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, like other biophosphonates, 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, have been reported in
patients receiving treatment with alendronate sodium. In some cases these have been severe and
required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a
possible esophageal reaction and patients should be instructed to discontinue alendronate sodium
and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or
worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down
after taking alendronate sodium and/or who fail to swallow it with a full glass (6-8 oz) of water,
and/or who continue to take alendronate sodium after developing symptoms suggestive of
esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to,
and understood by, the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot
comply with dosing instructions due to mental disability, therapy with alendronate sodium should be
used under appropriate supervision.
Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and
a potential for worsening of the underlying disease, caution should be used when alendronate
sodium is given to patients with active upper gastrointestinal problems (such as dysphagia,
esophageal diseases, gastritis, duodenitis, or ulcers).
There have been post-marketing reports of gastric and duodenal ulcers, some severe and with
complications, although no increased risk was observed in controlled clinical trials.
PRECAUTIONS
General
Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be
considered.
Hypocalcemia must be corrected before initiating therapy with alendronate sodium (see
CONTRAINDICATIONS). Other disturbances of mineral metabolism (such as vitamin D
deficiency) should also be effectively treated. Presumably due to the effects of alendronate sodium
on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may
occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover
may be greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may
be decreased.
Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's
disease of bone and in patients receiving glucocorticoids.
Renal Insufficiency
Alendronate sodium is not recommended for patients with renal insufficiency (creatinine clearance
<35 ml/min). (See DOSAGE AND ADMINISTRATION.)
Glucocorticoid-Induced Osteoporosis
The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less
than 7.5 mg of prednisone or equivalent has not been established (see INDICATIONS AND
USAGE). Before initiating treatment, the hormonal status of both men and women should be
ascertained and appropriate replacement considered.
A bone mineral density measurement should be made at the initiation of therapy and repeated after
6-12 months of combined alendronate sodium and glucocorticoid treatment.
The efficacy of alendronate sodium for the treatment of glucocorticoid-induced osteoporosis has
been shown in patients with a median bone mineral density which was 1.2 standard deviations
below the mean for healthy young adults.
The efficacy of alendronate sodium has been established in studies of 2 years' duration. The
greatest increase in bone mineral density occurred in the first year with maintenance or smaller
gains during the second year. Efficacy of alendronate sodium beyond 2 years has not been studied.
The efficacy of alendronate sodium in respect to fracture prevention has been demonstrated for
vertebral fractures. However, this finding was based on very few fractures that occurred primarily
in postmenopausal women. The efficacy for prevention of non-vertebral fractures has not been
demonstrated.
Information for the Patient
General
Physicians should instruct their patients to read the patient package insert before starting therapy
with alendronate sodium and to reread it each time the prescription is renewed.
Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is
inadequate. Weight-bearing exercise should be considered along with the modification of certain
behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors
exist.
Dosing Instructions
Patients should be instructed that the expected benefits of alendronate sodium may only be obtained
when 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 alendronate sodium (see CLINICAL
PHARMACOLOGY, Pharmacokinetics, Absorption).
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients
should be instructed to swallow alendronate sodium 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 at bedtime or before arising for the day.
Patients should be informed that failure to follow these instructions may increase their risk of
esophageal problems. Patients should be instructed that if they develop symptoms of esophageal
disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening
heartburn) they should stop taking alendronate sodium and consult their physician.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Harderian gland (a retro-orbital gland not present in human) 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 0.5-4 times
the 10 mg human dose 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
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 body surface area. 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 was weakly
positive at concentrations ³5 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 (4
times the 10 mg human dose based on surface area).
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/m2. 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/m2).
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. Alendronate sodium should be used during pregnancy only
if the potential benefit justifies the potential risk to the mother and fetus.
Nursing Mothers
It is not known whether alendronate is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when alendronate 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 2 large osteoporosis treatment studies,
glucocorticoid-induced osteoporosis studies, and Paget's disease studies (see CLINICAL
STUDIES), 45%, 37%, and 70%, respectively, were 65 years of age or over. No overall
differences in efficacy or safety were observed between these patients and younger patients but
greater sensitivity of some older individuals cannot be ruled out.
Use in Men
Safety and effectiveness have been demonstrated in clinical studies in men receiving alendronate
sodium both for Paget's disease of bone and for treatment of glucocorticoid-induced osteoporosis.
However, the safety and effectiveness in men for osteoporosis due to other causes have not been
established.