Alendronate Sodium
DESCRIPTION:
BIFOSA (alendronate sodium) is an aminobisphosphonate that acts as a specific
inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic
analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene)
bisphosphonic acid monosodium salt trihydrate.
The empirical formula of alendronate sodium is C4H12NNaO7P2.3H2O and its formula
weight is 325.12.
Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble
in water, very slightly soluble in alcohol, and practically insoluble in
chloroform.
Tablets BIFOSA for oral administration contain either 6.53, 13.05 mg or 52.21
mg of alendronate monosodium salt trihydrate, which is the molar equivalent of
5.0, 10.0 and 40.0 mg, respectively, of free acid, and the following inactive
ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose
sodium, and magnesium stearate.
ACTIONS/CLINICAL PHARMACOLOGY:
Mechanism Of Action
Animal studies have indicated the following mode of action. At the cellular
level, alendronate shows preferential localization to sites of bone resorption,
specifically under osteoclasts. The osteoclasts adhere normally to the bone
surface but lack the ruffled border that is indicative of active resorption.
Alendronate does not interfere with osteoclast recruitment or attachment, but it
does inhibit osteoclast activity. Studies in mice on the localization of
radioactive (3H)alendronate in bone showed about 10-fold higher uptake on
osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days
after (3H)alendronate administration in rats and mice, respectively, showed that
normal bone was formed on top of the alendronate, which was incorporated inside
the matrix. While incorporated in bone matrix, alendronate is not
pharmacologically active. Thus, alendronate must be continuously administered to
suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in
baboons and rats showed that alendronate treatment reduces bone turnover (i.e.,
the number of sites at which bone is remodeled). In addition, bone formation
exceeds bone resorption at these remodeling sites, leading to progressive gains
in bone mass.
Pharmacokinetics
Absorption
Relative to an intravenous (IV) reference dose, the mean oral bioavailability of
alendronate in women was 0.7% for doses ranging from 5 to 40 mg when
administered after an overnight fast and two hours before a standardized
breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar
to that in women (0.78%) when administered after an overnight fast and 2 hours
before breakfast.
A study examining the effect of timing of a meal on the bioavailability of
alendronate was performed in 49 postmenopausal women. Bioavailability was
decreased (by approximately 40%) when 10 mg alendronate was administered either
0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours
before eating. In studies of treatment and prevention of osteoporosis,
alendronate was effective when administered at least 30 minutes before
breakfast.
Bioavailability was negligible whether alendronate was administered with or up
to two hours after a standardized breakfast. Concomitant administration of
alendronate with coffee or orange juice reduced bioavailability by approximately
60%.
Distribution
Preclinical studies (in male rats) show that alendronate transiently distributes
to soft tissues following 1 mg/kg IV administration but is then rapidly
redistributed to bone or excreted in the urine. The mean steady-state volume of
distribution, exclusive of bone, is at least 28 L in humans. Concentrations of
drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL)
for analytical detection. Protein binding in human plasma is approximately 78%.
Metabolism
There is no evidence that alendronate is metabolized in animals or humans.
Excretion
Following a single IV dose of (14C)alendronate, approximately 50% of the
radioactivity was excreted in the urine within 72 hours and little or no
radioactivity was recovered in the feces. Following a single 10 mg IV dose, the
renal clearance of alendronate was 71 mL/min, and systemic clearance did not
exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours
following IV administration. The terminal half-life in humans is estimated to
exceed 10 years, probably reflecting release of alendronate from the skeleton.
Based on the above, it is estimated that after 10 years of oral treatment with
BIFOSA (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 (>/=65 years of age) and younger patients. No dosage adjustment is
necessary (see DOSAGE AND ADMINISTRATION).
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: Preclinical studies show that, in rats with kidney
failure, increasing amounts of drug are present in plasma, kidney, spleen, and
tibia. In healthy controls, drug that is not deposited in bone is rapidly
excreted in the urine. No evidence of saturation of bone uptake was found after
3 weeks dosing with cumulative IV doses of 35 mg/kg in young male rats. Although
no clinical information is available, it is likely that, as in animals,
elimination of alendronate via the kidney will be reduced in patients with
impaired renal function. Therefore, somewhat greater accumulation of alendronate
in bone might be expected in patients with impaired renal function.
No dosage adjustment is necessary for patients with mild-to-moderate renal
insufficiency (creatinine clearance 35 to 60 mL/min).BIFOSA IS NOT RECOMMENDED
FOR PATIENTS WITH MORE SEVERE RENAL INSUFFICIENCY (CREATININE CLEARANCE <35
ML/MIN) DUE TO LACK OF EXPERIENCE.
Hepatic Insufficiency: As there is evidence that alendronate is not metabolized
or excreted in the bile, no studies were conducted in patients with hepatic
insufficiency. No dosage adjustment is necessary.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Intravenous ranitidine was shown to double the bioavailability of oral
alendronate. The clinical significance of this increased bioavailability and
whether similar increases will occur in patients given oral H2-antagonists is
unknown; no other specific drug interaction studies were performed.
Products containing calcium and other multivalent cations likely will interfere
with absorption of alendronate.
Summary Of Pharmacokinetic Parameters In The Normal Population
90%
Mean Confidence
Interval
--------------------------------------------------------------------------------------------------------------------
Absolute bioavailability of 0.63% (0.48, 0.83)
5 mg tablet, taken 2 hours (females)
before first meal of the day
--------------------------------------------------------------------------------------------------------------------
Absolute bioavailability of 0.78% (0.61, 1.04)
10 mg tablet, taken 2 hours (females)
before first meal of the day
-------------------------------------------------------------------------------------------------------------------
0.59% (0.43, 0.81)
(males)
-------------------------------------------------------------------------------------------------------------------
Absolute bioavailability of 0.60% (0.46, 0.78)
40 mg tablet, taken 2 hours (females)
before first meal of the day
------------------------------------------------------------------------------------------------------------------
Renal Clearance (mL/min) 71 (64, 78)
(n=6)
-----------------------------------------------------------------------------------------------------------------
Pharmacodynamics
Osteoporosis In Postmenopausal Women
Osteoporosis is characterized by low bone mass that leads to an increased risk
of fracture. The diagnosis can be confirmed by the finding of low bone mass,
evidence of fracture on x-ray, a history of osteoporotic fracture, or height
loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs
in both males and females but is most common among women following the
menopause, when bone turnover increases and the rate of bone resorption exceeds
that of bone formation. These changes result in progressive bone loss and lead
to osteoporosis in a significant proportion of women over age 50. Fractures,
usually of the spine, hip, and wrist, are the common consequences. From age 50
to age 90, the risk of hip fracture in white women increases 50-fold and the
risk of vertebral fracture 15- to 30-fold. It is estimated that approximately
40% of 50-year-old women will sustain one or more osteoporosis-related fractures
of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in
particular, are associated with substantial morbidity, disability, and
mortality.
Alendronate is an aminobisphosphonate that binds to bone hydroxyapatite and
specifically inhibits the activity of osteoclasts, the bone-resorbing cells.
Alendronate reduces bone resorption with no direct effect on bone formation,
although the latter process is ultimately reduced because bone resorption and
formation are coupled during bone turnover. Alendronate thus reduces the
elevated rate of bone turnover observed in postmenopausal women to approximate
more closely that in premenopausal women.
Alendronate is not an estrogen and does not have the benefits and risks of
estrogen replacement therapy.
Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in
postmenopausal women produced biochemical changes indicative of dose-dependent
inhibition of bone resorption, including decreases in urinary calcium and
urinary markers of bone collagen degradation (such as deoxypyridinoline and
cross-linked N-telopeptides of type I collagen). These biochemical changes
tended to return toward baseline values as early as 3 weeks following the
discontinuation of therapy with alendronate and did not differ from placebo
after 7 months.
In long-term (two- or three-year) osteoporosis treatment studies, FOSAMAX 10
mg/day reduced urinary excretion of markers of bone resorption, including
deoxypyridinoline and cross-linked N- telopeptides of type I collagen, by
approximately 50-60% to reach levels similar to those seen in healthy
premenopausal women. Similar decreases were seen in patients in osteoporosis
prevention studies who received FOSAMAX 5 mg/day. The decrease in the rate of
bone resorption indicated by these markers was evident as early as one month and
at three to six months reached a plateau that was maintained for the entire
duration of treatment with BIFOSA. In osteoporosis treatment studies BIFOSA 10
mg/day decreased the markers of bone formation, osteocalcin and total serum
alkaline phosphatase, by approximately 50% and 25-30%, respectively, to reach a
plateau after 6 to 12 months. In osteoporosis prevention studies BIFOSA 5
mg/day decreased these markers by approximately 40% and 15% respectively. These
data indicate that the rate of bone turnover reached a new steady state, despite
the progressive increase in the total amount of alendronate deposited within
bone.
As a result of inhibition of bone resorption, asymptomatic reductions in serum
calcium and phosphate concentrations were also observed following treatment with
BIFOSA. In the long- term studies, reductions from baseline in serum calcium
(approximately 2%) and phosphate (approximately 4 to 6%) were evident the first
month after the initiation of BIFOSA 10 mg, but no further decreases were
observed for the three- year duration of the studies. Similar reductions were
observed with BIFOSA 5 mg/day. The reduction in serum phosphate may reflect not
only the positive bone mineral balance due to BIFOSA but also a decrease in
renal phosphate reabsorption.
Paget's Disease Of Bone
Paget's disease of bone is a chronic, focal skeletal disorder characterized by
greatly increased and disorderly bone remodeling. Excessive osteoclastic bone
resorption is followed by osteoblastic new bone formation, leading to the
replacement of the normal bone architecture by disorganized, enlarged, and
weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms to severe
morbidity due to bone pain, bone deformity, pathological fractures, and
neurological and other complications. Serum alkaline phosphatase, the most
frequently used biochemical index of disease activity, provides an objective
measure of disease severity and response to therapy.
BIFOSA decreases the rate of bone resorption directly, which leads to an
indirect decrease in bone formation. In clinical trials, BIFOSA 40 mg once
daily for six months produced highly significant decreases in serum alkaline
phosphatase as well as in urinary markers of bone collagen degradation. As a
result of the inhibition of bone resorption, BIFOSA induced generally mild,
transient, and asymptomatic decreases in serum calcium and phosphate.
CLINICAL STUDIES:
Treatment Of Osteoporosis In Postmenopausal Women
Effect On Bone Mineral Density
The efficacy of BIFOSA 10 mg once daily in postmenopausal women, 44 to 84 years
of age, with osteoporosis (lumbar spine bone mineral density (BMD) of at least 2
standard deviations below the premenopausal mean) was demonstrated in four
double-blind, placebo-controlled clinical studies of two or three years'
duration. These included two large three-year, multicenter studies of virtually
identical design, one performed in the United States (U.S.) and the other in 15
different countries (Multinational), which enrolled 478 and 516 patients,
respectively. The following graph shows the mean increases in BMD of the lumbar
spine, femoral neck, and trochanter in patients receiving BIFOSA 10 mg/day
relative to placebo-treated patients at three years for each of these studies.
Click here for illustration(s).
Highly significant increases in BMD, relative both to baseline and placebo, were
seen at each measurement site in each study in patients who received BIFOSA 10
mg/day. Total body BMD also increased significantly in each study, suggesting
that the increases in bone mass of the spine and hip did not occur at the
expense of other skeletal sites. Increases in BMD were evident as early as three
months and continued throughout the three years of treatment. (See figures below
for lumbar spine results.) Thus, BIFOSA appears to reverse the progression of
osteoporosis. BIFOSA was similarly effective regardless of age, race, baseline
rate of bone turnover, and baseline BMD in the range studied (at least 2
standard deviations below the premenopausal mean).
In patients with postmenopausal osteoporosis treated with BIFOSA for one or two
years, the effects of treatment withdrawal were assessed. Following
discontinuation, there were no further increases in bone mass and the rates of
bone loss were similar to those of the placebo groups. These data indicate that
continuous daily treatment with BIFOSA is required to maintain the effect of
the drug.
Effect On Fracture Incidence
To assess the effects of BIFOSA on vertebral fracture incidence, the U.S. and
Multinational studies were combined in an analysis that compared placebo to the
pooled dosage groups of BIFOSA (5 or 10 mg for three years or 20 mg for two
years followed by 5 mg for one year). There was a significant 48% reduction in
the proportion of patients treated with BIFOSA experiencing one or more new
vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%). A
reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100
patients) was also observed. In the pooled analysis, patients who received
BIFOSA had a statistically significant smaller loss in stature than those who
received placebo (-3.0 mm vs. -4.6 mm). Furthermore, of patients who sustained
any vertebral fracture, those treated with BIFOSA experienced less height loss
(5.9 mm vs. 23.3 mm) due to a reduction in both the number and severity of
fractures.
The Vertebral Fracture Study of the Fracture Intervention Trial (FIT) included
results from 2027 patients who had at least one baseline vertebral (compression)
fracture. The results of this study demonstrated the reduction in fracture
incidence due to BIFOSA . In this three-year, randomized, double-blind,
placebo-controlled study, 1022 patients received BIFOSA and 1005 patients
received placebo. Treatment with BIFOSA resulted in statistically significant
and clinically meaningful reductions in the proportion of patients experiencing
fractures as shown in the table below.
Effect of BIFOSA on Fracture Incidence Over Three Years
in the Vertebral Fracture Study of FIT
------------------------------------------------------------------------------
% of Patients Reduction % in
BIFOSA Placebo Fracture Incidence
------------------------------------------------------------------------------
PATIENTS WITH:
>/= 1 new vertebral fracture 8.0 15.0 47
>/= 2 new vertebral fractures 0.5 4.9 90
>/= 1 painful vertebral fracture 2.3 5.0 55
Hip fractures 1.1 2.2 51
Wrist (forearm) fractures 2.2 4.1 48
------------------------------------------------------------------------------
Furthermore, treatment with BIFOSA significantly reduced the incidence of total
hospitalizations (24.9% vs. 30.4%).
The reduction in the incidence of vertebral fractures (BIFOSA versus placebo)
in the Vertebral Fracture Study of FIT (in which all women had a least one
baseline vertebral fracture) was consistent with that in the combined U.S. and
Multinational (U.S./Mult) treatment studies (see above), in which 80% of the
women did not have a vertebral fracture at baseline. During these three-year
studies, treatment with BIFOSA reduced the proportion of women experiencing at
least one new vertebral fracture in both study populations by approximately 50%
(FIT: 47% reduction, p<0.001; U.S./Mult: 48% reduction, p = 0.034). Similarly,
BIFOSA reduced the proportion of women experiencing multiple (two or more) new
vertebral fractures by approximately 90% in both studies (p<0.001). Thus,
BIFOSA reduces the incidence of fractures whether or not patients have
experienced a previous vertebral fracture.
The two figures below display the cumulative incidence of patients with hip and
wrist fractures over 3 years in the Vertebral Fracture Study of FIT. In both
figures, the cumulative incidence of patients with these types of fracture is
lower with BIFOSA compared with placebo at all time points.BIFOSA reduced the
proportion of women experiencing hip fracture by 51% and wrist fracture by 48%.
Proportionately similar reductions of hip and wrist fractures were seen in
pooled earlier osteoporosis treatment studies.
Click here for illustration(s).
Overall, these results demonstrate the efficacy of BIFOSA to reduce the
incidence of fractures at the spine, hip and wrist, which are the three most
common sites of osteoporotic fracture.
Bone Histology
Bone histology in 270 postmenopausal patients with osteoporosis treated with
BIFOSA at doses ranging from 1 to 20 mg/day for one, two, or three years
revealed normal mineralization and structure, as well as the expected decrease
in bone turnover relative to placebo. These data, together with the normal bone
histology and increased bone strength observed in rats and baboons exposed to
long-term alendronate treatment, support the conclusion that bone formed during
therapy with BIFOSA is of normal quality.
Prevention Of Osteoporosis In Postmenopausal Women
Prevention of bone loss was demonstrated in two double-blind, placebo-controlled
studies of postmenopausal women 40-60 years of age. One thousand six hundred
nine patients (BIFOSA 5 mg/day; n = 498) who were at least six months
postmenopausal were entered into a two-year study without regard to their
baseline BMD. In the other study, 447 patients (BIFOSA 5 mg/day; n = 88), who
were between six months and three years postmenopause, were treated for up to
three years. In the placebo-treated patients BMD losses of approximately 1% per
year were seen at the spine, hip (femoral neck and trochanter) and total body.
In contrast, BIFOSA 5 mg/day prevented bone loss in the majority of patients
and induced significant increases in mean bone mass at each of these sites (see
figures below). In addition,BIFOSA 5 mg/day reduced the rate of bone loss at
the forearm by approximately half relative to placebo.BIFOSA 5 mg/day was
similarly effective in this population regardless of age, time since menopause,
race and baseline rate of bone turnover.
Bone histology was normal in the 28 patients biopsied at the end of three years
who received BIFOSA at doses of up to 10 mg/day.
Paget's Disease Of Bone
The efficacy of BIFOSA 40 mg once daily for six months was demonstrated in two
double-blind clinical studies of male and female patients with moderate to
severe Paget's disease (alkaline phosphatase at least twice the upper limit of
normal): a placebo-controlled multinational study and a U.S. comparative study
with etidronate disodium 400 mg/day. The following figure shows the mean percent
changes from baseline in serum alkaline phosphatase for up to six months of
randomized treatment.
At six months the suppression in alkaline phosphatase in patients treated with
BIFOSA 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 BIFOSA in the combined studies vs. 30% in the etidronate group and 0% in
the placebo group. BIFOSA was similarly effective irrespective of age, gender,
race, prior use of other bisphosphonates, or baseline alkaline phosphatase
within the range studied (at least twice the upper limit of normal).
Bone histology was evaluated in 33 patients with Paget's disease treated with
BIFOSA 40 mg/day for 6 months. As in patients treated for osteoporosis (see
Clinical Studies, Treatment Of Osteoporosis In Postmenopausal Women, Bone
Histology), BIFOSA did not impair mineralization, and the expected decrease in
the rate of bone turnover was observed. Normal lamellar bone was produced during
the treatment with BIFOSA, even where preexisting bone was woven and
disorganized. Overall, bone histology data support the conclusion that bone
formed during treatment with BIFOSA is of normal quality.
ANIMAL PHARMACOLOGY:
The relative inhibitory activities on bone resorption and mineralization of
alendronate and etidronate were compared in the Schenk assay, which is based on
histological examination of the epiphyses of growing rats. In this assay, the
lowest dose of alendronate that interfered with bone mineralization (leading to
osteomalacia) was 6000-fold the antiresponsive dose. The corresponding ratio for
etidronate was one to one. These data suggest that alendronate administered in
therapeutic doses is highly unlikely to induce osteomalacia.
INDICATIONS AND USAGE:
BIFOSA is indicated for the treatment and prevention of osteoporosis in
postmenopausal women.
--For the treatment of osteoporosis,BIFOSA increases bone mass and prevents
fractures including those of the hip, wrist, and spine (vertebral compression
fractures). Osteoporosis may be confirmed by the finding of low bone mass (for
example, at least 2 standard deviations below the premenopausal mean) or by the
presence or history of osteoporotic fracture. (See ACTIONS/CLINICAL
PHARMACOLOGY, Pharmacodynamics.)
--For the prevention of osteoporosis,BIFOSA 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
BIFOSA for prevention of osteoporosis.
BIFOSA is indicated for the treatment of Paget's disease of bone.
--Treatment is indicated in patients with Paget's disease of bone having
alkaline phosphatase at least two times the upper limit of normal, or those who
are symptomatic, or those at risk for future complications from their disease.
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:
BIFOSA, like other bisphosphonates, may cause local irritation of the upper
gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and
esophageal erosions occasionally with bleeding, have been reported in patients
receiving treatment with BIFOSA. 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 BIFOSA and seek medical attention if they develop
dysphagia, odynophagia or retrosternal pain.
The risk of severe esophageal adverse experiences appears to be greater in
patients who lie down after taking BIFOSA and/or who fail to swallow it with a
full glass (6-8 oz) of water, and/or who continue to take FOSAMAX after
developing symptoms suggestive of esophageal irritation. Therefore, it is very
important that the full dosing instructions are provided to, and understood by,
the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with
dosing instructions due to mental disability, therapy with BIFOSA should be
used under appropriate supervision.
Because of possible irritant effects of FOSAMAX on the upper gastrointestinal
mucosa and a potential for worsening of the underlying disease, caution should
be used when BIFOSA is given to patients with active upper gastrointestinal
problems,(such as dysphagia, esophageal diseases, gastritis, duodenitis, or
ulcers).
PRECAUTIONS:
General
There have been rare (post-marketing) reports of gastric and duodenal ulcers,
some severe and with complications, although no increased risk was observed in
pre-marketing clinical trials.
BIFOSA is not recommended for patients with renal insufficiency (creatinine
clearance <35 mL/min). (See DOSAGE AND ADMINISTRATION.)
Causes of osteoporosis other than estrogen deficiency and aging should be
considered.
Hypocalcemia must be corrected before initiating therapy with BIFOSA (see
CONTRAINDICATIONS). Other disturbances of mineral metabolism (such as vitamin D
deficiency) should also be effectively treated. Presumably due to the effects of
BIFOSA on increasing bone mineral, small, asymptomatic decreases in serum
calcium and phosphate may occur, especially in patients with Paget's disease, in
whom the pretreatment rate of bone turnover may be greatly elevated. Adequate
calcium and vitamin D intake should be ensured to provide for these enhanced
needs.
Information For Patients
Patients should be instructed that the expected benefits of BIFOSA may only be
obtained when each tablet is swallowed with plain water the first thing upon
arising for the day at least 30 minutes before the first food, beverage, or
medication of the day. Even dosing with orange juice or coffee has been shown to
markedly reduce the absorption of BIFOSA (see ACTIONS/CLINICAL PHARMACOLOGY,
Pharmacokinetics, Absorption).
To facilitate delivery to the stomach and thus reduce the potential for
esophageal irritation patients should be instructed to swallow BIFOSA 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 BIFOSA 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 BIFOSA and consult their physician.
Patients should be instructed to take supplemental calcium and vitamin D, if
daily dietary intake is inadequate. Weight-bearing exercise should be considered
along with the modification of certain behavioral factors, such as excessive
cigarette smoking, and/or alcohol consumption, if these factors exist.
Physicians should instruct their patients to read the patient package insert
before starting therapy with BIFOSA and to reread it each time the prescription
is renewed.
Drug Interactions (also see ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetics,
Drug Interactions)
Estrogen
The safety and effectiveness of the concomitant use of hormone replacement
therapy and BIFOSA in postmenopausal women has not been established.
Calcium Supplements/Antacids
It is likely that calcium supplements, antacids, and some oral medications will
interfere with absorption of BIFOSA. Therefore, patients must wait at least
one-half hour after taking BIFOSA before taking any other drug.
Aspirin
In clinical studies, the incidence of upper gastrointestinal adverse events was
increased in patients receiving concomitant therapy with doses of BIFOSA
greater than 10 mg/day and aspirin- containing compounds.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
BIFOSA 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 BIFOSA 5 or 10 mg compared to those taking placebo.
However, since NSAID use is associated with gastrointestinal irritation, caution
should be used during concomitant use with BIFOSA.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Harderian gland (a retro-orbital gland not present in humans) adenomas were
increased in high-dose female mice (p=0.003) in a 92-week carcinogenicity study
at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5
mg/kg/day (females). These doses are equivalent to 0.5 to 4 times the 10 mg
human dose based on surface area, mg/M(square).
Parafollicular cell (thyroid) adenomas were increased in high-dose male rats
(p=0.003) in a 2-year carcinogenicity study at doses of 1 and 3.75 mg/kg body
weight. These doses are equivalent to 1 and 3 times the 10 mg human dose based
on surface area.
Alendronate was not genotoxic in the In Vitro microbial mutagenesis assay with
and without metabolic activation, in an In Vitro mammalian cell mutagenesis
assay, in an In Vitro alkaline elution assay in rat hepatocytes, and in an In
Vivo chromosomal aberration assay in mice. In an In Vitro chromosomal aberration
assay in Chinese hamster ovary cells, however, alendronate was weakly positive
at concentrations >/=5 mM in the presence of cytotoxicity.
Alendronate had no effect on fertility (male or female) in rats at oral doses up
to 5 mg/kg/day (four times the 10 mg human dose based on surface area).
Pregnancy
Pregnancy Category C:
Reproduction studies in rats showed decreased postimplantation survival at 2
mg/kg/day and decreased body weight gain in normal pups at 1 mg/kg/day. Sites of
incomplete fetal ossification were statistically significantly increased in rats
beginning at 10 mg/kg/day in vertebral (cervical, thoracic, and lumbar), skull,
and sternebral bones. The above doses ranged from 1 times (1 mg/kg) to 9 times
(10 mg/kg) the 10 mg human dose based on surface area, mg/M(square). No similar
fetal effects were seen when pregnant rabbits were treated at doses up to 35
mg/kg/day (50 times the 10 mg human dose based on surface area, mg/M(square)).
Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day (13
times the 10 mg human dose based on surface area) resulting in delays and
failures of delivery. Protracted parturition due to maternal hypocalcemia
occurred in rats at doses as low as 0.5 mg/kg/day (0.5 times the recommended
human dose) when rats were treated from before mating through gestation.
Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with
15 mg/kg/day for varying periods of time ranging from treatment only during pre-
mating to treatment only during early, middle, or late gestation; these deaths
were lessened but not eliminated by cessation of treatment. Calcium
supplementation either in the drinking water or by minipump could not ameliorate
the hypocalcemia or prevent maternal and neonatal deaths due to delays in
delivery; calcium supplementation IV prevented maternal, but not fetal deaths.
There are no studies in pregnant women. BIFOSA 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 BIFOSA is
administered to nursing women.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Use In The Elderly
Of the patients receiving BIFOSA in the two large osteoporosis treatment
studies and Paget's disease studies (see ACTIONS/CLINICAL PHARMACOLOGY, Clinical
Studies), 45% and 70%, respectively, were 65 years of age or over. No overall
differences in efficacy or safety were observed between these patients and
younger patients but greater sensitivity of some older individuals cannot be
ruled out.
Use In Men
Safety and effectiveness in male osteoporosis have not been established.
DRUG INTERACTIONS:
(Also see ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions.)
Estrogen
The safety and effectiveness of the concomitant use of hormone replacement
therapy and BIFOSA in postmenopausal women has not been established.
Calcium Supplements/Antacids
It is likely that calcium supplements, antacids, and some oral medications will
interfere with absorption of BIFOSA. Therefore, patients must wait at least
one-half hour after taking BIFOSA before taking any other drug.
Aspirin
In clinical studies, the incidence of upper gastrointestinal adverse events was
increased in patients receiving concomitant therapy with doses of BIFOSA
greater than 10 mg/day and aspirin- containing compounds.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
BIFOSA 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 BIFOSA 5 or 10 mg compared to those taking placebo.
However, since NSAID use is associated with gastrointestinal irritation, caution
should be used during concomitant use with BIFOSA.
ADVERSE REACTIONS:
Clinical Studies
In clinical studies adverse experiences associated with BIFOSA usually were
mild, and generally did not require discontinuation of therapy.
BIFOSA has been evaluated for safety in approximately 3800 postmenopausal women
in clinical studies.
Treatment Of Osteoporosis
In two large, three-year, placebo-controlled, double-blind, multicenter studies
(United States and Multinational), discontinuation of therapy due to any
clinical adverse experience occurred in 4.1% of 196 patients treated with
BIFOSA 10 mg/day and 6.0% of 397 patients treated with placebo. Adverse
experiences reported by the investigators as possible, probably, or definitely
drug related in >/=1% of patients treated with either BIFOSA 10 mg/day or
placebo are presented in the following table.
Drug-Related** Adverse Experiences
Reported in >/=1% of Patients
-----------------------------------------------------------------------------
BIFOSA Placebo
10 mg/day
% %
(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
-----------------------------------------------------------------------------
** Considered possibly, probably, or definitely drug related as assessed by
the investigators
Rarely, rash and erythema have occurred.
One patient treated with BIFOSA (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 BIFOSA 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 BIFOSA in the United States and Multinational
studies.
In the Vertebral Fracture Study of the Fracture Intervention Trial,
discontinuation of therapy due to any clinical adverse experience occurred in
7.6% of 1022 patients treated with BIFOSA 5 mg/day for 2 years and 10 mg/day
for the third year and 9.4% of 1005 patients treated with placebo. Similarly,
discontinuations due to upper gastrointestinal adverse experiences were
comparable: BIFOSA, 2.6%; placebo, 2.6%. The overall adverse experience profile
was similar to that seen in other studies with FOSAMAX 5 or 10 mg/day.
Prevention Of Osteoporosis
The safety of BIFOSA in postmenopausal women 40-60 years of age has been
evaluated in three double-blind, placebo-controlled studies involving over 1,400
patients randomized to receive BIFOSA for either two or three years. In these
studies the overall safety profiles of BIFOSA 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 BIFOSA 5 mg/day and 5.7% of 648
patients treated with placebo. The adverse experiences reported by the
investigators as possibly, probably, or definitely drug related in >/= 1% of
patients treated with either BIFOSA 5 mg/day or placebo are presented in the
following table.
Drug-Related* Adverse Experiences
Reported in >/= 1% of Patients
------------------------------------------------------------------------------
BIFOSA Placebo
5 mg/day
% %
n = 642 n = 648
Gastrointestinal
abdominal pain 1.7 3.4
acid regurgitation 1.4 2.5
diarrhea 1.1 1.7
dyspepsia 1.9 1.7
nausea 1.4 1.4
------------------------------------------------------------------------------
*Considered possibly, probably or definitely drug related as assessed by the
investigators
Paget's Disease Of Bone
In clinical studies (osteoporosis and Paget's disease), adverse experiences
reported in 175 patients taking BIFOSA 40 mg/day for 3-12 months were similar
to those in postmenopausal women treated with BIFOSA 10 mg/day. However, there
was an apparent increased incidence of upper gastrointestinal adverse
experiences in patients taking BIFOSA 40 mg/day (17.7% BIFOSA vs. 10.2%
placebo). One case of esophagitis and two cases of gastritis resulted in
discontinuation of treatment.
Additionally, musculoskeletal (bone, muscle or joint) pain, which has been
described in patients with Paget's disease treated with other bisphosphonates,
was reported by the investigators as possibly, probably, or definitely drug
related in approximately 6% of patients treated with BIFOSA 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 BIFOSA 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 phosphate were observed in approximately
18% and 10%, respectively, of patients taking BIFOSA 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 =2.0mg/dL (0.65 mM) were
similar in both treatment groups.
Post-Marketing Experience
The following adverse reactions have been reported in post-marketing use:
Body As A Whole: hypersensitivity reactions have been including urticaria and
rarely angioedema.
Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers and
oropharyngeal ulceration. Rarely, gastric or duodenal ulcers, some severe and
with complications have been reported (see WARNINGS, PRECAUTIONS, General and
Information For Patients, and DOSAGE AND ADMINISTRATION.
OVERDOSAGE:
Significant lethality after single oral doses was seen in female rats and mice
at 552 mg/kg (3256 mg/M(square)) and 966 mg/kg (2898 mg/M(square)),
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/M(square)).
No specific information is available on the treatment of overdosage with
BIFOSA. 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:
BIFOSA must be taken At Least one-half hour before the first food, beverage, or
medication of the day with plain water only (see PRECAUTIONS, Information For
Patients). Other beverages (including mineral water), food, and some medications
are likely to reduce the absorption of BIFOSA (see PRECAUTIONS, Drug
Interactions). Waiting less than 30 minutes, or taking BIFOSA with food,
beverages (other than plain water) or other medications will lessen the effect
of BIFOSA by decreasing its absorption into the body.
To facilitate delivery to the stomach and thus reduce the potential for
esophageal irritation, BIFOSA 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. BIFOSA should not
be taken at bedtime or before arising for the day. Failure to follow these
instructions may increase the risk of esophageal adverse experiences (see
WARNINGS).
Patients should receive supplemental calcium and vitamin D, if dietary intake is
inadequate (see PRECAUTIONS, General).
No dosage adjustment is necessary for the elderly or for patients with mild-to-
moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). BIFOSA is
not recommended for patients with more severe renal insufficiency (creatinine
clearance <35 mL/min) due to lack of experience.
Treatment Of Osteoporosis In Postmenopausal Women (see INDICATIONS AND USAGE
The recommended dosage is 10 mg once a day.
Prevention Of Osteoporosis In Postmenopausal Women (see INDICATIONS AND USAGE)
The recommended dosage is 5 mg once a day.
Safety of treatment or prevention of osteoporosis with BIFOSA for longer than
four years has not been studied; extension studies are ongoing.
Paget's Disease Of Bone
The recommended treatment regimen is 40 mg once a day for six months.
Retreatment Of Paget's Disease
In clinical studies in which patients were followed every six months, relapses
during the 12 months following therapy occurred in 9% (3 out of 32) of patients
who responded to treatment with BIFOSA. Specific retreatment data are not
available, although responses to BIFOSA were similar in patients who had
received prior bisphosphonate therapy and those who had not. Retreatment with
FOSAMAX may be considered, following a six-month post-treatment evaluation
period in patients who have relapsed, based on increases in serum alkaline
phosphatase, which should be measured periodically. Retreatment may also be
considered in those who failed to normalize their serum alkaline phosphatase.
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