Alendronate Sodium (Page 3 of 9)

6 ADVERSE REACTIONS

6.1 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 sodium 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 sodium. 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 sodium group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium 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 sodium 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 sodium 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 ≥ 1% of Patients
United States/Multinational Studies Fracture Intervention Trail
Alendronate sodium * % (n=196) Placebo % (n=397) Alendronate sodium % (n=3236) Placebo % (n=3223)
*
10 mg/day for three years
5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years.

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/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 sodium 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.

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 ≥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 ≥ 1% of Patients
Once Weekly Alendronate Alendronate
70 mg % (n=519) 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 or 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 sodium 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 ≥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 ≥ 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 ≥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 ≥ 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) Once Weekly % (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 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 ≥1% of patients treated with either alendronate 5 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 ≥ 1% of Patients
Alendronate 10 mg/day Alendronate 5 mg/day Placebo
% (n=157) % (n=161) % (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 sodium: 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 sodium 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.

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