Alendronate Sodium (3232)
[ a-len-droe'-nate soe'-dee-um ]
| Ingredients: |
Alendronate Sodium |
| Indications: |
Osteoporosis, glucocorticoid- induced; Osteoporosis; Paget's disease |
| Pregnancy Category: |
C |
| FDA Approved: |
1995- 09- 01 |
| Classes: |
Bisphosphonates; WHO Formulary |
| Brand Names: |
Aldrox
-
Chile
;
Alenato
-
Argentina
;
Alend
-
Korea
;
Alnax
-
Paraguay
;
Alovell
-
Indonesia
;
Arendal
-
Peru
;
Armol
-
Colombia
;
Bifemelan
-
Colombia
;
Bifosa
-
India
;
Bonapex
-
Egypt
;
Defixal
-
Costa-rica, Dominican-republic, El-salvador, Guatemala, Nicaragua, Panama
;
Endronax
-
Brazil
;
Eucalen
-
Colombia
;
Fixopan
-
Ecuador
;
Fosalan
-
Israel
;
Fosamax
-
US; Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Costa-rica, Czech-republic, Denmark, Ecuador, Egypt, El-salvador, England, France, Germany, Guatemala, Honduras, Hong-kong, Hungary, Indonesia, Ireland, Italy, Korea, Malaysia, Mexico, Netherlands, Nicaragua, Norway, Panama, Peru, Philippines, Poland, Singapore, South-africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Venezuela
;
Fosmin
-
Peru
;
Fosval
-
Paraguay
;
Marvil
-
Peru, Uruguay
;
MaxiBone
-
Israel
;
MaxiBone 70
-
Israel
;
Neobon
-
Colombia
;
Osdron
-
Brazil
;
Osdronat
-
Colombia
;
Oseotenk
-
Argentina
;
Osficar
-
Colombia
;
Oslene
-
Indonesia
;
Osteofar
-
Indonesia
;
Osteofos
-
Hong-kong
;
Osteopor
-
Uruguay
;
Osteosan
-
Chile
;
Osteovan
-
Costa-rica
;
Osticalcin
-
Colombia
;
Porosal
-
Venezuela
;
Tibolene
-
Colombia
;
Voroste
-
Indonesia
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$76.90
(
Osteoporosis ;
Fosamax ;
70 mg ;
1 tablet(s)/week ;
28 day supply
)
$82.37
(
Osteoporosis ;
Fosamax ;
10 mg ;
1 tablet(s)/day ;
30 day supply
)
$247.12
(
Osteoporosis Prevention ;
Fosamax ;
5 mg ;
1 tablet/day ;
90 day supply
)
$1,069.80
(
Paget's Disease ;
Fosamax ;
40 mg ;
1 tablet(s)/day ;
180 day supply
)
|
DESCRIPTION
|
| |
Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast- mediated bone resorption. Bisphosphonates
are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
Alendronate sodium is chemically described as (4- amino- 1- hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.
The empirical formula of alendronate sodium is C4 H12 NNaO7 P2 ·3H2 O and its formula weight is 325.12.
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 tablets 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. Fosamax tablets 10 mg also contain
carnauba wax.
|
Oral Solution
|
| |
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 IV reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5-
70 mg when administered after an overnight fast and 2 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.
Alendronate sodium 70- mg oral solution and alendronate sodium 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 2 hours after a standardized breakfast.
Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
|
Distribution
|
| |
Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/ kg IV administration
but is then rapidly redistributed to bone or excreted in the urine. The mean steady- state volume of distribution, exclusive
of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than
5 ng/ ml) for analytical detection. Protein binding in human plasma is approximately 78%.
|
Metabolism
|
| |
There is no evidence that alendronate is metabolized in animals or humans.
|
Excretion
|
| |
Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity
was recovered in the feces. Following a single 10- mg IV dose, the renal clearance of alendronate was 71 ml/ min [64, 78;
90% confidence interval (CI)], and systemic clearance did not exceed 200 ml/ min. Plasma concentrations fell by more than
95% within 6 hours following IV administration. The terminal half- life in humans is estimated to exceed 10 years, probably
reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment
with alendronate sodium (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that
absorbed from the gastrointestinal tract.
|
Special Populations
|
| |
Pediatric
|
| |
Alendronate pharmacokinetics have not been investigated in patients <18 years of age.
|
Gender
|
| |
Bioavailability and the fraction of an IV dose excreted in urine were similar in men and women.
|
Geriatric
|
| |
Bioavailability and disposition (urinary excretion) were similar in elderly 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- 60 ml/
min). Alendronate sodium is not recommended for patients with more severe renal insufficiency (creatinine clearance <35 ml/ min)
due to lack of experience with alendronate in renal failure.
|
Hepatic Insufficiency
|
| |
As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with
hepatic insufficiency. No dosage adjustment is necessary.
|
|
Drug Interactions
|
| |
Also see 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 3 times daily for 5 days) did not produce a clinically meaningful change in the
oral bioavailability of alendronate (a mean increase ranging from 20- 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- 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 1 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 6 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 1 collagen). These biochemical changes tended
to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not
differ from placebo after 7 months.
Long- term treatment of osteoporosis with alendronate sodium 10 mg/ day (for up to 5 years) reduced urinary excretion of markers
of bone resorption, deoxypyridinoline and cross- linked N- telopeptides of Type 1 collagen, by approximately 50% and 70%,
respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients
in osteoporosis prevention studies who received alendronate sodium 5 mg/ day. The decrease in the rate of bone resorption
indicated by these markers was evident as early as 1 month and at 3- 6 months reached a plateau that was maintained for the
entire duration of treatment with alendronate sodium. In osteoporosis treatment studies alendronate sodium 10 mg/ day decreased
the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline
phosphatase, by approximately 25- 30% to reach a plateau after 6- 12 months. In osteoporosis prevention studies alendronate
sodium 5 mg/ day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar
reductions in the rate of bone turnover were observed in postmenopausal women during 1 year studies with once weekly alendronate
sodium 70 mg for the treatment of osteoporosis and once weekly alendronate sodium 35 mg for the prevention of osteoporosis.
These data indicate that the rate of bone turnover reached a new steady- state, despite the progressive increase in the total
amount of alendronate deposited within bone.
As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also
observed following treatment with alendronate sodium. In the long- term studies, reductions from baseline in serum calcium
(approximately 2%) and phosphate (approximately 4- 6%) were evident the first month after the initiation of alendronate sodium
10 mg. No further decreases in serum calcium were observed for the 5- year duration of treatment; however, serum phosphate
returned toward prestudy levels during Years 3- 5. Similar reductions were observed with alendronate sodium 5 mg/ day. In
1- year studies with once weekly alendronate sodium 35 and 70 mg, similar reductions were observed at 6 and 12 months. The
reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease
in renal phosphate reabsorption.
|
Osteoporosis in Men
|
| |
Treatment of men with osteoporosis with alendronate sodium 10 mg/ day for 2 years reduced urinary excretion of cross- linked
N- telopeptides of Type 1 collagen by approximately 60% and bone- specific alkaline phosphatase by approximately 40%. Similar
reductions were observed in a 1- year study in men with osteoporosis receiving once weekly alendronate sodium 70 mg.
|
Glucocorticoid-Induced Osteoporosis
|
| |
Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially
vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone
formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly
inhibiting bone formation.
In clinical studies of up to 2 years' duration, alendronate sodium 5 and 10 mg/ day reduced cross- linked N- telopeptides
of Type 1 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- 30% and 8- 18%, respectively. As a result
of inhibition of bone resorption, alendronate sodium 5 and 10 mg/ day induced asymptomatic decreases in serum calcium (approximately
1- 2%) and serum phosphate (approximately 1- 8%).
|
Paget's Disease of Bone
|
| |
Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling.
Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal
bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological
fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index
of disease activity, provides an objective measure of disease severity and response to therapy.
Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation.
In clinical trials, alendronate sodium 40 mg once daily for 6 months produced significant decreases in serum alkaline phosphatase
as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate
sodium induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.
|
|
|
CLINICAL STUDIES
|
| |
Treatment of Osteoporosis
|
| |
Postmenopausal Women
|
| |
Effect on Bone Mineral Density
|
| |
The efficacy of alendronate sodium 10 mg once daily in postmenopausal women, 44- 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 2 or 3 years duration. These included two 3- year, multicenter studies
of virtually identical design, one performed in the US and the other in 15 different countries (Multinational), which enrolled
478 and 516 patients, respectively.
At 3 years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each
study in patients who received alendronate sodium 10 mg/ day. Total body BMD also increased significantly in each study, suggesting
that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD
were evident as early as 3 months and continued throughout the 3 years of treatment. In the 2- year extension of these studies,
treatment of 147 patients with alendronate sodium 10 mg/ day resulted in continued increases in BMD at the lumbar spine and
trochanter (absolute additional increases between Years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral
neck, forearm and total body were maintained. Alendronate sodium was similarly effective regardless of age, race, baseline
rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).
Thus, overall alendronate sodium reverses the loss of bone mineral density, a central factor in the progression of osteoporosis.
In patients with postmenopausal osteoporosis treated with alendronate sodium 10 mg/ day for 1 or 2 years, the effects of treatment
withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss
were similar to those of the placebo groups. These data indicate that continued treatment with alendronate sodium is required
to maintain the effect of the drug.
The therapeutic equivalence of once weekly alendronate sodium 70 mg (n=519) and alendronate sodium 10 mg daily (n=370) was
demonstrated in a 1 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 1 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 2 treatment groups were also
similar with regard to BMD increases at other skeletal sites. The results of the intention- to- treat analysis were consistent
with the primary analysis of completers.
|
Effect on Fracture Incidence
|
| |
Data on the effects of alendronate sodium on fracture incidence are derived from three clinical studies:
- US 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.
- 3- Year Study of the Fracture Intervention Trial (FIT): A study of patients with at least 1 baseline vertebral fracture.
- 4- Year Study of FIT: A study of patients with low bone mass but without a baseline vertebral fracture.
To assess the effects of alendronate sodium on the incidence of vertebral fractures (detected by digitized radiography; approximately
one- third of these were clinically symptomatic), the US and Multinational studies were combined in an analysis that compared
placebo to the pooled dosage groups of alendronate sodium (5 or 10 mg for 3 years or 20 mg for 2 years followed by 5 mg for
1 year). There was a statistically significant reduction in the proportion of patients treated with alendronate sodium experiencing
1 or more new vertebral fractures relative to those treated with placebo (3.2% vs 6.2%; a 48% relative risk reduction). A
reduction in the total number of new vertebral fractures (4.2 vs 11.3 per 100 patients) was also observed. In the pooled analysis,
patients who received alendronate sodium had a loss in stature that was statistically significantly less than was observed
in those who received placebo (- 3.0 mm vs - 4.6 mm).
The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women. The 3- year study of patients who
had at least 1 baseline radiographic vertebral fracture and the 4- 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: 3-Year Study (patients with at least one baseline radiographic vertebral fracture)
|
| |
This randomized, double- blind, placebo- controlled, 2027- patient study (alendronate sodium, n=1022; placebo, n=1005) demonstrated
that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at 3 years as
shown in TABLE 1 .
| TABLE 1
Effect of Alendronate Sodium on Fracture Incidence in the 3- Year Study of FIT — Patients With Vertebral Fracture at Baseline
|
| Patients With: |
Alendronate Sodium (n=1022) |
Placebo (n=1005) |
Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk |
| Vertebral Fractures (Diagnosed by X- ray)*
|
| ≥1 New vertebral fracture |
7.9% |
15.0% |
7.1% |
47%§ |
| ≥2 New vertebral fractures |
0.5% |
4.9% |
4.4% |
90%§ |
| Clinical (Symptomatic) Fractures
|
| Any clinical (symptomatic) fracture |
13.8% |
18.1% |
4.3% |
26%¤ |
| ≥1 Clinical (symptomatic) vertebral fracture |
2.3% |
5.0% |
2.7% |
54%‡ |
| Hip fracture
|
1.1% |
2.2% |
1.1% |
51%† |
| Wrist (forearm) fracture
|
2.2% |
4.1% |
1.9% |
48%† |
|
| *
|
Number evaluable for vertebral fractures: alendronate sodium, 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 alendronate sodium significantly
reduced the incidence of hospitalizations (25.0% vs 30.7%).
In the 3- year study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022
patients on alendronate sodium, p=0.047.
|
Fracture Intervention Trial: 4-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture)
|
| |
This randomized, double- blind, placebo- controlled, 4432- patient study (alendronate sodium, n=2214; placebo, n=2218) further
investigated the reduction in fracture incidence due to alendronate sodium. The intent of the study was to recruit women with
osteoporosis, defined as a baseline femoral neck BMD at least 2 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 nonosteoporotic women. The results are shown in TABLE 2 for the patients with osteoporosis.
| TABLE 2
Effect of Alendronate Sodium on Fracture Incidence in Osteoporotic* Patients in the 4- Year Study of FIT — Patients Without
Vertebral Fracture at Baseline
|
| Patients With: |
Alendronate Sodium (n=1545) |
Placebo (n=1521) |
Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk |
| Vertebral Fractures (Diagnosed by X- ray)†
|
| ≥1 New vertebral fracture |
2.5% |
4.8% |
2.3% |
48%¶ |
| ≥2 New vertebral fractures |
0.1% |
0.6% |
0.5% |
78%§ |
| Clinical (Symptomatic) Fractures
|
| Any clinical (symptomatic) fracture |
12.9% |
16.2% |
3.3% |
22%¤ |
| ≥1 Clinical (symptomatic) vertebral fracture |
1.0% |
1.6% |
0.6% |
41% (NS)‡ |
| 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: alendronate sodium, 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 3- year study of FIT, alendronate sodium reduced the percentage of women experiencing at least 1 new radiographic vertebral
fracture from 15.0% to 7.9% (47% relative risk reduction, p <0.001); in the 4- 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 US/ Multinational studies, from 6.2% to 3.2%
(48% relative risk reduction, p=0.034).
Alendronate sodium reduced the percentage of women experiencing multiple (2 or more) new vertebral fractures from 4.2% to
0.6% (87% relative risk reduction, p <0.001) in the combined US/ Multinational studies and from 4.9% to 0.5% (90% relative
risk reduction, p <0.001) in the 3- year study of FIT. In the 4- year study of FIT, alendronate sodium reduced the percentage
of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).
Thus, alendronate sodium reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they
had a previous radiographic vertebral fracture.
Alendronate sodium, over a 3- or 4- year period, was associated with statistically significant reductions in loss of height
versus 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 3- year study and 1.3 mm in the 4- year study.
|
|
Bone Histology
|
| |
Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate sodium at doses ranging from 1- 20
mg/ day for 1, 2, or 3 years revealed normal mineralization and structure, as well as the expected decrease in bone turnover
relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and
baboons exposed to long- term alendronate treatment, support the conclusion that bone formed during therapy with alendronate
sodium is of normal quality.
|
|
Men
|
| |
The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.A
two- year, double- blind, placebo- controlled, multicenter study of alendronate sodium 10 mg once daily enrolled a total of
241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either: (1) a BMD T- score ≤ - 2 at the femoral
neck and ≤ - 1 at the lumbar spine; or (2) a baseline osteoporotic fracture and a BMD T- score ≤ - 1 at the femoral neck.
At 2 years, the mean increases relative to placebo in BMD in men receiving alendronate sodium 10 mg/ day were significant
at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. 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). Treatment with alendronate sodium also reduced height loss
(alendronate sodium, - 0.6 mm vs placebo, - 2.4 mm).
A 1- year, double- blind, placebo- controlled, multicenter study of once weekly alendronate sodium 70 mg enrolled a total
of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either: 1)A BMD T- score T- score ≤ - 2 at
the femoral neck and ≤- 1 at the lumbar spine, 2) A BMD T- score ≤- 2 at the lumbar spine and ≤- 1 at the femoral neck, or
3) A baseline osteoporotic fracture and a BMD T- score ≤- 1 at the femoral neck. At one year, the mean increases relative
to placebo in BMD in men receiving alendronate sodium 70 mg once weekly were significant at the following sites: lumbar spine,
2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at 1 year
in 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 (1609) (alendronate sodium 5 mg/ day; n=498) who were at least 6 months
postmenopausal were entered into a 2- year study without regard to their baseline BMD. In the other study, 447 patients (alendronate
sodium 5 mg/ day; n=88), who were between 6 months and 3 years postmenopause, were treated for up to 3 years. In the placebo-
treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total
body. In contrast, alendronate sodium 5 mg/ day prevented bone loss in the majority of patients and induced significant increases
in mean bone mass at each of these sites. In addition, alendronate sodium 5 mg/ day reduced the rate of bone loss at the forearm
by approximately half relative to placebo. Alendronate sodium 5 mg/ day was similarly effective in this population regardless
of age, time since menopause, race and baseline rate of bone turnover.
The therapeutic equivalence of once weekly alendronate sodium 35 mg (n=362) and alendronate sodium 5 mg daily (n=361) was
demonstrated in a 1- 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 1 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 2 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 3 years who received alendronate sodium at doses of up
to 10 mg/ day.
|
|
Concomitant Use With Estrogen/Hormone Replacement Therapy (HRT)
|
| |
The effects on BMD of treatment with alendronate sodium 10 mg once daily and conjugated estrogen (0.625 mg/ day) either alone
or in combination were assessed in a 2- year, double- blind, placebo- controlled study of hysterectomized postmenopausal osteoporotic
women (n=425). At 2 years, the increases in lumbar spine BMD from baseline were significantly greater with the combination
(8.3%) than with either estrogen or alendronate sodium alone (both 6.0%).
The effects on BMD when alendronate sodium was added to stable doses (for at least 1 year) of HRT (estrogen ± progestin) were
assessed in a 1- year, double- blind, placebo- controlled study in postmenopausal osteoporotic women (n=428). The addition
of alendronate sodium 10 mg once daily to HRT produced, at 1 year, significantly greater increases in lumbar spine BMD (3.7%)
versus HRT alone (1.1%).
In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen
at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.
Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there
was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with alendronate
sodium and HRT, 94% on alendronate sodium alone, and 78% on HRT alone. The long- term effects of combined alendronate sodium
and HRT on fracture occurrence and fracture healing have not been studied.
|
Glucocorticoid-Induced Osteoporosis
|
| |
The efficacy of alendronate sodium 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/ day
of prednisone or equivalent) was demonstrated in two, 1- year, double- blind, randomized, placebo- controlled, multicenter
studies of virtually identical design, one performed in the US and the other in 15 different countries [Multinational (which
also included alendronate sodium 2.5 mg/ day)]. These studies enrolled 232 and 328 patients, respectively, between the ages
of 17 and 83 with a variety of glucocorticoid- requiring diseases. Patients received supplemental calcium and vitamin D.
After 1 year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in
patients who received alendronate sodium 5 mg/ day. In the placebo- treated patients, a significant decrease in BMD occurred
at the femoral neck (- 1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained
with alendronate sodium 5 mg/ day. The increases in BMD with alendronate sodium 10 mg/ day were similar to those with alendronate
sodium 5 mg/ day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases
(relative to placebo) with alendronate sodium 10 mg/ day were greater than those with alendronate sodium 5 mg/ day at the
lumbar spine (4.1% vs 1.6%) and trochanter (2.8% vs 1.7%), but not at other sites. Alendronate sodium was effective regardless
of dose or duration of glucocorticoid use. In addition, alendronate sodium was similarly effective regardless of age (<65
vs ≥65 years), race (Caucasian versus 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 1 year who received alendronate sodium at doses of up
to 10 mg/ day.
Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/ day of prednisone or equivalent
continued into a 1- year double- blind extension. After 2 years of treatment, spine BMD increased by 3.7% and 5.0% relative
to placebo with alendronate sodium 5 and 10 mg/ day, respectively. Significant increases in BMD (relative to placebo) were
also observed at the femoral neck, trochanter, and total body.
After 1 year, 2.3% of patients treated with alendronate sodium 5 or 10 mg/ day (pooled) versus 3.7% of those treated with
placebo experienced a new vertebral fracture (not significant). However, in the population studied for 2 years, treatment
with alendronate sodium (pooled dosage groups: 5 or 10 mg for 2 years or 2.5 mg for 1 year followed by 10 mg for 1 year) significantly
reduced the incidence of patients with a new vertebral fracture (alendronate sodium 0.7% vs placebo 6.8%).
|
Paget's Disease of Bone
|
| |
The efficacy of alendronate sodium 40 mg once daily for 6 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 US comparative study with etidronate disodium 400 mg/ day.
At 6 months the suppression in alkaline phosphatase in patients treated with alendronate sodium was significantly greater
than that achieved with etidronate and contrasted with the complete lack of response in placebo- treated patients. Response
(defined as either normalization of serum alkaline phosphatase or decrease from baseline ≥60%) occurred in approximately 85%
of patients treated with alendronate sodium in the combined studies versus 30% in the etidronate group and 0% in the placebo
group. Alendronate sodium was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or
baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).
Bone histology was evaluated in 33 patients with Paget's disease treated with alendronate sodium 40 mg/ day for 6 months.
As in patients treated for osteoporosis (see Treatment of Osteoporosis, Postmenopausal Women, Bone Histology ), alendronate sodium did not impair mineralization, and the expected decrease in the rate of bone turnover was observed.
Normal lamellar bone was produced during treatment with alendronate sodium, even where pre- existing bone was woven and disorganized.
Overall, bone histology data support the conclusion that bone formed during treatment with alendronate sodium is of normal
quality.
|
|
INDICATIONS AND USAGE
|
| |
Alendronate sodium is indicated for:
| • |
Treatment and prevention of osteoporosis in postmenopausal women.
| • |
For the treatment of osteoporosis, alendronate sodium 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, alendronate sodium may be considered in postmenopausal women who are at risk of developing
osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture.
Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development
of postmenopausal osteoporosis include early menopause; moderately low bone mass (for example, at least 1 standard deviation
below the mean for healthy young adult women); thin body build; Caucasian or Asian race; and family history of osteoporosis.
The presence of such risk factors may be important when considering the use of alendronate sodium 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 2 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 alendronate sodium oral solution.
|
| • |
Hypersensitivity to any component of this product.
|
| • |
Hypocalcemia (see PRECAUTIONS, General ).
|
|
WARNINGS
|
| |
Alendronate sodium, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding
and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate
sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs
or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and
seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking alendronate
sodium and/ or who fail to swallow it with the recommended amount of water, and/ or who continue to take alendronate sodium
after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions
are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION ). In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should
be used under appropriate supervision.
Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and a potential for worsening
of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal
problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).
There have been postmarketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased
risk was observed in controlled clinical trials.
|
PRECAUTIONS
|
| |
General
|
| |
Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be considered.
Hypocalcemia must be corrected before initiating therapy with alendronate sodium (see CONTRAINDICATIONS ). Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients
with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium.
Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium
and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be
greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.
Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients
receiving glucocorticoids.
|
Musculoskeletal Pain
|
| |
In postmarketing 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 alendronate sodium. Most of the patients were
postmenopausal women. The time to onset of symptoms varied from 1 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 alendronate sodium, the percentages of patients with these symptoms were similar
in the alendronate sodium and placebo groups.
|
Dental
|
| |
Osteonecrosis of the jaw, generally associated with tooth extraction and/ or local infection, often with delayed healing,
has been reported in patients taking bisphosphonates. Most reported cases of bisphosphonate- associated osteonecrosis have
been in cancer patients treated with IV bisphosphonates, but some have occurred in patients with postmenopausal osteoporosis.
Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies ( e.g., chemotherapy, radiotherapy, corticosteroids), poor oral hygiene, and co- morbid disorders ( e.g., pre- existing dental disease, anemia, coagulopathy, infection).
Patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy should receive care by an oral surgeon.
Dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest
whether discontinuation of bisphosphonate treatment reduces the risk for ONJ. Clinical judgment of the treating physician
should guide the management plan of each patient based on individual benefit/ risk assessment.
|
Renal Insufficiency
|
| |
Alendronate sodium is not recommended for patients with renal insufficiency (creatinine clearance <35 ml/ min). (See DOSAGE AND ADMINISTRATION .)
|
Glucocorticoid-Induced Osteoporosis
|
| |
The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone
or equivalent has not been established (see INDICATIONS AND USAGE ). Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement
considered.
A bone mineral density measurement should be made at the initiation of therapy and repeated after 6- 12 months of combined
alendronate sodium and glucocorticoid treatment.
The efficacy of alendronate sodium for the treatment of glucocorticoid- induced osteoporosis has been shown in patients with
a median bone mineral density which was 1.2 standard deviations below the mean for healthy young adults.
The efficacy of alendronate sodium has been established in studies of 2 years' duration. The greatest increase in bone mineral
density occurred in the first year with maintenance or smaller gains during the second year. Efficacy of alendronate sodium
beyond 2 years has not been studied.
The efficacy of alendronate sodium in respect to fracture prevention has been demonstrated for vertebral fractures. However,
this finding was based on very few fractures that occurred primarily in postmenopausal women. The efficacy for prevention
of nonvertebral fractures has not been demonstrated.
|
Information for the Patient
|
| |
General
|
| |
Physicians should instruct their patients to read the patient package insert before starting therapy with alendronate sodium
and to reread it each time the prescription is renewed.
Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight- bearing
exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/ or
excessive alcohol consumption, if these factors exist.
|
Dosing Instructions
|
| |
Patients should be instructed that the expected benefits of alendronate sodium may only be obtained when it is taken with
plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of
the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption ).
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed
to swallow each tablet of alendronate sodium with a full glass of water (6- 8 oz). To facilitate gastric emptying patients
should drink at least 2 oz (a quarter of a cup) of water after taking alendronate sodium 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 alendronate sodium at bedtime or before arising for the
day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems.
Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing,
retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician.
Patients should be instructed that if they miss a dose of once weekly alendronate sodium, they should take 1 dose on the morning
after they remember. They should not take 2 doses on the same day but should return to taking 1 dose once a week, as originally
scheduled on their chosen day.
|
|
Carcinogenesis, Mutagenesis, and 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- 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 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 (IV versus oral) on the risk has not been studied.
There are no studies in pregnant women. Alendronate sodium 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 alendronate sodium is administered to nursing women.
|
Pediatric Use
|
| |
Safety and effectiveness in pediatric patients have not been established.
|
Geriatric Use
|
| |
Of the patients receiving alendronate sodium 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 alendronate sodium in the US and Multinational osteoporosis
treatment studies in women, the osteoporosis study in men, glucocorticoid- induced osteoporosis studies, and Paget's disease
studies (see CLINICAL STUDIES ), 45%, 50%, 37%, and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed
between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
|
|
DRUG INTERACTIONS
|
| |
Also see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions .
Calcium Supplements/Antacids
|
| |
It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate sodium.
Therefore, patients must wait at least ½ hour after taking alendronate sodium 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 alendronate sodium greater than 10 mg and aspirin- containing products.
|
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
|
| |
Alendronate sodium 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 alendronate sodium 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 alendronate sodium.
|
|
ADVERSE REACTIONS
|
| |
Clinical Studies
|
| |
In clinical studies of up to 5 years in duration adverse experiences associated with alendronate sodium usually were mild,
and generally did not require discontinuation of therapy.
Alendronate sodium has been evaluated for safety in approximately 8000 postmenopausal women in clinical studies.
Treatment of Osteoporosis
|
| |
Postmenopausal Women
|
| |
In two identically designed, 3- year, placebo- controlled, double- blind, multicenter studies (US and Multinational; n=994),
discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate
sodium 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 alendronate sodium 5 mg/
day for 2 years and 10 mg/ day for either 1 or 2 additional years and 10.1% of 3223 patients treated with placebo. Discontinuations
due to upper gastrointestinal adverse experiences were: alendronate sodium, 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 alendronate sodium or placebo are presented in TABLE 3 .
| TABLE 3
Osteoporosis Treatment Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
US/ Multinational Studies |
Fracture Intervention Trial |
| |
|
Alendronate Sodium* |
Placebo |
Alendronate Sodium† |
Placebo |
| |
|
(n=196) |
(n=397) |
(n=3236) |
(n=3223) |
| Gastrointestinal
|
| |
Abdominal pain |
6.6% |
4.8% |
1.5% |
1.5% |
| |
Nausea |
3.6% |
4.0% |
1.1% |
1.5% |
| |
Dyspepsia |
3.6% |
3.5% |
1.1% |
1.2% |
| |
Constipation |
3.1% |
1.8% |
0.0% |
0.2% |
| |
Diarrhea |
3.1% |
1.8% |
0.6% |
0.3% |
| |
Flatulence |
2.6% |
0.5% |
0.2% |
0.3% |
| |
Acid regurgitation |
2.0% |
4.3% |
1.1% |
0.9% |
| |
Esophageal ulcer |
1.5% |
0.0% |
0.1% |
0.1% |
| |
Vomiting |
1.0% |
1.5% |
0.2% |
0.3% |
| |
Dysphagia |
1.0% |
0.0% |
0.1% |
0.1% |
| |
Abdominal distention |
1.0% |
0.8% |
0.0% |
0.0% |
| |
Gastritis |
0.5% |
1.3% |
0.6% |
0.7% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle, or joint) pain |
4.1% |
2.5% |
0.4% |
0.3% |
| |
Muscle cramp |
0.0% |
1.0% |
0.2% |
0.1% |
| Nervous System/ Psychiatric
|
| |
Headache |
2.6% |
1.5% |
0.2% |
0.2% |
| |
Dizziness |
0.0% |
1.0% |
0.0% |
0.1% |
| Special Senses
|
| |
Taste perversion |
0.5% |
1.0% |
0.1% |
0.0% |
|
| *
|
10 mg/ day for 3 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 alendronate sodium (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 alendronate sodium 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 alendronate sodium
in the US and Multinational studies. The adverse experience profile for the 296 patients who received continued treatment
with either 5- or 10- mg doses of alendronate sodium in the 2- year extension of these studies (treatment Years 4 and 5) was
similar to that observed during the 3- year placebo- controlled period. During the extension period, of the 151 patients treated
with alendronate sodium 10 mg/ day, the proportion of patients who discontinued therapy due to any clinical adverse experience
was similar to that during the first 3 years of the study.
In a 1- year, double- blind multicenter study, the overall safety and tolerability profiles of once weekly alendronate sodium
70 mg and alendronate sodium 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 TABLE 4 .
| TABLE 4
Osteoporosis Treatment Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
Alendronate Sodium |
| |
|
Once Weekly 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 distension |
1.0% |
1.4% |
| |
Constipation |
0.8% |
1.6% |
| |
Flatulence |
0.4% |
1.6% |
| |
Gastritis |
0.2% |
1.1% |
| |
Gastric ulcer |
0.0% |
1.1% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle, joint) pain |
2.9% |
3.2% |
| |
Muscle cramp |
0.2% |
1.1% |
|
|
Men
|
| |
In two placebo- controlled, double- blind, multicenter studies in men (a 2- year study of alendronate sodium 10 mg/ day and
a 1- year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse
experience were 2.7% for alendronate sodium 10 mg/ day vs 10.5% for placebo, and 6.4% for once weekly alendronate sodium 70
mg vs 8.6% for placebo. The adverse experiences considered by the investigators as possibly, probably, of definitely drug
related in ≥2% of patients treated with either alendronate sodium or placebo are presented in TABLE 5A and TABLE 5B .
| TABLE 5A
Osteoporosis Study in Men — 2- Year Study — Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related
by the Investigators and Reported in ≥2% of Patients
|
| |
|
Alendronate Sodium 10 mg/ day |
Placebo |
| |
|
(n=146) |
(n=95) |
| Gastrointestinal
|
| |
Acid regurgitation |
4.1% |
3.2% |
| |
Flatulence |
4.1% |
1.1% |
| |
Gastroedophageal reflux disease |
0.7% |
3.2% |
| |
Dyspepsia |
3.4% |
0.0% |
| |
Diarrhea |
1.4% |
1.1% |
| |
Abdominal pain |
2.1% |
1.1% |
| |
Nausea |
2.1% |
0.0% |
|
| TABLE 5B
Osteoporosis Study in Men — 1 Year Study — Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by
the Investigators and Reported in ≥2% of Patients
|
| |
|
Once Weekly Alendronate Sodium 70 mg |
Placebo |
| |
|
(n=109) |
(n=58) |
| Gastrointestinal
|
| |
Acid regurgitation |
0.0% |
0.0% |
| |
Flatulence |
0.0% |
0.0% |
| |
Gastroesophageal reflux disease |
2.8% |
0.0% |
| |
Dyspepsia |
2.8% |
1.7% |
| |
Diarrhea |
2.8% |
0.0% |
| |
Abdominal pain |
0.9% |
3.4% |
| |
Nausea |
0.0% |
0.0% |
|
|
|
Prevention of Osteoporosis in Postmenopausal Women
|
| |
The safety of alendronate sodium 5 mg/ day in postmenopausal women 40- 60 years of age has been evaluated in three double-
blind, placebo- controlled studies involving over 1400 patients randomized to receive alendronate sodium for either 2 or 3
years. In these studies the overall safety profiles of alendronate sodium 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 alendronate sodium 5 mg/ day
and 5.7% of 648 patients treated with placebo.
In a 1- year, double- blind multicenter study, the overall safety and tolerability profiles of once weekly alendronate sodium
35 mg and alendronate sodium 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 alendronate sodium 35 mg, alendronate sodium 5 mg/ day, or placebo are
presented in TABLE 6 .
| TABLE 6
Osteoporosis Prevention Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
2- and 3- Year Studies |
1- Year Study |
| |
|
Alendronate Sodium |
|
Alendronate Sodium |
Once Weekly Alendronate Sodium |
| |
|
5 mg/ day |
Placebo |
5 mg/ day |
35 mg |
| |
|
(n=642) |
(n=648) |
(n=361) |
(n=362) |
| Gastrointestinal
|
| |
Dyspepsia |
1.9% |
1.4% |
2.2% |
1.7% |
| |
Abdominal pain |
1.7% |
3.4% |
4.2% |
2.2% |
| |
Acid regurgitation |
1.4% |
2.5% |
4.2% |
4.7% |
| |
Nausea |
1.4% |
1.4% |
2.5% |
1.4% |
| |
Diarrhea |
1.1% |
1.7% |
1.1% |
0.6% |
| |
Constipation |
0.9% |
0.5% |
1.7% |
0.3% |
| |
Abdominal distension |
0.2% |
0.3% |
1.4% |
1.1% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle, or joint) pain |
0.8% |
0.9% |
1.9% |
2.2% |
|
|
Concomitant Use With Estrogen/Hormone Replacement Therapy
|
| |
In two studies (of 1 and 2 years' duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability
profile of combined treatment with alendronate sodium 10 mg once daily and estrogen ± progestin (n=354) was consistent with
those of the individual treatments.
|
Treatment of Glucocorticoid-Induced Osteoporosis
|
| |
In two, 1- year, placebo- controlled, double- blind, multicenter studies in patients receiving glucocorticoid treatment, the
overall safety and tolerability profiles of alendronate sodium 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 alendronate sodium 5 or 10 mg/ day or placebo are presented in TABLE 7 .
| TABLE 7
1- Year Studies in Glucocorticoid- Treated Patients — Adverse Experiences Considered Possibly, Probably, or Definitely Drug
Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
Alendronate Sodium |
|
| |
|
10 mg/ day |
5 mg/ day |
Placebo |
| |
|
(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 (alendronate sodium: 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 alendronate sodium
40 mg/ day for 3- 12 months were similar to those in postmenopausal women treated with alendronate sodium 10 mg/ day. However,
there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking alendronate sodium
40 mg/ day (17.7% alendronate sodium vs 10.2% placebo). One (1) case of esophagitis and 2 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 alendronate sodium 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 alendronate sodium 40 mg/ day and 2.4% of patients treated with placebo.
|
Laboratory Test Findings
|
| |
In double- blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate
were observed in approximately 18% and 10%, respectively, of patients taking alendronate sodium 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.
|
|
Postmarketing Experience
|
| |
The following adverse reactions have been reported in postmarketing use:
- Body as a Whole: Hypersensitivity reactions including urticaria and rarely angioedema. Transient symptoms of myalgia, malaise and rarely, fever
have been reported with alendronate sodium, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia
has occurred, generally in association with predisposing conditions.
- 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 the Patient ; 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 ).
- Skin: Rash (occasionally with photosensitivity), pruritus, rarely severe skin reactions, including Stevens- Johnson syndrome and
toxic epidermal necrolysis.
- Special Senses: Rarely uveitis, rarely 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 alendronate sodium. 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
|
| |
Alendronate sodium must be taken at least ½ hour before the first food, beverage, or medication of the day with plain water only (see PRECAUTIONS, Information for the Patient ). Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate
sodium (see DRUG INTERACTIONS ). Waiting less than 30 minutes, or taking alendronate sodium with food, beverages (other than plain water) or other medications
will lessen the effect of alendronate sodium by decreasing its absorption into the body.
Alendronate sodium should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the
potential for esophageal irritation, an alendronate sodium tablet should be swallowed with a full glass of water (6- 8 oz).
To facilitate gastric emptying alendronate sodium 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. Alendronate sodium 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 and PRECAUTIONS, Information for the Patient ).
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- 60 ml/ min). Alendronate sodium is not recommended for patients with more severe renal insufficiency (creatinine
clearance <35 ml/ min) due to lack of experience.
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 alendronate sodium 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 6 months.
|
Retreatment of Paget's Disease
|
| |
In clinical studies in which patients were followed every 6 months, relapses during the 12 months following therapy occurred
in 9% (3 out of 32) of patients who responded to treatment with alendronate sodium. Specific retreatment data are not available,
although responses to alendronate sodium were similar in patients who had received prior bisphosphonate therapy and those
who had not. Retreatment with alendronate sodium may be considered, following a 6- month posttreatment 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.
|
|
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 1 to 1. These data suggest that alendronate administered in therapeutic doses is
highly unlikely to induce osteomalacia.
|
HOW SUPPLIED
|
| |
Tablets
|
| |
Fosamax tablets are available in:
- 5 mg: White, round, uncoated tablets with an outline of a bone image on one side and code "MRK 925" on the other.
- 10 mg: White, oval, wax- polished tablets with code "MRK" on one side and "936" on the other.
- 35 mg: White, oval, uncoated tablets with code "77" on one side and a bone image on the other.
- 40 mg: White, triangular- shaped, uncoated tablets with code "MRK 212" on one side and "FOSAMAX" on the other.
- 70 mg: White, oval, uncoated tablets with code "31" on one side and an outline of a bone image on the other.
Storage of tablets: Store in a well- closed container at room temperature 15- 30°C (59- 86°F).
|
Oral Solution
|
| |
Fosamax oral solution is supplied as:
- 70 mg: Clear, colorless solution with a raspberry flavor.
Storage of oral solution: Store at 25°C (77°F), excursions permitted to 15- 30°C (59- 86°F). Do not freeze.
|
|
PRODUCT IDENTIFICATION
|
| |
Alendronate Sodium ,
tablet ,
40 mg
[ Merck & Company Inc
]
Alendronate Sodium ,
tablet ,
70 mg
[ Merck & Company Inc
]
Alendronate Sodium ,
tablet ,
70 mg
[ Southwood Pharmaceuticals Inc
]
Alendronate Sodium ,
tablet ,
70 mg
[ DispenseXpress Inc
]
Alendronate Sodium ,
tablet ,
35 mg
[ Merck & Company Inc
]
Alendronate Sodium ,
tablet ,
5 mg
[ Merck & Company Inc
]
Alendronate Sodium ,
tablet ,
10 mg
[ Merck & Company Inc
]
Alendronate Sodium ,
tablet ,
10 mg
[ Allscripts Healthcare Solutions
]
Alendronate Sodium ,
tablet ,
10 mg
[ Southwood Pharmaceuticals Inc
]
Alendronate Sodium ,
tablet ,
10 mg
[ DispenseXpress Inc
]
|
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| solution - oral - 70 mg/ 75 ml -
|
| 75.0 ml x 4.0 |
$84.30 |
Fosamax
Merck & Company Inc
|
00006383334 |
| tablet - oral - 5 mg -
|
| 30.0's |
$75.40 |
Fosamax
Merck & Company Inc
|
00006092531 |
| 100.0's |
$251.32 |
Fosamax
Merck & Company Inc
|
00006092558 |
| tablet - oral - 10 mg -
|
| 30.0's |
$73.47 |
Fosamax
Allscripts Healthcare Solutions
|
54569486600 |
| 30.0's |
$75.40 |
Fosamax
Merck & Company Inc
|
00006093631 |
| 31.0's x 25.0 |
$1441.01 |
Fosamax
Merck & Company Inc
|
00006093672 |
| 100.0's |
$251.32 |
Fosamax
Merck & Company Inc
|
00006093658 |
| 100.0's |
$261.79 |
Fosamax
Merck & Company Inc
|
00006093628 |
| 1000.0's |
$2513.19 |
Fosamax
Merck & Company Inc
|
00006093682 |
| tablet - oral - 35 mg -
|
| 4.0's |
$70.37 |
Fosamax
Merck & Company Inc
|
00006007744 |
| 20.0's |
$366.56 |
Fosamax
Merck & Company Inc
|
00006007721 |
| tablet - oral - 40 mg -
|
| 30.0's |
$169.97 |
Fosamax
Merck & Company Inc
|
00006021231 |
| tablet - oral - 70 mg -
|
| 4.0's |
$68.58 |
Fosamax
Southwood Pharmaceuticals Inc
|
58016061304 |
| 4.0's |
$70.37 |
Fosamax
Merck & Company Inc
|
00006003144 |
| 20.0's |
$366.56 |
Fosamax
Merck & Company Inc
|
00006003121 |
|
|