ADVERSE REACTIONS
Clinical TrialsExperience
Because clinical
trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not
reflect the rates observed in clinical practice.
The safety of BINOSTO (alendronate sodium) effervescent
tablet 70 mg is based on clinical trial data of alendronate sodium
10 mg daily and alendronate sodium 70 mg weekly.
Treatment of Osteoporosis in Postmenopausal Women
Daily Dosing
The safety of alendronate sodium 10 mg daily in the treatment
of postmenopausal osteoporosis was assessed in four clinical trials
that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were
identically designed, three-year, placebo-controlled, double-blind,
multicenter studies (United States and Multinational n=994); Study
3 was the three year vertebral fracture cohort of the Fracture Intervention
Trial [FIT] (n=2027) and Study 4 was the four-year clinical fracture
cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo
and 3432 patients exposed to alendronate. Patients with pre-existing
gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory
drugs were included in these clinical trials. In Study 1 and Study
2 all women received 500 mg elemental calcium as carbonate. In Study
3 and Study 4 all women with dietary calcium intake less than 1000
mg per day received 500 mg calcium and 250 IU Vitamin D per day.
Among patients treated with alendronate
10 mg or placebo in Study 1 and Study 2, and all patients in Study
3 and Study 4, the incidence of all-cause mortality was 1.8% in the
placebo group and 1.8% in the alendronate group. The incidence of
serious adverse events was 30.7% in the placebo group and 30.9% in
the alendronate group. The percentage of patients who discontinued
the study due to any clinical adverse event was 9.5% in the placebo
group and 8.9% in the alendronate group. Adverse reactions from these
studies considered by the investigators as possibly, probably, or
definitely drug related in greater than or equal to 1% of patients
treated with either alendronate or placebo are presented in Table
1.
Table 1 Osteoporosis Treatment Studies in Postmenopausal Women
Adverse Reactions Considered Possibly, Probably, or Definitely Drug
Related by the Investigators and Reported in Greater Than or Equal
to 1% of Patients
* 10 mg/day for three years
** 5 mg/day
for 2 years and 10 mg/day for either 1 or 2 additional years |
| |
United
States/Multinational Studies
|
Fracture
Intervention Trial
|
| |
Alendronate
Sodium*
%
(N=196)
|
Placebo
%
(N=397)
|
Alendronate
Sodium**
%
(N=3236)
|
Placebo
%
(N=3223)
|
| Gastrointestinal |
| Abdominal pain |
6.6 |
4.8 |
1.5 |
1.5 |
| Nausea |
3.6 |
4.0 |
1.1 |
1.5 |
| Dyspepsia |
3.6 |
3.5 |
1.1 |
1.2 |
| Constipation |
3.1 |
1.8 |
0.0 |
0.2 |
| Diarrhea |
3.1 |
1.8 |
0.6 |
0.3 |
| Flatulence |
2.6 |
0.5 |
0.2 |
0.3 |
| Acid regurgitation |
2.0 |
4.3 |
1.1 |
0.9 |
| Esophageal ulcer |
1.5 |
0.0 |
0.1 |
0.1 |
| Vomiting |
1.0 |
1.5 |
0.2 |
0.3 |
| Dysphagia |
1.0 |
0.0 |
0.1 |
0.1 |
| Abdominal distention |
1.0 |
0.8 |
0.0 |
0.0 |
| Gastritis |
0.5 |
1.3 |
0.6 |
0.7 |
| Musculoskeletal |
| Musculoskeletal (bone, muscle or joint)
pain |
4.1 |
2.5 |
0.4 |
0.3 |
| Muscle cramp |
0.0 |
1.0 |
0.2 |
0.1 |
| Nervous system/psychiatric |
| Headache |
2.6 |
1.5 |
0.2 |
0.2 |
| Dizziness |
0.0 |
1.0 |
0.0 |
0.1 |
| Special senses |
| Taste perversion |
0.5 |
1.0 |
0.1 |
0.0 |
Rarely, rash and erythema have occurred.
Gastrointestinal Adverse Reactions: 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. In the Study 1 and Study
2 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 [see Warnings and
Precautions (5.1)].
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
versus approximately 12% and 3% of those taking placebo. However,
the incidences of decreases in serum calcium to less than 8.0 mg/dL
(2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65
mM) were similar in both treatment groups.
Weekly Dosing
The
safety of alendronate sodium 70 mg once weekly for the treatment of
postmenopausal osteoporosis was assessed in a one-year, double-blind,
multicenter study comparing alendronate 70 mg once weekly and alendronate
10 mg daily. The overall safety and tolerability profiles of once
weekly alendronate 70 mg and alendronate 10 mg daily were similar.
The adverse reactions considered by the investigators as possibly,
probably, or definitely drug related in greater than or equal to 1%
of patients in either treatment group are presented in Table 2.
Table 2 Osteoporosis
Treatment Studies in Postmenopausal Women
Adverse Reactions
Considered Possibly, Probably, or Definitely Drug Related by the Investigators
and Reported in Greater Than or Equal to 1% of Patients
| |
Once Weekly
Alendronate Sodium
70 mg
%
(N=519)
|
Once Daily
Alendronate
Sodium
10 mg
%
(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, joint) pain |
2.9 |
3.2 |
| Muscle cramp |
0.2 |
1.1 |
Osteoporosis in Men
In two placebo-controlled, double-blind, multicenter
studies in men (a two-year study of alendronate sodium 10 mg/day and
a one-year study of once weekly alendronate sodium 70 mg) the rates
of discontinuation of therapy due to any clinical adverse event were
2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for
once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions
considered by the investigators as possibly, probably, or definitely
drug related in greater than or equal to 2% of patients treated with
either alendronate or placebo are presented in the following table.
Table 3 Osteoporosis
Studies in Men
Adverse Reactions Considered Possibly, Probably,
or Definitely Drug Related by the Investigators and Reported in Greater
Than or Equal to 2% of Patients
| |
Two-Year
Study
|
One-Year
Study
|
| |
Once Daily
Alendronate
Sodium
10 mg
%
(N=146)
|
Placebo
%
(N=95)
|
Once Weekly
Alendronate
Sodium
70 mg
%
(N=109)
|
Placebo
%
(N=58)
|
| Gastrointestinal |
|
|
|
|
| Acid regurgitation |
4.1 |
3.2 |
0.0 |
0.0 |
| Flatulence |
4.1 |
1.1 |
0.0 |
0.0 |
| Gastroesophageal reflux disease |
0.7 |
3.2 |
2.8 |
0.0 |
| Dyspepsia |
3.4 |
0.0 |
2.8 |
1.7 |
| Diarrhea |
1.4 |
1.1 |
2.8 |
0.0 |
| Abdominal pain |
2.1 |
1.1 |
0.9 |
3.4 |
| Nausea |
2.1 |
0.0 |
0.0 |
0.0 |
Post-Marketing Experience
The following adverse reactions have been identified
during post-approval use of alendronate sodium. Because these reactions
are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Body as a Whole: hypersensitivity
reactions including urticaria and angioedema. Transient symptoms of
myalgia, malaise, asthenia and fever have been reported with alendronate,
typically in association with initiation of treatment. Symptomatic
hypocalcemia has occurred, generally in association with predisposing
conditions. Peripheral edema.
Gastrointestinal: esophagitis, esophageal erosions,
esophageal ulcers, esophageal stricture or perforation, and oropharyngeal
ulceration. Gastric or duodenal ulcers, some severe and with complications
have also been reported [see Dosage and Administration ; Warnings and Precautions].
Dental: Localized osteonecrosis of the jaw, generally associated
with tooth extraction and/or local infection with delayed healing,
has been reported [see Warnings and Precautions ].
Musculoskeletal: bone, joint, and/or muscle pain,
occasionally severe and incapacitating [see Warnings and Precautions]; joint swelling; low-energy
femoral shaft and subtrochanteric fractures [see Warnings
and Precautions].
Nervous system: dizziness
and vertigo.
Pulmonary: asthma exacerbations.
Skin: rash (occasionally with photosensitivity), pruritus,
alopecia, severe skin reactions, including Stevens-Johnson syndrome
and toxic epidermal necrolysis.
Special Senses: uveitis, scleritis or episcleritis.
|
