ADVERSE REACTIONS
Clinical Trials Experience
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.
Treatment of Osteoporosis in Postmenopausal Women
Daily Dosing
The safety of Alendronate 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 international units 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 event 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 ≥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
| |
United States/Multinational Studies |
Fracture Intervention Trial |
| |
Alendronate
%
(n=196) |
Placebo
%
(n=397) |
Alendronate
%
(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 |
Rash and erythema have occurred.
Gastrointestinal Adverse Reactions: One patient treated with Alendronate (10 mg alendronate /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 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].
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 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
70 mg
%
(n=519) |
Alendronate
10 mg/day
%
(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 |
Prevention of Osteoporosis in Postmenopausal Women
Daily Dosing
The safety of Alendronate 5 mg/day 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 Alendronate for either two or three years. In these studies the overall safety profiles of Alendronate 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse event occurred in 7.5% of 642 patients treated with Alendronate 5 mg/day and 5.7% of 648 patients treated with placebo.
Weekly Dosing
The safety of Alendronate 35 mg once weekly compared to Alendronate 5 mg daily was evaluated in a one-year, double-blind, multicenter study of 723 patients. The overall safety and tolerability profiles of once weekly Alendronate 35 mg and Alendronate 5 mg daily were similar.
The 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 once weekly Alendronate 35 mg, Alendronate 5 mg/day or placebo are presented in Table 3.
Table 3: Osteoporosis Prevention 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
|
| Two/Three-Year Studies
|
One-Year Study
|
|
| Alendronate
5 mg/day
%
(n=642) |
Placebo
%
(n=648) |
Alendronate
5 mg/day
%
(n=361) |
Once Weekly
Alendronate
35 mg
%
(n=362) |
|
Gastrointestinal |
|
|
|
|
| dyspepsia |
1.9 |
1.4 |
2.2 |
1.7 |
| abdominal pain |
1.7 |
3.4 |
4.2 |
2.2 |
| acid regurgitation |
1.4 |
2.5 |
4.2 |
4.7 |
| nausea |
1.4 |
1.4 |
2.5 |
1.4 |
| diarrhea |
1.1 |
1.7 |
1.1 |
0.6 |
| constipation |
0.9 |
0.5 |
1.7 |
0.3 |
| abdominal distention |
0.2 |
0.3 |
1.4 |
1.1 |
|
Musculoskeletal |
|
|
|
|
musculoskeletal (bone,
muscle or joint) pain |
0.8 |
0.9 |
1.9 |
2.2 |
Concomitant Use with Estrogen/Hormone Replacement Therapy
In two studies (of one and two years’ duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with Alendronate 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.
Osteoporosis in Men
In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of Alendronate 10 mg/day and a one-year study of once weekly Alendronate 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 Table 4.
Table 4: 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 |
| |
Alendronate 10 mg/day
%
(n=146) |
Placebo
%
(n=95) |
Once Weekly Alendronate
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 |
Glucocorticoid-Induced Osteoporosis
In two, one-year, placebo-controlled, double-blind, multicenter studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of Alendronate 5 mg and 10 mg/day were generally similar to that of placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either Alendronate 5 mg or 10 mg/day or placebo are presented in Table 5.
Table 5: One-Year Studies in Glucocorticoid-Treated Patients: Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients
|
| Alendronate
10 mg/day
%
(n=157) |
Alendronate
5 mg/day
%
(n=161) |
Placebo
%
(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: 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 events reported in 175 patients taking Alendronate 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with Alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking Alendronate 40 mg/day (17.7% Alendronate 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 considered by the investigators as possibly, probably, or definitely drug related in approximately 6% of patients treated with Alendronate 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 events occurred in 6.4% of patients with Paget's disease treated with Alendronate 40 mg/day and 2.4% of patients treated with placebo.
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Alendronate. 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 rarely angioedema. Transient symptoms of myalgia, malaise, asthenia 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. Rarely, peripheral edema.
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 Dosage and Administration Warnings and Precautions].
Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported rarely [see Warnings and Precautions].
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and rarely incapacitating [see Warnings and Precautions]; joint swelling; low-energy femoral shaft and subtrochanteric fractures. [see Warnings and Precautions].
Nervous system: dizziness and vertigo.
Pulmonary: acute asthma exacerbations.
Skin: rash (occasionally with photosensitivity), pruritus, alopecia, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: rarely uveitis, scleritis or episcleritis.
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