ALENDRONATE SODIUM
Generic: ALENDRONATE SODIUM
Basic Information
Manufacturer
EXELAN PHARMACEUTICALS INC.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
91a0f73a-d8cd-4197-b431-40707a2150b9
Indications & Usage
1 INDICATIONS AND USAGE Alendronate sodium is a bisphosphonate indicated for: Treatment and prevention of osteoporosis in postmenopausal women ( 1.1 , 1.2 ) Treatment to increase bone mass in men with osteoporosis ( 1.3 ) Treatment of glucocorticoid-induced osteoporosis ( 1.4 ) Treatment of Paget's disease of bone ( 1.5 ) Limitations of use: Optimal duration of use has not been determined.
For patients at low- risk for fracture, consider drug discontinuation after 3 to 5 years of use.
(1.6) 1.1 Treatment of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the treatment of osteoporosis in postmenopausal women.
In postmenopausal women, alendronate sodium tablets, USP increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).
[See Clinical Studies ( 14.1 ).] 1.2 Prevention of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies ( 14.2 )].
1.3 Treatment to Increase Bone Mass in Men with Osteoporosis Alendronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies ( 14.3 )].
1.4 Treatment of Glucocorticoid-Induced Osteoporosis Alendronate sodium tablets, USP are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density [see Clinical Studies ( 14.4 )].
1.5 Treatment of Paget's Disease of Bone Alendronate sodium tablets, USP are indicated for the treatment of Paget's disease of bone in men and women.
Treatment is indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease.
[See Clinical Studies ( 14.5 ).] 1.6 Important Limitations of Use The optimal duration of use has not been determined.
The safety and effectiveness of alendronate sodium for the treatment of osteoporosis are based on clinical data of four years duration.
All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use.
Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
For patients at low- risk for fracture, consider drug discontinuation after 3 to 5 years of use.
(1.6) 1.1 Treatment of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the treatment of osteoporosis in postmenopausal women.
In postmenopausal women, alendronate sodium tablets, USP increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).
[See Clinical Studies ( 14.1 ).] 1.2 Prevention of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies ( 14.2 )].
1.3 Treatment to Increase Bone Mass in Men with Osteoporosis Alendronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies ( 14.3 )].
1.4 Treatment of Glucocorticoid-Induced Osteoporosis Alendronate sodium tablets, USP are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density [see Clinical Studies ( 14.4 )].
1.5 Treatment of Paget's Disease of Bone Alendronate sodium tablets, USP are indicated for the treatment of Paget's disease of bone in men and women.
Treatment is indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease.
[See Clinical Studies ( 14.5 ).] 1.6 Important Limitations of Use The optimal duration of use has not been determined.
The safety and effectiveness of alendronate sodium for the treatment of osteoporosis are based on clinical data of four years duration.
All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use.
Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
Adverse Reactions
6 ADVERSE REACTIONS Most common adverse reactions (greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exelan Pharmaceuticals, Inc., at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 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 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 greater than or equal to 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 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 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 sodium 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 sodium 70 mg once weekly and alendronate sodium 10 mg daily.
The overall safety and tolerability profiles of once weekly alendronate sodium 70 mg and alendronate sodium 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) Alendronate Sodium 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 sodium 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 sodium 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 sodium 5 mg/day and 5.7% of 648 patients treated with placebo.
Weekly Dosing The safety of alendronate sodium 35 mg once weekly compared to alendronate sodium 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 sodium 35 mg and alendronate sodium 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 sodium 35 mg, alendronate sodium 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 Sodium 5 mg/day % (n=642) Placebo % (n=648) Alendronate Sodium 5 mg/day % (n=361) Once Weekly Alendronate Sodium 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 sodium 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 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 sodium 10 mg/day vs.
10.5% for placebo, and 6.4% for once weekly alendronate sodium 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 sodium 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 Sodium 10 mg/day % (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 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 sodium 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 greater than or equal to 1% of patients treated with either alendronate sodium 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 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 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 sodium 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with alendronate sodium 10 mg/day.
However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate sodium 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 sodium 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 sodium 40 mg/day and 2.4% of patients treated with placebo.
6.2 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 sodium, 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 ( 2.6 ); Warnings and Precautions ( 5.1 )] .
Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see Warnings and Precautions ( 5.4 )] .
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating [see Warnings and Precautions ( 5.3 )]; joint swelling; low-energy femoral shaft and subtrochanteric fractures [see Warnings and Precautions ( 5.5 )] .
Nervous System: dizziness and vertigo.
Pulmonary: acute 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.
Cholesteatoma of the external auditory canal (focal osteonecrosis).
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exelan Pharmaceuticals, Inc., at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 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 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 greater than or equal to 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 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 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 sodium 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 sodium 70 mg once weekly and alendronate sodium 10 mg daily.
The overall safety and tolerability profiles of once weekly alendronate sodium 70 mg and alendronate sodium 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) Alendronate Sodium 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 sodium 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 sodium 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 sodium 5 mg/day and 5.7% of 648 patients treated with placebo.
Weekly Dosing The safety of alendronate sodium 35 mg once weekly compared to alendronate sodium 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 sodium 35 mg and alendronate sodium 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 sodium 35 mg, alendronate sodium 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 Sodium 5 mg/day % (n=642) Placebo % (n=648) Alendronate Sodium 5 mg/day % (n=361) Once Weekly Alendronate Sodium 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 sodium 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 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 sodium 10 mg/day vs.
10.5% for placebo, and 6.4% for once weekly alendronate sodium 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 sodium 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 Sodium 10 mg/day % (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 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 sodium 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 greater than or equal to 1% of patients treated with either alendronate sodium 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 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 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 sodium 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with alendronate sodium 10 mg/day.
However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate sodium 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 sodium 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 sodium 40 mg/day and 2.4% of patients treated with placebo.
6.2 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 sodium, 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 ( 2.6 ); Warnings and Precautions ( 5.1 )] .
Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see Warnings and Precautions ( 5.4 )] .
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating [see Warnings and Precautions ( 5.3 )]; joint swelling; low-energy femoral shaft and subtrochanteric fractures [see Warnings and Precautions ( 5.5 )] .
Nervous System: dizziness and vertigo.
Pulmonary: acute 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.
Cholesteatoma of the external auditory canal (focal osteonecrosis).