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 practice.

FOSAMAX

FOSAMAX has been evaluated for safety in approximately 8000 postmenopausal women in clinical studies.

Postmenopausal women

FOSAMAX daily

In two identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994), 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. In the Fracture Intervention Trial (n=6459), discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with FOSAMAX 5 mg/day for 2 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%. In these study 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. Adverse experiences from these studies considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients treated with either FOSAMAX or placebo are presented in Table 1.

Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients

Rarely, rash and erythema have occurred.

The adverse experience profile was similar for the 401 patients treated with either 5- or 20--mg doses of FOSAMAX in the United States and Multinational studies. The adverse experience profile for the 296 patients who received continued treatment with either 5 or 10 mg doses of FOSAMAX in the two-year extension of these studies (treatment years 4 and 5) was similar to that observed during the three-year placebo-controlled period. During the extension period, of the 151 patients treated with FOSAMAX 10 mg/day, the proportion of patients who discontinued therapy due to any clinical adverse experience was similar to that during the first three years of the study.

FOSAMAX once-weekly

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once weekly FOSAMAX 70 mg 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 Table 2.

Table 2: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients

Concomitant use with estrogen or estrogen/progestin products

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.

Men

In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day and a one-year study of once weekly FOSAMAX 70 mg) the rates of discontinuation of therapy due to any clinical adverse experience were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for placebo. The adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥2% of patients treated with either FOSAMAX or placebo are presented in Table 3.

Table 3: Osteoporosis Studies in Men Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥2% of Patients

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 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/dL (0.65 mM) were similar in both treatment groups.

FOSAMAX PLUS D

In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS D (70 mg/2800 IU) was similar to that of FOSAMAX once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS D (70 mg/2800 IU) administered with an additional 2800 IU vitamin D₃ was similar to that of FOSAMAX PLUS D (70 mg/2800 IU).

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of FOSAMAX and FOSAMAX PLUS D. 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; Patient Counseling Information].

Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often 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.

Nervous System: dizziness and vertigo.

Skin: rash (occasionally with photosensitivity), pruritus, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Special Senses: rarely uveitis, scleritis or episcleritis.

Calcium Supplemesnts/Antacids

It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking FOSAMAX PLUS D before taking any other oral medications.

Aspirin

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of FOSAMAX greater than 10 mg and aspirin-containing products.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

FOSAMAX PLUS D may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking FOSAMAX 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with FOSAMAX PLUS D.

Drugs that may impair the absorption of cholecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Additional vitamin D supplementation should be considered [see CLINICAL PHARMACOLOGY].

Drugs that may increase the catabolism of cholecalciferol

Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D. Additional vitamin D supplementation should be considered [see CLINICAL PHARMACOLOGY].

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