FDA label a643a85a-becd-112d-e053-2995a90a1fca

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 an incomplete femoral fracture. ( 5.5 ) 5.1 Upper Gastrointestinal Adverse Reactions Alendronate sodium, 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 alendronate sodium 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 alendronate sodium 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 fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6-8 oz) of water, 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 (2.6) ] . In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium 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 alendronate sodium [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 alendronate sodium. Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased. Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids. 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 prevention and treatment of osteoporosis [see Adverse Reactions (6.2) ] . This category of drugs includes alendronate. 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. 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 Alendronate sodium is not recommended for patients with creatinine clearance <35 mL/min. 5.7 Glucocorticoid-Induced Osteoporosis The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established [see Indications and Usage (1.4) ] . Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered. A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.

6 ADVERSE REACTIONS Most common adverse reactions (≥3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals LLC at 1-888-848-3593 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 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 10 mg/day for three years % (n=196) Placebo % (n=397) Alendronate sodium 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years. % (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 (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. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of alendronate. 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 (2.6) ; 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.

<table width="75%" ID="table1"> <caption>Table 1. Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in &#x2265; 1% of Patients</caption> <col width="32%" align="left" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="2" styleCode="Rrule Botrule">United States/Multinational Studies</th> <th colspan="2" styleCode="Botrule">Fracture Intervention Trail</th> </tr> <tr> <th/> <th>Alendronate sodium <footnote ID="t1f1">10 mg/day for three years</footnote> % (n=196) </th> <th styleCode="Rrule">Placebo % (n=397) </th> <th>Alendronate sodium <footnote ID="t1f2">5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years.</footnote> % (n=3236) </th> <th>Placebo % (n=3223) </th> </tr> </thead> <tbody> <tr> <td> <content styleCode="italics">Gastrointestinal</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> abdominal pain</td> <td>6.6</td> <td styleCode="Rrule">4.8</td> <td>1.5</td> <td>1.5</td> </tr> <tr> <td> nausea</td> <td>3.6</td> <td styleCode="Rrule">4.0</td> <td>1.1</td> <td>1.5</td> </tr> <tr> <td> dyspepsia</td> <td>3.6</td> <td styleCode="Rrule">3.5</td> <td>1.1</td> <td>1.2</td> </tr> <tr> <td> constipation</td> <td>3.1</td> <td styleCode="Rrule">1.8</td> <td>0.0</td> <td>0.2</td> </tr> <tr> <td> diarrhea</td> <td>3.1</td> <td styleCode="Rrule">1.8</td> <td>0.6</td> <td>0.3</td> </tr> <tr> <td> flatulence</td> <td>2.6</td> <td styleCode="Rrule">0.5</td> <td>0.2</td> <td>0.3</td> </tr> <tr> <td> acid regurgitation</td> <td>2.0</td> <td styleCode="Rrule">4.3</td> <td>1.1</td> <td>0.9</td> </tr> <tr> <td> esophageal ulcer</td> <td>1.5</td> <td styleCode="Rrule">0.0</td> <td>0.1</td> <td>0.1</td> </tr> <tr> <td> vomiting</td> <td>1.0</td> <td styleCode="Rrule">1.5</td> <td>0.2</td> <td>0.3</td> </tr> <tr> <td> dysphagia</td> <td>1.0</td> <td styleCode="Rrule">0.0</td> <td>0.1</td> <td>0.1</td> </tr> <tr> <td> abdominal distention</td> <td>1.0</td> <td styleCode="Rrule">0.8</td> <td>0.0</td> <td>0.0</td> </tr> <tr> <td> gastritis</td> <td>0.5</td> <td styleCode="Rrule">1.3</td> <td>0.6</td> <td>0.7</td> </tr> <tr> <td> <content styleCode="italics">Musculoskeletal</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> Musculoskeletal (bone, muscle or joint) pain</td> <td valign="bottom">4.1</td> <td styleCode="Rrule" valign="bottom">2.5</td> <td valign="bottom">0.4</td> <td valign="bottom">0.3</td> </tr> <tr> <td> muscle cramp</td> <td>0.0</td> <td styleCode="Rrule">1.0</td> <td>0.2</td> <td>0.1</td> </tr> <tr> <td> <content styleCode="italics">Nervous System/Psychiatric</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> headache</td> <td>2.6</td> <td styleCode="Rrule">1.5</td> <td>0.2</td> <td>0.2</td> </tr> <tr> <td> dizziness</td> <td>0.0</td> <td styleCode="Rrule">1.0</td> <td>0.0</td> <td>0.1</td> </tr> <tr> <td> <content styleCode="italics">Special Senses</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> taste perversion</td> <td>0.5</td> <td styleCode="Rrule">1.0</td> <td>0.1</td> <td>0.0</td> </tr> </tbody> </table>

<table width="75%" ID="table2"> <caption>Table 2: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in &#x2265; 1% of Patients</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th/> <th>Once Weekly Alendronate</th> <th>Alendronate</th> </tr> <tr> <th/> <th>70 mg % (n=519) </th> <th>10 mg/day % (n=370) </th> </tr> </thead> <tbody> <tr> <td> <content styleCode="italics">Gastrointestinal</content> </td> <td/> <td/> </tr> <tr> <td> abdominal pain</td> <td>3.7</td> <td>3.0</td> </tr> <tr> <td> dyspepsia</td> <td>2.7</td> <td>2.2</td> </tr> <tr> <td> acid regurgitation</td> <td>1.9</td> <td>2.4</td> </tr> <tr> <td> nausea</td> <td>1.9</td> <td>2.4</td> </tr> <tr> <td> abdominal distention</td> <td>1.0</td> <td>1.4</td> </tr> <tr> <td> constipation</td> <td>0.8</td> <td>1.6</td> </tr> <tr> <td> flatulence</td> <td>0.4</td> <td>1.6</td> </tr> <tr> <td> gastritis</td> <td>0.2</td> <td>1.1</td> </tr> <tr> <td> gastric ulcer</td> <td>0.0</td> <td>1.1</td> </tr> <tr> <td> <content styleCode="italics">Musculoskeletal</content> </td> <td/> <td/> </tr> <tr> <td> musculoskeletal (bone, muscle or joint) pain</td> <td>2.9</td> <td>3.2</td> </tr> <tr> <td> muscle cramp</td> <td>0.2</td> <td>1.1</td> </tr> </tbody> </table>

<table width="75%" ID="table3"> <caption>Table 3. Osteoporosis Prevention Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in &#x2265; 1% of Patients</caption> <col width="32%" align="left" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="2" styleCode="Botrule">Two/Three-Year Studies</th> <th colspan="2" styleCode="Botrule">One-Year Study</th> </tr> <tr> <th/> <th>Alendronate 5 mg/day % (n=642) </th> <th>Placebo % (n=648) </th> <th>Alendronate 5 mg/day % (n=361) </th> <th>Once Weekly Alendronate 35 mg % (n=362) </th> </tr> </thead> <tbody> <tr> <td> <content styleCode="italics">Gastrointestinal</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> dyspepsia</td> <td>1.9</td> <td styleCode="Rrule">1.4</td> <td>2.2</td> <td>1.7</td> </tr> <tr> <td> abdominal pain</td> <td>1.7</td> <td styleCode="Rrule">3.4</td> <td>4.2</td> <td>2.2</td> </tr> <tr> <td> acid regurgitation</td> <td>1.4</td> <td styleCode="Rrule">2.5</td> <td>4.2</td> <td>4.7</td> </tr> <tr> <td> nausea</td> <td>1.4</td> <td styleCode="Rrule">1.4</td> <td>2.5</td> <td>1.4</td> </tr> <tr> <td> diarrhea</td> <td>1.1</td> <td styleCode="Rrule">1.7</td> <td>1.1</td> <td>0.6</td> </tr> <tr> <td> constipation</td> <td>0.9</td> <td styleCode="Rrule">0.5</td> <td>1.7</td> <td>0.3</td> </tr> <tr> <td> abdominal distention</td> <td>0.2</td> <td styleCode="Rrule">0.3</td> <td>1.4</td> <td>1.1</td> </tr> <tr> <td> <content styleCode="italics">Musculoskeletal</content> </td> <td/> <td styleCode="Rrule"/> <td/> <td/> </tr> <tr> <td> musculoskeletal (bone, muscle or joint) pain</td> <td>0.8</td> <td styleCode="Rrule">0.9</td> <td>1.9</td> <td>2.2</td> </tr> </tbody> </table>