FDA label 0a222fd7-f2ca-301c-e063-6294a90a6d81

5 WARNINGS AND PRECAUTIONS Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. ( 5.1 ) Hypocalcemia can worsen and must be corrected prior to use. ( 5.2 ) Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. ( 5.3 ) Osteonecrosis of the Jaw has been reported. ( 5.4 ) Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. ( 5.5 ) Sodium Content: Each tablet contains 650 mg sodium, equivalent to 1650 mg NaCl. Use caution in patients on sodium restriction. ( 5.7 ) 5.1 Upper Gastrointestinal Adverse Reactions BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration ( 2.3 )] . In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions ( 6.2 )] . 5.2 Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications ( 4 )]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO. Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake. 5.3 Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions ( 6.2 )] . This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. 5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. 5.6 Renal Impairment BINOSTO is not recommended for patients with creatinine clearance <35 mL/min. 5.7 Patients Sensitive to High Sodium Intake Each BINOSTO effervescent tablet contains 650 mg of sodium, equivalent to approximately 1650 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with a history of heart failure, hypertension, or other cardiovascular diseases [see Patient Counseling Information ( 17.3 )].

5.1 Upper Gastrointestinal Adverse Reactions BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration ( 2.3 )] . In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions ( 6.2 )] .

5.2 Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications ( 4 )]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO. Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake.

5.3 Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions ( 6.2 )] . This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.

6 ADVERSE REACTIONS The most common adverse reactions (incidence greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ASCEND Therapeutics at 1-877-204-1013 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. The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily 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 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 group. The incidence of serious adverse events 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 greater than or equal to 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 * 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 Rarely, 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 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 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 Sodium 70 mg % (N=519) Once Daily Alendronate Sodium 10 mg % (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 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 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 the following table. Table 3 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 Once Daily Alendronate Sodium 10 mg % (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 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, 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 ( 2.3 ); Warnings and Precautions ( 5.1 )] . Dental : 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 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. The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily 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 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 group. The incidence of serious adverse events 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 greater than or equal to 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 * 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 Rarely, 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 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 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 Sodium 70 mg % (N=519) Once Daily Alendronate Sodium 10 mg % (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 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 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 the following table. Table 3 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 Once Daily Alendronate Sodium 10 mg % (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

Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily 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 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 group. The incidence of serious adverse events 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 greater than or equal to 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 * 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 Rarely, 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 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 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 Sodium 70 mg % (N=519) Once Daily Alendronate Sodium 10 mg % (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 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 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 the following table. Table 3 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 Once Daily Alendronate Sodium 10 mg % (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

<table ID="t8484622" border="0" width="100%"><col width="32*"/><col width="14*"/><col width="14*"/><col width="14*"/><col width="14*"/><tfoot><tr><td colspan="5">* 10 mg/day for three years ** 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years </td></tr></tfoot><tbody><tr><td/><td colspan="2" align="center"><content styleCode="bold"><content styleCode="underline">United States/Multinational Studies</content></content></td><td colspan="2" align="center"><content styleCode="bold"><content styleCode="underline">Fracture Intervention Trial</content></content></td></tr><tr><td styleCode="Botrule"/><td align="center" styleCode="Botrule" valign="bottom"><content styleCode="bold">Alendronate Sodium* % (N=196) </content></td><td align="center" styleCode="Botrule" valign="bottom"><content styleCode="bold">Placebo % (N=397) </content></td><td align="center" styleCode="Botrule" valign="bottom"><content styleCode="bold">Alendronate Sodium** % (N=3236) </content></td><td align="center" styleCode="Botrule" valign="bottom"><content styleCode="bold">Placebo % (N=3223) </content></td></tr><tr><td colspan="5">Gastrointestinal</td></tr><tr><td> Abdominal pain</td><td align="center">6.6</td><td align="center">4.8</td><td align="center">1.5</td><td align="center">1.5</td></tr><tr><td> Nausea</td><td align="center">3.6</td><td align="center">4.0</td><td align="center">1.1</td><td align="center">1.5</td></tr><tr><td> Dyspepsia</td><td align="center">3.6</td><td align="center">3.5</td><td align="center">1.1</td><td align="center">1.2</td></tr><tr><td> Constipation</td><td align="center">3.1</td><td align="center">1.8</td><td align="center">0.0</td><td align="center">0.2</td></tr><tr><td> Diarrhea</td><td align="center">3.1</td><td align="center">1.8</td><td align="center">0.6</td><td align="center">0.3</td></tr><tr><td> Flatulence</td><td align="center">2.6</td><td align="center">0.5</td><td align="center">0.2</td><td align="center">0.3</td></tr><tr><td> Acid regurgitation</td><td align="center">2.0</td><td align="center">4.3</td><td align="center">1.1</td><td align="center">0.9</td></tr><tr><td> Esophageal ulcer</td><td align="center">1.5</td><td align="center">0.0</td><td align="center">0.1</td><td align="center">0.1</td></tr><tr><td> Vomiting</td><td align="center">1.0</td><td align="center">1.5</td><td align="center">0.2</td><td align="center">0.3</td></tr><tr><td> Dysphagia</td><td align="center">1.0</td><td align="center">0.0</td><td align="center">0.1</td><td align="center">0.1</td></tr><tr><td> Abdominal distention</td><td align="center">1.0</td><td align="center">0.8</td><td align="center">0.0</td><td align="center">0.0</td></tr><tr><td> Gastritis</td><td align="center">0.5</td><td align="center">1.3</td><td align="center">0.6</td><td align="center">0.7</td></tr><tr><td colspan="5">Musculoskeletal</td></tr><tr><td> Musculoskeletal (bone, muscle or joint) pain</td><td align="center">4.1</td><td align="center">2.5</td><td align="center">0.4</td><td align="center">0.3</td></tr><tr><td> Muscle cramp</td><td align="center">0.0</td><td align="center">1.0</td><td align="center">0.2</td><td align="center">0.1</td></tr><tr><td colspan="5">Nervous system/psychiatric</td></tr><tr><td> Headache</td><td align="center">2.6</td><td align="center">1.5</td><td align="center">0.2</td><td align="center">0.2</td></tr><tr><td> Dizziness</td><td align="center">0.0</td><td align="center">1.0</td><td align="center">0.0</td><td align="center">0.1</td></tr><tr><td colspan="5">Special senses</td></tr><tr><td> Taste perversion</td><td align="center">0.5</td><td align="center">1.0</td><td align="center">0.1</td><td align="center">0.0</td></tr></tbody></table>