Alendronate Sodium; Cholecalciferol (4085)
| Ingredients: |
Alendronate Sodium; Cholecalciferol |
| Indications: |
Osteoporosis |
| Pregnancy Category: |
C |
| FDA Approved: |
2005- 04- 01 |
| Classes: |
Bisphosphonates; Vitamins/ minerals |
| Brand Names: |
Fosamax Plus D
-
US
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$80.35
(
Osteoporosis-PM Women ;
Fosamax Plus D ;
70 mg; 2800 iu ;
1 tablet/week ;
28 day supply
)
$80.35
(
Osteoporosis-Men ;
Fosamax Plus D ;
70 mg; 2800 iu ;
1 tablet/week ;
28 day supply
)
|
DESCRIPTION
|
| |
Fosamax Plus D 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 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.
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 (3β, 5 Z , 7 E )- 9, 10- secocholesta- 5, 7, 10(19)- trien- 3- ol. The empirical formula of cholecalciferol is C27 H44 O and its molecular weight is 384.6.
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 µg 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
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Mechanism of Action
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Alendronate Sodium
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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
|
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Vitamin D3 is produced in the skin by photochemical conversion of 7- dehydrocholesterol to previtamin D3 by UV 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
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Absorption
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Alendronate Sodium
|
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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.
The alendronate in the alendronate sodium; cholecalciferol tablet and the 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.
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%.
|
Cholecalciferol
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Following administration of alendronate sodium; cholecalciferol tablets after an overnight fast and 2 hours before a standard
meal, the baseline adjusted mean area under the serum- concentration- time curve [AUC(0- 120 h)] for vitamin D3 was 120.7 ng·h/ 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 h.The bioavailability of the 2800 IU vitamin D3 in alendronate sodium; cholecalciferol are similar to 2800 IU vitamin D3 administered alone.
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Distribution
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Alendronate Sodium
|
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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
|
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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.
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Metabolism
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Alendronate Sodium
|
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There is no evidence that alendronate is metabolized in animals or humans.
|
Cholecalciferol
|
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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.
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Excretion
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Alendronate Sodium
|
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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.
|
Cholecalciferol
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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 alendronate sodium; cholecalciferol is approximately 14 hours.
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Special Populations
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Pediatric
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Alendronate pharmacokinetics have not been investigated in patients <18 years of age.
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Gender
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Bioavailability and the fraction of an IV dose of alendronate excreted in urine were similar in men and women.
|
Geriatric
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Alendronate Sodium
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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
|
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Dietary requirements of vitamin D3 are increased in the elderly.
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Race
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Pharmacokinetic differences due to race have not been studied.
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Renal Insufficiency
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Alendronate Sodium
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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; cholecalciferol 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
|
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Patients with renal insufficiency will have decreased ability to form the active 1, 25- dihydroxyvitamin D3 metabolite.
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Hepatic Insufficiency
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Alendronate Sodium
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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
|
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Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.
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Drug Interactions
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Also see DRUG INTERACTIONS .
Alendronate Sodium
|
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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.
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Cholecalciferol
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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.
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Pharmacodynamics
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Alendronate Sodium
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Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the
bone- resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process
is ultimately reduced because bone resorption and formation are coupled during bone turnover.
Osteoporosis in Postmenopausal Women
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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 crosslinked 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 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 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 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. 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.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. In 1- year studies with once weekly alendronate sodium 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.
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Osteoporosis in Men
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Treatment of men with osteoporosis with alendronate sodium 10 mg/ day for 2 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 1- year study in men with osteoporosis receiving once weekly alendronate sodium 70 mg.
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Cholecalciferol
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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 alendronate
sodium; cholecalciferol 70 mg/ 2800 IU vitamin D or weekly alendronate sodium 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 alendronate
sodium; cholecalciferol 70 mg/ 2800 IU resulted in a smaller reduction in serum calcium levels (- 0.9%) when compared to alendronate
sodium 70 mg alone (- 1.4%). As well, treatment with alendronate sodium; cholecalciferol 70 mg/ 2800 IU resulted in a significantly
smaller increase in parathyroid hormone levels when compared to alendronate sodium 70 mg alone (14% and 24%, respectively).
The sufficiency of patients’ vitamin D status is best assessed by measuring 25- hydroxyvitamin D levels. In the 15- week trial
mentioned above, baseline 25- hydroxyvitamin D levels were 22.2 ng/ ml in the alendronate sodium; cholecalciferol group and
22.1 ng/ ml in the alendronate sodium only group. After 15 weeks of treatment, the mean levels were 23.1 ng/ ml and 18.4 ng/
ml in the alendronate sodium; cholecalciferol and alendronate sodium only groups, respectively. The final levels of 25- hydroxyvitamin
D at Week 15 are summarized in TABLE 1 .
| TABLE 1
25- Hydroxyvitamin D Levels After Treatment With Alendronate Sodium; Cholecalciferol and Alendronate Sodium 70 mg at Week
15*
|
| |
Alendronate Sodium; Cholecalciferol |
Alendronate Sodium 70 mg |
| 25- Hydroxyvitamin D Ranges |
(n=357) |
(n=351) |
| <9 ng/ ml |
4 (1.1%) |
46 (13.1%) |
| 9- 14 ng/ ml |
37 (10.4%) |
66 (18.8%) |
| 15- 19 ng/ ml |
87 (24.4%) |
108 (30.8%) |
| 20- 24 ng/ ml |
84 (23.5%) |
58 (16.5%) |
| 25- 29 ng/ ml |
82 (23.0%) |
37 (10.5%) |
| 30- 62 ng/ ml |
63 (17.7%) |
36 (10.3%) |
|
| *
|
Patients who were vitamin D deficient (25- hydroxyvitamin D <9 ng/ ml) at baseline were excluded. |
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CLINICAL STUDIES
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Treatment of Osteoporosis
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Postmenopausal Women
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Effect on Bone Mineral Density
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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 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
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Data on the effects of alendronate sodium on fracture incidence are derived from three clinical studies: (1) 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, (2) 3-
Year Study of the Fracture Intervention Trial (FIT): a study of patients with at least 1 baseline vertebral fracture, and
(3) 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
1/ 3 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
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 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 1 baseline radiographic vertebral fracture)
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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 2A and TABLE 2B .
| TABLE 2A
Effect of Alendronate Sodium on Fracture Incidence in the 3- Year Study of FIT*
|
| |
|
Alendronate Sodium |
Placebo |
| Patients With: |
(n=1022) |
(n=1005) |
| Vertebral Fractures (diagnosed by X- ray)†
|
| |
≥1 New vertebral fracture |
7.9% |
15.0% |
| |
≥2 New vertebral fractures |
0.5% |
4.9% |
| Clinical (symptomatic) Fractures
|
| |
Any clinical (symptomatic) fracture |
13.8% |
18.1% |
| |
≥1 Clinical (symptomatic) vertebral fracture |
2.3% |
5.0% |
| Hip fracture |
1.1% |
2.2% |
| Wrist (forearm) fracture |
2.2% |
4.1% |
|
| *
|
Patients with vertebral fracture at baseline. |
| †
|
Number evaluable for vertebral fractures: alendronate sodium, n=984; placebo, n=966. |
|
| TABLE 2B
Effect of Alendronate Sodium on Fracture Incidence in the 3- Year Study of FIT*
|
| Patients With: |
Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk % |
| Vertebral Fractures (diagnosed by X- ray)†
|
| |
≥1 New vertebral fracture |
7.1% |
47%‡ |
| |
≥2 New vertebral fractures |
4.4% |
90%‡ |
| Clinical (symptomatic) Fractures
|
| |
Any clinical (symptomatic) fracture |
4.3% |
26%§ |
| |
≥1 Clinical (symptomatic) vertebral fracture |
2.7% |
54%¤ |
| Hip fracture |
1.1% |
51%¶ |
| Wrist (forearm) fracture |
1.9% |
48%¶ |
|
| *
|
Patients with vertebral fracture at baseline. |
| †
|
Number evaluable for vertebral fractures: alendronate sodium, n=984; placebo, n=966. |
| ‡
|
p <0.001. |
| §
|
p=0.007. |
| ¤
|
p <0.01. |
| ¶
|
p <0.05. |
|
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 non- osteoporotic women. The results are shown in TABLE 3A and TABLE 3B for the patients with osteoporosis.
| TABLE 3A
Effect of Alendronate Sodium on Fracture Incidence in Osteoporotic* Patients in the 4- Year Study of FIT†
|
| |
|
Alendronate Sodium |
Placebo |
| Patients With: |
(n=1545) |
(n=1521) |
| Vertebral Fractures (diagnosed by X- ray)‡
|
| |
≥1 New vertebral fracture |
2.5% |
4.8% |
| |
≥2 New vertebral fractures |
0.1% |
0.6% |
| Clinical (symptomatic) Fractures
|
| |
Any clinical (symptomatic) fracture |
12.9% |
16.2% |
| |
≥1 Clinical (symptomatic) vertebral fracture |
1.0% |
1.6% |
| Hip fracture |
1.0% |
1.4% |
| Wrist (forearm) fracture |
3.9% |
3.8% |
|
| *
|
Baseline femoral neck BMD at least 2 SD below the mean for young adult women. |
| †
|
Patients without vertebral fracture at baseline. |
| ‡
|
Number evaluable for vertebral fractures: alendronate sodium, n=1426; placebo, n=1428. |
|
| TABLE 3B
Effect of Alendronate Sodium on Fracture Incidence in Osteoporotic* Patients in the 4- Year Study of FIT†
|
| Patients With: |
Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk % |
| Vertebral Fractures (diagnosed by X- ray)‡
|
| |
≥1 New vertebral fracture |
2.3% |
48%§ |
| |
≥2 New vertebral fractures |
0.5% |
78%¤ |
| Clinical (symptomatic) Fractures
|
| |
Any clinical (symptomatic) fracture |
3.3% |
22%¶ |
| |
≥1 Clinical (symptomatic) vertebral fracture |
0.6% |
41% (NS) |
| Hip fracture |
0.4% |
29% (NS) |
| Wrist (forearm) fracture |
- 0.1% |
NS |
|
| *
|
Baseline femoral neck BMD at least 2 SD below the mean for young adult women. |
| †
|
Patients without vertebral fracture at baseline. |
| ‡
|
Number evaluable for vertebral fractures: alendronate sodium, n=1426; placebo, n=1428. |
| §
|
p <0.001. |
| ¤
|
p=0.035. |
| ¶
|
p=0.01. |
| NS
|
Not significant. This study was not powered to detect differences at these sites. |
|
|
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- 7.9% (47% relative risk reduction, p <0.001); in the 4- Year Study of FIT, the percentage was reduced
from 3.8- 2.1% (44% relative risk reduction, p=0.001); and in the combined US/ Multinational studies, from 6.2- 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- 0.6%
(87% relative risk reduction, p <0.001) in the combined US/ multinational studies and from 4.9- 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- 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 2- 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%. Treatment with alendronate
sodium also reduced height loss (alendronate sodium, - 0.6 mm versus 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 ≤- 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 1 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 the 10
mg once- daily study.
In both studies, BMD responses were similar regardless of age (≥65 years versus <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).
|
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.
|
|
|
INDICATIONS AND USAGE
|
| |
Alendronate sodium; cholecalciferol is indicated for:
| • |
Treatment of osteoporosis in postmenopausal women.
| • |
For the treatment of osteoporosis, alendronate sodium; cholecalciferol 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 .)
|
|
| • |
Treatment to increase bone mass in men with osteoporosis.
|
|
CONTRAINDICATIONS
|
| |
| • |
Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
|
| • |
Inability to stand or sit upright for at least 30 minutes.
|
| • |
Hypersensitivity to any component of this product.
|
| • |
Hypocalcemia (see PRECAUTIONS, General ).
|
|
WARNINGS
|
| |
Alendronate sodium; cholecalciferol, like other bisphosphonate- containing products, may cause local irritation of the upper
gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding
and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate.
In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms
signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium; cholecalciferol
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; cholecalciferol and/ or who fail to swallow it with a full glass (6- 8 oz) of water, and/ or who continue to take
alendronate sodium; cholecalciferol 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; cholecalciferol
should be used under appropriate supervision.
Because of possible irritant effects of alendronate on the upper gastrointestinal mucosa and a potential for worsening of
the underlying disease, caution should be used when alendronate sodium; cholecalciferol 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 with alendronate, 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.
Alendronate Sodium
|
| |
Hypocalcemia must be corrected before initiating therapy with alendronate sodium; cholecalciferol (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;
cholecalciferol.
Presumably due to the effects of alendronate on increasing bone mineral, small, asymptomatic decreases in serum calcium and
phosphate may occur.
|
Cholecalciferol
|
| |
Alendronate sodium; cholecalciferol alone should not be used to treat vitamin D deficiency (commonly defined as 25- hydroxyvitamin
D level below 9 ng/ ml). Patients at increased risk for vitamin D insufficiency ( e.g., those who are nursing home bound, chronically ill, over the age of 70 years) should receive vitamin D supplementation in addition
to that provided in alendronate sodium; cholecalciferol. Patients with gastrointestinal malabsorption syndromes may require
higher doses of vitamin D supplementation and measurement of 25- hydroxyvitamin D should be considered.
Vitamin D3 supplementation may worsen hypercalcemia and/ or hypercalciuria when administered to patients with diseases associated with
unregulated overproduction of 1, 25 dihyroxyvitamin D ( e.g., leukemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
|
|
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 (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 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; cholecalciferol is not recommended for patients with renal insufficiency (creatinine clearance <35 ml/
min). (See DOSAGE AND ADMINISTRATION .)
|
Information for the Patient
|
| |
General
|
| |
Physicians should instruct their patients to read the patient package insert before starting therapy with alendronate sodium;
cholecalciferol and to reread it each time the prescription is renewed.
Patients should be instructed to take supplemental calcium if intake is inadequate. Patients at increased risk for Vitamin
D insufficiency ( e.g., those who are nursing home bound, chronically ill, over the age of 70 years) should be instructed to take additional vitamin
D. Patients with gastrointestinal malabsorption syndromes should be informed that they may require additional vitamin D supplementation.Weight-
bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking
and/ or excessive alcohol consumption, if these factors exist.
|
Dosing Instructions
|
| |
Patients should be instructed that the expected benefits of alendronate sodium; cholecalciferol 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
(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; cholecalciferol with a full glass of water (6- 8 oz) and not to lie down for
at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of
a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take alendronate sodium; cholecalciferol
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; cholecalciferol and consult their physician.
Patients should be instructed that if they miss a dose of alendronate sodium; cholecalciferol, they should take 1 tablet on
the morning after they remember. They should not take 2 tablets on the same day but should return to taking 1 tablet once
a week, as originally scheduled on their chosen day.
|
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
The following data are based on findings for the individual components of alendronate sodium; cholecalciferol.
Alendronate Sodium
|
| |
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).
|
Cholecalciferol
|
| |
The carcinogenic potential of cholecalciferol (vitamin D3 ) has not been studied in rodents. Calcitriol, the hormonal metabolite of cholecalciferol, was not genotoxic in the Ames microbial
mutagenesis assay with or without metabolic activation, and in an in vivo micronucleus assay in mice.
Ergocalciferol (vitamin D2 ) at high doses (150, 000- 200, 000 IU/ kg/ day) administered prior to mating resulted in altered estrous cycle and inhibition
of pregnancy in rats. The potential effect of cholecalciferol on male fertility is unknown in rats.
|
|
Pregnancy Category C
|
| |
Alendronate Sodium
|
| |
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 premating 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.
|
Cholecalciferol
|
| |
No data are available for cholecalciferol (vitamin D3 ). Administration of high doses (≥10, 000 IU/ every other day) of ergocalciferol (vitamin D2 ) to pregnant rabbits, resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin
D2 (40, 000 IU/ day) to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones
postnatally.
There are no studies in pregnant women. alendronate sodium; cholecalciferol should be used during pregnancy only if the potential
benefit justifies the potential risk to the mother and fetus.
|
|
Nursing Mothers
|
| |
Cholecalciferol and some of its active metabolites pass into breast milk. It is not known whether alendronate is excreted
in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate sodium; cholecalciferol
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, and osteoporosis studies in men (see CLINICAL STUDIES ), 45% and 54%, 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. Dietary requirements
of vitamin D3 are increased in the elderly.
|
|
DRUG INTERACTIONS
|
| |
Also see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions .
Alendronate Sodium
|
| |
Calcium Supplements/Antacids
|
| |
It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate.
Therefore, patients must wait at least one- half hour after taking alendronate sodium; cholecalciferol 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; cholecalciferol 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;
cholecalciferol.
|
|
Cholecalciferol
|
| |
Drugs That May Impair the Absorption of Cholecalciferol
|
| |
Olestra, mineral oils, orlistat, and bile acid sequestrants ( e.g., cholestyramine, colestipol) may impair the absorption of vitamin D.
|
Drugs That May Increase the Catabolism of Cholecalciferol
|
| |
Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.
|
|
|
ADVERSE REACTIONS
|
| |
Clinical Studies — Alendronate Sodium
|
| |
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 4A and TABLE 4B .
| TABLE 4A
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 |
| |
|
Alendronate Sodium* |
Placebo |
| Adverse Experience |
(n=196) |
(n=397) |
| Gastrointestinal
|
| |
Abdominal pain |
6.6% |
4.8% |
| |
Nausea |
3.6% |
4.0% |
| |
Dyspepsia |
3.6% |
3.5% |
| |
Constipation |
3.1% |
1.8% |
| |
Diarrhea |
3.1% |
1.8% |
| |
Flatulence |
2.6% |
0.5% |
| |
Acid regurgitation |
2.0% |
4.3% |
| |
Esophageal ulcer |
1.5% |
0.0% |
| |
Vomiting |
1.0% |
1.5% |
| |
Dysphagia |
1.0% |
0.0% |
| |
Abdominal distention |
1.0% |
0.8% |
| |
Gastritis |
0.5% |
1.3% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle or joint) pain |
4.1% |
2.5% |
| |
Muscle cramp |
0.0% |
1.0% |
| Nervous System/ Psychiatric
|
| |
Headache |
2.6% |
1.5% |
| |
Dizziness |
0.0% |
1.0% |
| Special Senses
|
| |
Taste perversion |
0.5% |
1.0% |
|
| *
|
10 mg/ day for 3 years. |
|
| TABLE 4B
Osteoporosis Treatment Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
Fracture Intervention Trial |
| |
|
Alendronate Sodium* |
Placebo |
| Adverse Experience |
(n=3236) |
(n=3223) |
| Gastrointestinal
|
| |
Abdominal pain |
1.5% |
1.5% |
| |
Nausea |
1.1% |
1.5% |
| |
Dyspepsia |
1.1% |
1.2% |
| |
Constipation |
0.0% |
0.2% |
| |
Diarrhea |
0.6% |
0.3% |
| |
Flatulence |
0.2% |
0.3% |
| |
Acid regurgitation |
1.1% |
0.9% |
| |
Esophageal ulcer |
0.1% |
0.1% |
| |
Vomiting |
0.2% |
0.3% |
| |
Dysphagia |
0.1% |
0.1% |
| |
Abdominal distention |
0.0% |
0.0% |
| |
Gastritis |
0.6% |
0.7% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle or joint) pain |
0.4% |
0.3% |
| |
Muscle cramp |
0.2% |
0.1% |
| Nervous System/ Psychiatric
|
| |
Headache |
0.2% |
0.2% |
| |
Dizziness |
0.0% |
0.1% |
| Special Senses
|
| |
Taste perversion |
0.1% |
0.0% |
|
| *
|
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 5 .
| TABLE 5
Osteoporosis Treatment Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
Once Weekly Alendronate Sodium 70 mg |
Alendronate Sodium 10 mg/ day |
| Adverse Experience |
(n=519) |
(n=370) |
| Gastrointestinal
|
| |
Abdominal pain |
3.7% |
3.0% |
| |
Dyspepsia |
2.7% |
2.2% |
| |
Acid regurgitation |
1.9% |
2.4% |
| |
Nausea |
1.9% |
2.4% |
| |
Abdominal distention |
1.0% |
1.4% |
| |
Constipation |
0.8% |
1.6% |
| |
Flatulence |
0.4% |
1.6% |
| |
Gastritis |
0.2% |
1.1% |
| |
Gastric ulcer |
0.0% |
1.1% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle or 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 versus 10.5% for placebo, and 6.4% for once weekly alendronate sodium
70 mg versus 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 alendronate sodium or placebo are presented in TABLE 6A and TABLE 6B .
| TABLE 6A
Osteoporosis Studies in Men — Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators
and Reported in ≥2% of Patients
|
| |
|
2- Year Study |
| |
|
Alendronate Sodium 10 mg/ day |
Placebo |
| Adverse Experience |
(n=146) |
(n=95) |
| Gastrointestinal
|
| |
Acid regurgitation |
4.1% |
3.2% |
| |
Flatulence |
4.1% |
1.1% |
| |
Gastroesophageal 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 6B
Osteoporosis Studies in Men — Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators
and Reported in ≥2% of Patients
|
| |
|
1- Year Study |
| |
|
Once Weekly Alendronate Sodium 70 mg |
Placebo |
| Adverse Experience |
(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% |
|
|
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.
|
|
Other Studies With Alendronate Sodium
|
| |
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 7A and TABLE 7B .
| TABLE 7A
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/ 3- Year Studies |
| |
|
Alendronate Sodium 5 mg/ day |
Placebo |
| Adverse Experience |
(n=642) |
(n=648) |
| Gastrointestinal
|
| |
Dyspepsia |
1.9% |
1.4% |
| |
Abdominal pain |
1.7% |
3.4% |
| |
Acid regurgitation |
1.4% |
2.5% |
| |
Nausea |
1.4% |
1.4% |
| |
Diarrhea |
1.1% |
1.7% |
| |
Constipation |
0.9% |
0.5% |
| |
Abdominal distention |
0.2% |
0.3% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle or joint) pain |
0.8% |
0.9% |
|
| TABLE 7B
Osteoporosis Prevention Studies in Postmenopausal Women — Adverse Experiences Considered Possibly, Probably, or Definitely
Drug Related by the Investigators and Reported in ≥1% of Patients
|
| |
|
1- year Study |
| |
|
Alendronate Sodium 5 mg/ day |
Once Weekly Alendronate Sodium 35 mg |
| Adverse Experience |
(n=361) |
(n=362) |
| Gastrointestinal
|
| |
Dyspepsia |
2.2% |
1.7% |
| |
Abdominal pain |
4.2% |
2.2% |
| |
Acid regurgitation |
4.2% |
4.7% |
| |
Nausea |
2.5% |
1.4% |
| |
Diarrhea |
1.1% |
0.6% |
| |
Constipation |
1.7% |
0.3% |
| |
Abdominal distention |
1.4% |
1.1% |
| Musculoskeletal
|
| |
Musculoskeletal (bone, muscle or joint) pain |
1.9% |
2.2% |
|
|
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 8 .
| TABLE 8
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 |
| Adverse Experience |
(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 versus 10.2% placebo). One 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.
|
|
|
Alendronate Sodium; Cholecalciferol
|
| |
In a 15- week double- blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile
of alendronate sodium; cholecalciferol was similar to that of alendronate sodium once weekly 70 mg.
Postmarketing Experience
|
| |
The following adverse reactions have been reported in post- marketing use with alendronate:
- Body as a Whole: Hypersensitivity reactions including urticaria and rarely angioedema. Transient symptoms of myalgia, malaise and rarely, fever
have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia
has occurred, generally in association with predisposing conditions.
- 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, scleritis or episcleritis.
|
|
|
OVERDOSAGE
|
| |
Alendronate Sodium
|
| |
Significant lethality after single oral doses with alendronate 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. 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.
|
Cholecalciferol
|
| |
Significant lethality occurred in mice treated with a single high oral dose of calcitriol (4 mg/ kg), the hormonal metabolite
of cholecalciferol.
There is limited information regarding doses of cholecalciferol associated with acute toxicity, although intermittent (yearly
or twice yearly) single doses of cholecalciferol as high as 600, 000 units have been given without reports of toxicity. Signs
and symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia,
weakness, and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity.
Standard therapy includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe
hypercalcemia.
Dialysis to remove vitamin D would not be beneficial.
|
|
DOSAGE AND ADMINISTRATION
|
| |
Alendronate sodium; cholecalciferol 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 the Patient ). Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate
(see DRUG INTERACTIONS ). Waiting less than 30 minutes, or taking alendronate sodium; cholecalciferol with food, beverages (other than plain water)
or other medications will lessen the effect of alendronate by decreasing its absorption into the body.
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, alendronate sodium; cholecalciferol
should only be swallowed upon arising for the day with a full glass of water (6- 8 oz) and patients should not lie down for
at least 30 minutes and until after their first food of the day. Alendronate sodium; cholecalciferol 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 if dietary intake is inadequate (see PRECAUTIONS, General ). Patients at increased risk for vitamin D insufficiency ( e.g., those who are nursing home bound, chronically ill, over the age of 70 years) should receive vitamin D supplementation in addition
to that provided in alendronate sodium; cholecalciferol. Patients with gastrointestinal malabsorption syndromes may require
higher doses of vitamin D supplementation and measurement of 25- hydroxyvitamin D should be considered.
The recommended intake of vitamin D is 400- 800 IU daily. Alendronate sodium; cholecalciferol is intended to provide 7 days’
worth of 400 IU daily vitamin D in a single, once- weekly dose.
No dosage adjustment is necessary for the elderly or for patients with mild- to- moderate renal insufficiency (creatinine
clearance 35- 60 ml/ min). Alendronate sodium; cholecalciferol 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/ 2800 IU tablet once weekly.
|
Treatment to Increase Bone Mass in Men With Osteoporosis
|
| |
The recommended dosage is one 70- mg/ 2800 IU tablet once weekly.
|
|
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.
|
HOW SUPPLIED
|
| |
Tablets Fosamax Plus D 70 mg/ 2800 IU are white to off- white, modified capsule- shaped tablets with code "710" on one side
and an outline of a bone image on the other.
Storage
|
| |
Store at 20- 25°C (68- 77°F), excursions between 15- 30°C (59- 86°F) are allowed. Protect from moisture and light. Store tablets
in the original blister package until use.
|
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PATIENT DRUG CONSULT HANDOUT
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| tablet - oral - 70 mg- 2800 intl units -
|
| 4.0's |
$80.35 |
Fosamax Plus D
Merck & Company Inc
|
00006071044 |
|
|