WARNINGS AND PRECAUTIONS
Upper Gastrointestinal Adverse Reactions
BINOSTO, like other bisphosphonates administered
orally, may cause local irritation of the upper gastrointestinal mucosa.
Because of these possible irritant effects and a potential for worsening
of the underlying disease, caution should be used when BINOSTO is
given to patients with active upper gastrointestinal problems (such
as known Barrett's esophagus, dysphagia, other esophageal diseases,
gastritis, duodenitis, or ulcers).
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 oral bisphosphonates including 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 BINOSTO 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 oral bisphosphonates
including alendronate sodium, and/or who continue to take oral bisphosphonates
including 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 BINOSTO should be used under appropriate
supervision.
There have been post-marketing
reports of gastric and duodenal ulcers with oral bisphosphonate use,
some severe and with complications, although no increased risk was
observed in controlled clinical trials [see Adverse Reactions].
Mineral Metabolism
Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications (4)]. 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 BINOSTO.
Presumably
due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic
decreases in serum calcium and phosphate may occur. Patients should
receive adequate calcium and vitamin D intake.
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating
bone, joint, and/or muscle pain has been reported in patients taking
bisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions ].
This category of drugs includes BINOSTO. Most of the patients were
postmenopausal women. The time to onset of symptoms varied from one
day to several months after starting the drug. Discontinue use if
severe symptoms develop. 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.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ), which
can occur spontaneously, is generally associated with tooth extraction
and/or local infection with delayed healing, and has been reported
in patients taking bisphosphonates, including alendronate sodium.
Known risk factors for osteonecrosis of the jaw include invasive dental
procedures (e.g., tooth extraction, dental implants, boney surgery),
diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids),
poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or
other pre-existing dental disease, anemia, coagulopathy, infection,
ill-fitting dentures). The risk of ONJ may increase with duration
of exposure to bisphosphonates.
For patients requiring invasive dental procedures, discontinuation
of bisphosphonate treatment may reduce the risk for ONJ. Clinical
judgment of the treating physician and/or oral surgeon should guide
the management plan of each patient based on individual benefit/risk
assessment.
Patients who develop
osteonecrosis of the jaw while on bisphosphonate therapy should receive
care by an oral surgeon. In these patients, extensive dental surgery
to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate
therapy should be considered based on individual benefit/risk assessment.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy, or low trauma fractures
of the femoral shaft have been reported in bisphosphonate-treated
patients. These fractures can occur anywhere in the femoral shaft
from just below the lesser trochanter to above the supracondylar flare
and are transverse or short oblique in orientation without evidence
of comminution. Causality has not been established as these fractures
also occur in osteoporotic patients who have not been treated with
bisphosphonates.
Atypical femur
fractures most commonly occur with minimal or no trauma to the affected
area. They may be bilateral and many patients report prodromal pain
in the affected area, usually presenting as dull, aching thigh pain,
weeks to months before a complete fracture occurs. A number of reports
note that patients were also receiving treatment with glucocorticoids
(e.g., prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure
who presents with thigh or groin pain should be suspected of having
an atypical fracture and should be evaluated to rule out an incomplete
femur fracture. Patients presenting with an atypical fracture should
also be assessed for symptoms and signs of fracture in the contralateral
limb. Interruption of bisphosphonate therapy should be considered,
pending a risk/benefit assessment, on an individual basis.
Renal Impairment
BINOSTO is not recommended for patients with creatinine clearance
<35 mL/min.
Patients Sensitive to High Sodium Intake
Each BINOSTO effervescent tablet contains
650 mg of sodium, equivalent to approximately 1650 mg of salt (NaCl).
Use caution in patients who must restrict their sodium intake, including
some patients with a history of heart failure, hypertension, or other
cardiovascular diseases [see Patient Counseling Information].
USEIN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C:
There are no studies in
pregnant women. BINOSTO should be used during pregnancy only if the
potential benefit justifies the potential risk to the mother and fetus.
Bisphosphonates are incorporated into
the bone matrix, from which they are gradually released over a period
of years. The amount of bisphosphonate incorporated into adult bone,
and hence, the amount available for release back into the systemic
circulation, is directly related to the dose and duration of bisphosphonate
use. There are no data on fetal risk in humans. However, there is
a theoretical risk of fetal harm, predominantly skeletal, if a woman
becomes pregnant after completing a course of bisphosphonate therapy.
The impact of variables such as time between cessation of bisphosphonate
therapy to conception, the particular bisphosphonate used, and the
route of administration (intravenous versus oral) on the risk has
not been studied.
Reproduction
studies in rats showed decreased postimplantation survival and decreased
body weight gain in normal pups at doses less than half of the recommended
clinical dose. Sites of incomplete fetal ossification were statistically
significantly increased in rats beginning at approximately 3 times
the clinical dose in vertebral (cervical, thoracic, and lumbar), skull,
and sternebral bones. No similar fetal effects were seen when pregnant
rabbits were treated with doses approximately 10 times the clinical
dose.
Both total and ionized
calcium decreased in pregnant rats at approximately 4 times the clinical
dose resulting in delays and failures of delivery. Protracted parturition
due to maternal hypocalcemia occurred in rats at doses as low as one
tenth the clinical dose when rats were treated from before mating
through gestation. Maternotoxicity (late pregnancy deaths) also occurred
in the female rats treated at approximately 4 times the clinical dose
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; intravenous calcium supplementation prevented
maternal, but not fetal deaths.
Exposure multiples based on surface area, mg/m2, were calculated using a 40-mg human daily dose. Animal dose ranged
between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.
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 BINOSTO is administered to nursing
women.
Pediatric Use
BINOSTO is not indicated for use in pediatric
patients.
The safety and efficacy
of alendronate sodium were examined in a randomized, double-blind,
placebo-controlled two-year study of 139 pediatric patients, aged
4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine
patients were randomized to 5 mg alendronate sodium daily (weight
less than 40 kg) or 10 mg alendronate sodium daily (weight greater
than or equal to 40 kg) and 30 patients to placebo. The mean baseline
lumbar spine BMD Z-score of the patients was -4.5. The mean change
in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the
alendronate-treated patients and 0.1 in the placebo-treated patients.
Treatment with alendronate sodium did not reduce the risk of fracture.
Sixteen percent of the alendronate-treated patients who sustained
a radiologically-confirmed fracture by Month 12 of the study had delayed
fracture healing (callus remodeling) or fracture non-union when assessed
radiographically at Month 24 compared with 9% of the placebo-treated
patients. In alendronate-treated patients, bone histomorphometry data
obtained at Month 24 demonstrated decreased bone turnover and delayed
mineralization time; however, there were no mineralization defects.
There were no statistically significant differences between the alendronate
sodium and placebo groups in reduction of bone pain. The oral bioavailability
in children was similar to that observed in adults.
The overall safety profile of alendronate sodium in
osteogenesis imperfecta patients treated for up to 24 months was generally
similar to that of adults with osteoporosis treated with alendronate
sodium. However, there was an increased occurrence of vomiting in
osteogenesis imperfecta patients treated with alendronate sodium compared
to placebo. During the 24-month treatment period, vomiting was observed
in 32 of 109 (29.4%) patients treated with alendronate sodium and
3 of 30 (10%) patients treated with placebo.
In a pharmacokinetic study, 6 of 24 pediatric osteogenesis
imperfecta patients who received a single oral dose of alendronate
sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild
lymphocytopenia within 24 to 48 hours after administration. These
events, lasting no more than 2 to 3 days and responding to acetaminophen,
are consistent with an acute-phase response that has been reported
in patients receiving bisphosphonates, including alendronate sodium. [See Adverse Reactions .]
Geriatric Use
Of the patients receiving alendronate sodium
in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater
than or equal to 65 years of age and 17% (n=550) were greater than
or equal to 75 years of age. Of the patients receiving alendronate
sodium in the United States 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.
Renal Impairment
BINOSTO is not recommended for patients
with creatinine clearance less than 35 mL/min. No
dosage adjustment is necessary in patients with creatinine clearance
values between 35-60 mL/min [see Clinical Pharmacology ].
Hepatic Impairment
As there is evidence that alendronate is
not metabolized or excreted in the bile, no studies were conducted
in patients with hepatic impairment. No dosage adjustment is necessary [see Clinical Pharmacology].
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