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In clinical studies, FOSAMAX was generally well tolerated. In studies of up to five years in duration, side effects, which usually were mild, generally did not require discontinuation of therapy.
Fosamax Plus has been evaluated for safety in clinical studies in approximately 7200 postmenopausal women (Fosamax Plus only)
Treatment of osteoporosis: Postmenopausal Women: In two, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational) of virtually identical design, with a total of 994 postmenopausal women, the overall safety profiles of FOSAMAX 10 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with FOSAMAX 10 mg/day and 6.0% of 397 patients treated with placebo.
Adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥ 1% of patients treated with either FOSAMAX 10 mg/day or placebo are presented in the following table. (See Table 3.)
Click on icon to see table/diagram/imageOne patient treated with FOSAMAX (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant acetylsalicylic acid (ASA) developed an anastomotic ulcer with mild hemorrhage, which was considered drug-related. ASA and FOSAMAX were discontinued and the patient recovered.
In the two-year extension (treatment years 4 and 5) of the previously mentioned studies, the overall safety profile of FOSAMAX 10 mg/day was similar to that observed during the three-year placebo-controlled period. Additionally, the proportion of patients who discontinued FOSAMAX 10 mg/day due to any clinical adverse experience was similar to that during the first three years of the study.
In the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with FOSAMAX 5 mg/day for two years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo.
Discontinuations due to upper gastrointestinal adverse experiences were: FOSAMAX, 3.2%; placebo, 2.7%. The overall adverse experience profile was similar to that seen in other studies with FOSAMAX 5 or 10 mg/day.
In a one-year, double-blind multicenter study, the overall safety and tolerability profiles of FOSAMAX 70 mg once weekly and FOSAMAX 10 mg daily were similar. The adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients in either treatment group are presented in the following table: See Table 4.
Click on icon to see table/diagram/imageMen: In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day [n=146] and a one-year study of FOSAMAX 70 mg once weekly [n=109]), the safety profile of FOSAMAX was generally similar to that seen in postmenopausal women. The rates of discontinuation of therapy due to any clinical adverse experience were 2.7% for FOSAMAX 10mg/day vs. 10.5% for placebo, and 6.4% for FOSAMAX 70 mg once weekly vs. 8.6% for placebo.
Other studies in men and women: In a ten-week endoscopy study in men and women (n=277; mean age: 55) no difference was seen in upper gastrointestinal tract lesions between FOSAMAX 70 mg once weekly and placebo.
In an additional one-year study in men and women (n=335; mean age: 50) the overall safety and tolerability profiles of FOSAMAX 70 mg once weekly were similar to that of placebo and no difference was seen between men and women.
Prevention of Osteoporosis in Postmenopausal Women: The safety of FOSAMAX 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 FOSAMAX for either two or three years. In these studies the overall safety profiles of FOSAMAX 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 FOSAMAX 5 mg/day and 5.7% of 648 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug-related in ≥ 1% of patients treated with either FOSAMAX 5 mg/day or placebo are presented in the following table: See Table 5.
Click on icon to see table/diagram/imageConcomitant 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 FOSAMAX 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.
Treatment and Prevention of 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 FOSAMAX 5 or 10 mg/day were generally similar to that of placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug-related in ≥ 1% of patients treated with either FOSAMAX 5 or 10 mg/day or placebo are presented in the following table: See Table 6.
Click on icon to see table/diagram/imageThe overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies was consistent with that observed in the first year.
Paget's Disease of Bone: Fosamax Plus: In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in 175 patients taking FOSAMAX 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with FOSAMAX 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking FOSAMAX 40 mg/day (17.7% FOSAMAX vs. 10.2% placebo). Isolated cases of esophagitis and gastritis resulted in discontinuation of treatment.
Additionally, musculoskeletal pain (bone, muscle or joint), 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 FOSAMAX 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 FOSAMAX 40 mg/day and 2.4% of patients treated with placebo.
In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS (70 mg/2800 IU) was similar to that of FOSAMAX 70 mg once weekly. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS (70 mg/2800 IU) administered with an additional 2800 IU vitamin D3 was similar to that of FOSAMAX PLUS (70 mg/2800 IU).
Less Common Clinical Trial Adverse Drug Reactions (<1%): Skin: rash and erythema.
Abnormal Hematologic and Clinical Chemistry Findings: Laboratory Tests: 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 FOSAMAX 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 ≤ 2.0 mg P1/dL (0.65 mM) were similar in both treatment groups.
In a small, open-label study, at higher doses (80 mg/day) some patients had elevated transaminases. However, this was not observed at 40 mg/day. No clinically significant toxicity was associated with these laboratory abnormalities.
Rare cases of leukemia have been reported following therapy with other bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.
1P: Elemental phosphorus
Post-Market Adverse Drug Reactions: The following adverse reactions have been reported in post-marketing use with alendronate:
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 both in association with predisposing conditions and in patients without known predisposing conditions; peripheral edema.
Dental: localized osteonecrosis of the jaw (ONJ) is generally associated with local infection (including osteomyelitis) and/or tooth extraction with delayed healing (see PRECAUTIONS).
Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration; gastric or duodenal ulcers, some severe and with complications (see PRECAUTIONS and DOSAGE & ADMINISTRATION).
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and/or incapacitating; joint swelling; low-energy femoral shaft fracture (see PRECAUTIONS).
Nervous System: dizziness, vertigo, dysgeusia.
Skin: rash (occasionally with photosensitivity), pruritus, alopecia; severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: uveitis, scleritis or episcleritis; osteonecrosis of the external auditory canal (cholesteatoma).
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