSAMAX on the morning
after you remember. Do not take 2 doses on the same day.
Continue your usual schedule of 1 dose once a week on your
chosen day.
-- If you think you took more than the prescribed dose of
FOSAMAX, drink a full glass of milk and contact your local
poison control center or emergency room right away. Do not try
to vomit. Do not lie down.
What should I avoid while taking FOSAMAX?
-- Do not eat, drink, or take other medicines or supplements
before taking FOSAMAX.
-- Wait for at least 30 minutes after taking FOSAMAX to eat,
drink, or take other medicines or supplements.
-- Do not lie down for at least 30 minutes after taking FOSAMAX.
Do not lie down until after your first food of the day.
What are the possible side effects of FOSAMAX?
Some patients may get severe digestive reactions from FOSAMAX.
(See "What is the most important information I should know about once
weekly FOSAMAX?") These reactions include irritation, inflammation, or
ulcers of the esophagus, which may sometimes bleed. This may occur
especially if patients do not drink the recommended amount of water
with FOSAMAX or if they lie down in less than 30 minutes or before
their first food of the day. Esophagus reactions may get worse if
patients continue to take FOSAMAX after developing symptoms of an
irritated esophagus.
Stop taking FOSAMAX and call your doctor right away if you get any
of these signs of possible serious problems:
-- Chest pain
-- Heartburn
-- Trouble or pain when swallowing
Side effects in patients taking FOSAMAX usually have been mild.
They generally have not caused patients to stop taking FOSAMAX.
The most common side effect is abdominal (stomach area) pain. Less
common side effects are nausea, vomiting, a full or bloated feeling in
the stomach, constipation, diarrhea, black or bloody stools (bowel
movements), gas, headache, a changed sense of taste, and bone, muscle,
and/or joint pain.
Severe bone, joint, and/or muscle pain has been reported in
patients taking, by mouth, bisphosphonates drugs that are used to
treat osteoporosis (thin bones). However, such reports have been rare.
This group of drugs includes FOSAMAX. Most of the patients were
postmenopausal women (women who had stopped having periods). Patients
developed pain within one day to several months after starting the
drug. Most patients experienced relief after stopping the drug.
Patients who develop severe bone, joint, and/or muscle pain after
starting FOSAMAX should contact their physician. Rarely, patients may
also experience joint swelling or swelling in their hands or legs.
Transient flu-like symptoms (rarely with fever), typically at the
start of treatment, have occurred.
In rare cases, patients taking FOSAMAX may get itching or eye
pain, or a rash that may be made worse by sunlight. Rarely, severe
skin reactions may occur. Patients may get allergic reactions, such as
hives or, in rare cases, swelling that can be of their face, lips,
tongue, or throat, which may cause trouble in breathing or swallowing.
Patients may experience dizziness. Mouth ulcers (sores) may occur if
the FOSAMAX tablet is chewed or dissolved in the mouth.
Rarely, patients have had jaw problems associated with delayed
healing and infection, often following tooth extraction.
Anytime you have a medical problem you think may be from 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. In
osteoporosis, bone is removed faster than it is formed, so overall
bone mass is lost and bones become weaker. Therefore, keeping bone
mass is important to keep your bones healthy. In both men and women,
osteoporosis may also be caused by certain medicines called
corticosteroids.
At first, osteoporosis usually has no symptoms, but it can cause
fractures (broken bones). Fractures usually cause pain. Fractures of
the bones of the spine may not be painful, but over time they can make
you shorter. Eventually, your spine can curve and your body can become
bent over. Fractures may happen during normal, everyday activity, such
as lifting, or from minor injury that would normally not cause bones
to break. Fractures most often occur at the hip, spine, or wrist. This
can lead to pain, severe disability, or loss of ability to move around
(mobility).
Who is at risk for osteoporosis?
Many things put people at risk of osteoporosis. The following
people have a higher chance of getting osteoporosis:
Women who:
-- Are going through or who are past menopause
Men who:
-- Are elderly
People who:
-- Are white (Caucasian) or oriental (Asian)
-- Are thin
-- Have family member with osteoporosis
-- Do not get enough calcium or vitamin D
-- Do not exercise
-- Smoke
-- Drink alcohol often
-- Take bone thinning medicines (like prednisone or other
corticosteroids) for a long time
What can I do to help prevent or treat osteoporosis?
In addition to FOSAMAX, your doctor may suggest one or more of the
following lifestyle changes:
-- Stop smoking. Smoking may increase your chance of getting
osteoporosis.
-- Reduce the use of alcohol. Too much alcohol may increase
the risk of osteoporosis and injuries that can cause
fractures.
-- Exercise regularly. Like muscles, bones need exercise to
stay strong and healthy. Exercise must be safe to prevent
injuries, including fractures. Talk with your doctor
before you begin any exercise program.
-- Eat a balanced diet. Having enough calcium in your diet 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.
What are the ingredients in FOSAMAX?
Tablets
FOSAMAX tablets contain alendronate sodium as the active
ingredient and the following inactive ingredients: cellulose, lactose,
croscarmellose sodium and magnesium stearate.
Oral Solution
FOSAMAX oral solution contains alendronate sodium as the active
ingredient and the following inactive ingredients: sodium citrate,
citric acid, sodium saccharin, artificial raspberry flavor, purified
water, sodium propylparaben and sodium butylparaben.
How do I store FOSAMAX?
Tablets
Store at room temperature, 59-86(degree)F (15-30(degree)C).
Oral Solution
Store at 77(degree)F (25(degree)C). Occasional storage between
59-86(degree)F (15-30(degree)C) is allowed. Do not freeze.
Discard all expired medicines. Keep all medicines out of the reach
of children.
General information about using FOSAMAX safely and effectively
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. This medicine was
prescribed for your particular condition. FOSAMAX acts specifically on
your bones. Do not use it for another condition or give it to others.
FOSAMAX is not indicated for use in children.
This leaflet is a summary of information about FOSAMAX. If you
have any questions or concerns about FOSAMAX or osteoporosis, talk to
your doctor, pharmacist, or other health care provider. You can ask
your doctor or pharmacist for information about FOSAMAX written for
health care providers. For more information, call 1-877-408-4699
(toll-free) or visit the following website: www.fosamax.com.
MERCK & CO., INC.
Issued February 2006 Whitehouse Station, NJ 08889, USA
*Registered trademark of MERCK & CO., Inc.
COPYRIGHT (C) 2000 MERCK & CO., Inc.
All rights reserved
9655602
FOSAMAX PLUS D(TM)
(ALENDRONATE SODIUM/CHOLECALCIFEROL) TABLETS
DESCRIPTION
FOSAMAX PLUS D*(C) contains alendronate sodium, a bisphosphonate,
and cholecalciferol (vitamin D3).
Alendronate sodium is a bisphosphonate that acts as a specific
inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are
synthetic analogs of pyrophosphate that bind to the hydroxyapatite
found in bone.
Alendronate sodium is chemically described as
(4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt
trihydrate.
The empirical formula of alendronate sodium is C4H12NNaO7P2--3H2O
and its formula weight is 325.12. The structural formula is:
(OBJECT OMITTED)
Alendronate sodium is a white, crystalline, nonhygroscopic powder.
It is soluble in water, very slightly soluble in alcohol, and
practically insoluble in chloroform.
Cholecalciferol (vitamin D3) is a secosterol that is the natural
precursor of the calcium-regulating hormone calcitriol (1,25
dihydroxyvitamin D3).
The chemical name of cholecalciferol is
(3a,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol. The empirical
formula of cholecalciferol is C27H44O and its molecular weight is
384.6. The structural formula is:
(OBJECT OMITTED)
* Trademark of MERCK & CO., Inc.
COPYRIGHT 2005 MERCK & CO., Inc.
All rights reserved
Cholecalciferol is a white, crystalline, odorless powder.
Cholecalciferol is practically insoluble in water, freely soluble in
usual organic solvents, and slightly soluble in vegetable oils.
FOSAMAX PLUS D for oral administration contains 91.37 mg of
alendronate monosodium salt trihydrate, the molar equivalent of 70 mg
of free acid, and 70 mcg of cholecalciferol equivalent to 2800
International Units (IU) vitamin D. Each tablet contains the following
inactive ingredients: microcrystalline cellulose, lactose anhydrous,
medium chain triglycerides, gelatin, croscarmellose sodium, sucrose,
colloidal silicon dioxide, magnesium stearate, butylated
hydroxytoluene, modified food starch, and sodium aluminum silicate.
CLINICAL PHARMACOLOGY
Mechanism of Action
Alendronate Sodium
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.
Cholecalciferol
Vitamin D3 is produced in the skin by photochemical conversion of
7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is
followed by non-enzymatic isomerization to vitamin D3. In the absence
of adequate sunlight exposure, vitamin D3 is an essential dietary
nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into
chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver.
Conversion to the active calcium-mobilizing hormone
1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by
both parathyroid hormone and hypophosphatemia. The principal action of
1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both
calcium and phosphate as well as regulate serum calcium, renal calcium
and phosphate excretion, bone formation and bone resorption.
Vitamin D is required for normal bone formation. Vitamin D
insufficiency develops when both sunlight exposure and dietary intake
are inadequate. Insufficiency is associated with negative calcium
balance, increased parathyroid hormone levels, bone loss, and
increased risk of skeletal fracture. In severe cases, deficiency
results in more severe hyperparathyroidism, hypophosphatemia, proximal
muscle weakness, bone pain and osteomalacia.
Pharmacokinetics
Absorption
Alendronate Sodium
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.
The alendronate in the FOSAMAX PLUS D tablet and the FOSAMAX(R)**
(alendronate sodium) 70 mg tablet is equally bioavailable.
A study examining the effect of timing of a meal on the
bioavailability of alendronate was performed in 49 postmenopausal
women. Bioavailability was decreased (by approximately 40%) when 10 mg
alendronate was administered either 0.5 or 1 hour before a
standardized breakfast, when compared to dosing 2 hours before eating.
In studies of treatment and prevention of osteoporosis, alendronate
was effective when administered at least 30 minutes before breakfast.
** Registered trademark of MERCK & CO., Inc.
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%.
Cholecalciferol
Following administration of FOSAMAX PLUS D after an overnight fast
and two hours before a standard meal, the baseline adjusted mean area
under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3
was 120.7 ng-hr/mL. The baseline adjusted mean maximal serum
concentration (Cmax) of vitamin D3 was 4.0 ng/mL, and the baseline
adjusted mean time to maximal serum concentration (Tmax) was 10.6 hrs.
The bioavailability of the 2800 IU vitamin D3 in FOSAMAX PLUS D is
similar to 2800 IU vitamin D3 administered alone.
Distribution
Alendronate Sodium
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%.
Cholecalciferol
Following absorption, vitamin D3 enters the blood as part of
chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver
where it undergoes metabolism to 25-hydroxyvitamin D3, the major
storage form. Lesser amounts are distributed to adipose tissue and
stored as vitamin D3 at these sites for later release into the
circulation. Circulating vitamin D3 is bound to vitamin D-binding
protein.
Metabolism
Alendronate Sodium
There is no evidence that alendronate is metabolized in animals or
humans.
Cholecalciferol
Vitamin D3 is rapidly metabolized by hydroxylation in the liver to
25-hydroxyvitamin D3, and subsequently metabolized in the kidney to
1,25-dihydroxyvitamin D3, which represents the biologically active
form. Further hydroxylation occurs prior to elimination. A small
percentage of vitamin D3 undergoes glucuronidation prior to
elimination.
Excretion
Alendronate Sodium
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.
Cholecalciferol
When radioactive vitamin D3 was intravenously administered to
healthy subjects, the mean urinary excretion of radioactivity after 48
hours was 2.4% of the administered dose, and the mean fecal excretion
of radioactivity after 48 hours was 4.9% of the administered dose. In
both cases, the excreted radioactivity was almost exclusively as
metabolites of the parent. The mean half-life of baseline adjusted
vitamin D3 in the serum following an oral dose of FOSAMAX PLUS D is
approximately 14 hours.
Special Populations
Pediatric: Alendronate pharmacokinetics have not been investigated
in patients <18 years of age.
Gender: Bioavailability and the fraction of an IV dose of
alendronate excreted in urine were similar in men and women.
Geriatric:
Alendronate Sodium
Bioavailability and disposition of alendronate (urinary excretion)
were similar in elderly and younger patients. No dosage adjustment of
alendronate is necessary (see DOSAGE AND ADMINISTRATION).
Cholecalciferol
Dietary requirements of vitamin D3 are increased in the elderly.
Race: Pharmacokinetic differences due to race have not been
studied.
Renal Insufficiency:
Alendronate Sodium
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 PLUS D is not recommended for patients with more
severe renal insufficiency (creatinine clearance <35 mL/min) due to
lack of experience with alendronate in renal failure.
Cholecalciferol
Patients with renal insufficiency will have decreased ability to
form the active 1,25-dihydroxyvitamin D3 metabolite.
Hepatic Insufficiency:
Alendronate Sodium
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.
Cholecalciferol
Vitamin D3 may not be adequately absorbed in patients who have
malabsorption due to inadequate bile production.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Alendronate Sodium
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.
Cholecalciferol
Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g.,
cholestyramine, colestipol) may impair the absorption of vitamin D.
Anticonvulsants, cimetidine, and thiazides may increase the catabolism
of vitamin D.
Pharmacodynamics
Alendronate Sodium
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. The
decrease in the rate of bone resorption indicated by these markers was
evident as early as one month and at three to six months reached a
plateau that was maintained for the entire duration of treatment with
FOSAMAX. In osteoporosis treatment studies FOSAMAX 10 mg/day decreased
the markers of bone formation, osteocalcin and bone specific alkaline
phosphatase by approximately 50%, and total serum alkaline phosphatase
by approximately 25 to 30% to reach a plateau after 6 to 12 months.
Similar reductions in the rate of bone turnover were observed in
postmenopausal women during one-year studies with once weekly FOSAMAX
70 mg for the treatment of osteoporosis. These data indicate that the
rate of bone turnover reached a new steady-state, despite the
progressive increase in the total amount of alendronate deposited
within bone.
As a result of inhibition of bone resorption, asymptomatic
reductions in serum calcium and phosphate concentrations were also
observed following treatment with FOSAMAX. In the long-term studies,
reductions from baseline in serum calcium (approximately 2%) and
phosphate (approximately 4 to 6%) were evident the first month after
the initiation of FOSAMAX 10 mg. No further decreases in serum calcium
were observed for the five-year duration of treatment; however, serum
phosphate returned toward prestudy levels during years three through
five. In one-year studies with once weekly FOSAMAX 70 mg, similar
reductions were observed at 6 and 12 months. The reduction in serum
phosphate may reflect not only the positive bone mineral balance due
to FOSAMAX but also a decrease in renal phosphate reabsorption.
Osteoporosis in men
Treatment of men with osteoporosis with FOSAMAX 10 mg/day for two
years reduced urinary excretion of cross-linked N-telopeptides of type
I collagen by approximately 60% and bone-specific alkaline phosphatase
by approximately 40%. Similar reductions were observed in a one-year
study in men with osteoporosis receiving once weekly FOSAMAX 70 mg.
Cholecalciferol
Vitamin D is required for normal bone formation. Vitamin D
insufficiency is associated with negative calcium balance, leading to
increased parathyroid hormone levels and worsening of bone loss
associated with osteoporosis. When taken without vitamin D,
alendronate is also associated with a reduction in serum calcium
concentrations and increased parathyroid hormone levels. In a 15-week
trial, 717 postmenopausal women and men, mean age 67 years, with
osteoporosis (lumbar spine bone mineral density (BMD) of at least 2.5
standard deviations below the premenopausal mean) were randomized to
receive either weekly FOSAMAX PLUS D 70 mg/2800 IU vitamin D or weekly
FOSAMAX 70 mg alone with no vitamin D supplementation. Patients who
were vitamin D deficient (25-hydroxyvitamin D <9 ng/mL) at baseline
were excluded. Treatment with FOSAMAX PLUS D 70 mg/2800 IU res |