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alendronate sodium 35 mg tab

Out of Stock Manufacturer VIRTUS PHARMACE 69543013004
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Uses

Osteoporosis

Alendronate is used in the treatment and prevention of osteoporosis in postmenopausal women; the drug also is used to increase bone mass in men with osteoporosis.

Osteoporosis, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with consequent increased bone fragility and susceptibility to fracture (usually of the spine, hip, and wrist), is observed in a large proportion of postmenopausal women. Adult women have less bone mass than men at all ages, and decreased production of estrogen at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years, during which time skeletal mass loss averages 3% per year. Osteoporosis from age-related bone loss can also develop in men. While the risk of osteoporosis and resulting fractures cannot be quantified by a single clinical finding or test result, many risk factors have been identified, with the probability of developing osteoporosis increasing with multiple risk factors. Risk factors include early menopause, advanced age, low bone mineral density (BMD), low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).

In addition to lifestyle modifications (e.g., regular weight-bearing exercise, avoidance of excessive alcohol and tobacco use), adequate intake of calcium (1-1.2 g daily) and vitamin D (800-1000 units daily) is essential in the prevention and treatment of osteoporosis and is recommended for all postmenopausal women and men 50 years of age or older. Additional pharmacologic therapy should be considered in such patients with high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low BMD). Pharmacologic therapy also may be considered in postmenopausal women and in men 50 years of age or older who have low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients. When selecting an appropriate pharmacologic agent, experts recommend use of a drug with proven antifracture efficacy; available options include bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate), denosumab, raloxifene, calcitonin, or teriparatide with varying levels of recommendation given in expert guidelines based on the evidence supporting fracture risk reduction for each drug. While estrogen/hormone therapy was commonly used in the past for the treatment of osteoporosis in postmenopausal women, there is some evidence indicating that such therapy is associated with an increased risk of breast cancer, cardiovascular, cerebrovascular, and thromboembolic events. Choice of osteoporosis therapy should be individualized based on the potential benefits and adverse effects of therapy as well as patient preferences, comorbidities, and risk factors.

Prevention in Postmenopausal Women

Alendronate is used for the prevention of osteoporosis in postmenopausal women. The drug is used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy, avoidance of excessive cigarette smoking and/or alcohol consumption) to retard further bone loss and the progression of osteoporosis in postmenopausal women. The goal of preventive therapy is preservation of bone mass and a resultant decrease in fracture risk.

Alendronate has been evaluated for the prevention of osteoporosis in postmenopausal women in 2 double-blind, placebo-controlled studies of 2 or 3 years' duration that included 2056 women (40-60 years of age). In these studies, therapy with alendronate 5 mg daily increased BMD, as determined by dual-energy radiographic absorption (DXA) measurements, in the lumbar spine, femoral neck, trochanter bone, and total body. While women receiving placebo lost approximately 1% of BMD per year, substantial increases in BMD were observed in women receiving alendronate. In one of the studies that included postmenopausal women who had experienced menopause 6-36 months before initiation of the study, administration of alendronate (5 or 10 mg daily given for 3 years or, alternatively, 20 mg daily given for 2 years, followed by administration of placebo daily for 1 year) at 3 years was associated with a 1-4% increase in lumbar spine, femoral neck, and trochanter BMD and 0.3-1% increase in total body BMD compared with baseline, while placebo recipients lost about 2-4% BMD in these sites; a lower dosage (1 mg daily) of alendronate for 3 years attenuated but did not fully prevent losses in BMD relative to those in women receiving placebo. Limited data indicate that alendronate (5 mg daily) reduced the rate of bone loss on forearm by about half relative to placebo. In a 1-year controlled study in postmenopausal women with osteoporosis, alendronate 70 mg once weekly produced increases in BMD similar to those observed with a dosage of 10 mg daily.

In osteoporosis prevention studies that evaluated alendronate therapy (Early Postmenopausal Intervention Cohort Study) for 24 months, raloxifene (European trial), or various estrogen/progestin combinations for hormone replacement therapy (HRT), alendronate (5 mg daily) therapy was associated with 1.3-1.9% increases in hip BMD compared with baseline, raloxifene hydrochloride therapy (60 mg daily) was associated with 1.6% increases, and HRT was associated with 1.8-3.2% increases. In these studies, alendronate, raloxifene, or HRT was associated with increases in BMD of lumbar spine of 2.9-3.5%, 1.6%, or 4-5.1%, respectively, compared with baseline.

Treatment in Postmenopausal Women

Alendronate is used alone or in fixed combination with cholecalciferol (vitamin D3) for the treatment of osteoporosis in postmenopausal women.

In several double-blind, placebo-controlled trials in postmenopausal women with osteoporosis (defined as lumbar spine BMD values at least 2 standard deviations below premenopausal mean values), therapy with alendronate 10 mg daily for 2-3 years substantially increased BMD in the lumbar spine, femoral neck, and trochanter; total body BMD also increased, suggesting that BMD increases in the spine and hip did not occur at the expense of other skeletal sites. In long-term trials (e.g., 3 years with several extensions up to 10 years), increases in BMD were apparent as early as 3 months after initiation of alendronate therapy and continued throughout therapy. Results of some studies indicate that some therapeutic effects on bone mass are maintained for up to 5 years following withdrawal of alendronate therapy (following 5 years of treatment) at the lumbar spine, trochanter, and total body; after discontinuance of therapy, BMD decreased appreciably at the femoral neck and forearm over the next 5 years of follow-up. Bone histology studies in postmenopausal women with osteoporosis treated with alendronate 1-20 mg daily for 1, 2, or 3 years indicate that bone formed during treatment with the drug is of normal quality. Among women who had sustained a vertebral fracture, alendronate therapy reduced the risk of new vertebral fractures, including women at high risk for further vertebral fractures (e.g., those with severe osteoporosis, those 75 years or older).

Analysis of pooled data from several US and multinational placebo-controlled trials in postmenopausal women indicates that alendronate therapy (5 or 10 mg daily for 3 years, or 20 mg daily for 2 years followed by 5 mg daily for 1 year) was associated with a reduced incidence of vertebral fractures (a 48% relative risk reduction) and, because of a reduction in the frequency and severity of fractures, less height loss than that occurring with placebo, even among patients who sustained a vertebral fracture. Several large, placebo-controlled clinical trials have noted a reduced incidence of vertebral and other types of fractures (e.g., hip, wrist) in postmenopausal women, most of whom had osteoporosis. In a large, placebo-controlled clinical trial in women with osteoporosis who had an existing vertebral fracture, alendronate therapy (5 or 10 mg once daily given concomitantly with calcium and vitamin D supplementation) reduced the incidence of hip fracture by 51% and wrist fracture by 48% at 3 years; the proportion of patients requiring hospitalization also was reduced (31 or 25% with placebo or alendronate, respectively). The frequency of adverse effects, including GI disorders, also was similar between alendronate or placebo. In another large, long-term (4-year), placebo-controlled trial in women with low BMD but without vertebral fractures, alendronate (5 mg daily for 2 years, then 10 mg daily thereafter) reduced the risk of clinical fractures in women with osteoporosis (baseline femoral neck BMD exceeding 2.5 standard deviations below the normal adult mean) but not in those with higher BMDs. The incidence of atrial fibrillation in these 2 placebo-controlled trials was numerically higher in the alendronate-treated groups compared with that observed in the placebo-treated groups.

Combination Therapy

Alendronate has been used concomitantly with various estrogen or estrogen/progestin combinations and calcium to increase bone mass in postmenopausal women with osteoporosis. In several clinical trials in postmenopausal women with osteoporosis, the combination of estrogen-containing hormone replacement therapy (HRT) and alendronate resulted in a greater degree of suppression of bone turnover than either therapy given alone. In a long-term, placebo-controlled trial comparing therapy with alendronate (10 mg once daily), conjugated estrogens (0.625 mg daily), or the combination of these drugs in postmenopausal women with osteoporosis who had undergone hysterectomy and were not currently receiving antiresorptive therapy, combination therapy increased lumbar spine and femoral neck BMD to a greater degree than either agent alone or placebo at 2 years. All women received supplementation with calcium 500 mg daily. Bone histology studies in these patients indicated that the bone formed during therapy was of normal quality. Compared with placebo, bone turnover after 18 months was suppressed by 98% with combined alendronate and HRT, 94% with alendronate therapy alone, and 78% with HRT alone. In another comparative study in postmenopausal women who had osteoporosis despite receiving estrogen or estrogen plus progestin (medroxyprogesterone) HRT for at least 1 year (mean duration almost 10 years), the addition of alendronate (10 mg once daily) to supplementation with daily vitamin D and calcium (if baseline calcium intake was less than 1000 mg daily) increased BMD in the lumbar spine and hip trochanter compared with HRT alone. In either trial, the incidence of new fractures was similar across treatment groups. However, the size and duration of these studies may have been inadequate to detect differences in fracture incidence for combination therapy compared with alendronate or placebo, and further studies are needed. The safety of combination therapy reportedly was consistent with that of each antiresorptive agent alone. However, some clinicians state that concomitant hormone replacement therapy currently is not recommended in patients receiving alendronate because of lack of clinical experience with such use.

Treatment in Men

Alendronate also is used alone or in fixed combination with cholecalciferol (vitamin D3) for the treatment of osteoporosis in men. In a double-blind, placebo-controlled trial in men 31-87 years of age (mean age: 63) with hypogonadal or idiopathic osteoporosis, therapy with alendronate (10 mg daily) substantially increased BMD in the lumbar spine, hip, femoral neck, and trochanter; total body BMD also increased, suggesting that BMD increases in the spine and hip did not occur at the expense of other skeletal sites. Osteoporosis in these men was defined as a femoral neck BMD value at least 2 standard deviations below the mean in healthy young men and a lumbar spine BMD value at least 1 standard deviation below the mean in healthy young men, or a femoral neck BMD of at least 1 standard deviation below the mean value in healthy young men and at least one sustained fracture. All patients in the study received supplemental calcium (500 mg daily as calcium carbonate) and vitamin D (400-450 units daily). Increases in BMD were apparent as early as 6 months after initiation of alendronate therapy and continued throughout therapy. Alendronate therapy was associated with a reduced incidence of new vertebral fractures and, because of a reduction in the frequency of fractures, less height loss than that occurring with calcium and vitamin D supplementation only.

In another double-blind, placebo-controlled trial in men 38-91 years of age (mean age: 66 years) with hypogonadal or idiopathic osteoporosis, therapy with alendronate (70 mg once weekly for 1 year) substantially increased BMD in the lumbar spine, femoral neck, trochanter, and total body. Osteoporosis in these men was defined as a femoral neck BMD value at least 2 standard deviations below the mean for healthy young men and a lumbar spine BMD value at least 1 standard deviation below the mean for healthy young men; a lumbar spine BMD of at least 2 standard deviations below the mean value for healthy young men and a femoral neck BMD value at least 1 standard deviation below the mean for healthy young men; or at least one sustained fracture and a femoral neck BMD value at least 1 standard deviation below the mean for healthy young men. The increases in BMD with weekly therapy were similar to those seen at 1 year in patients receiving 10 mg of alendronate daily. Among men receiving alendronate in both studies (daily or weekly therapy), response to therapy was similar regardless of age (65 years of age or older, younger than 65 years of age), gonadal function (baseline testosterone concentrations of at least 9 ng/dL, less than 9 ng/dL), or baseline BMD (femoral neck and lumbar spine BMD at least 2.5 standard deviations from the mean for young men, less than 2.5 standard deviations from the mean).

Glucocorticoid-induced Osteoporosis

Alendronate is used in the treatment of glucocorticoid-induced osteoporosis. The manufacturer recommends use of alendronate in men and women receiving a daily dosage equivalent to at least 7.5 mg of prednisone who have low BMD; risks versus benefits of alendronate therapy in patients receiving a lower dosage of glucocorticoids have not been established. Alendronate also has been used in the prevention of glucocorticoid-induced osteoporosis.

Osteoporosis and related fractures are some of the most serious complications of long-term glucocorticoid therapy. More than 10% of patients are diagnosed with a fracture and 30-40% have radiographic evidence of vertebral fractures during long-term glucocorticoid use. The risk of fracture is both dose and duration dependent, with higher daily or cumulative doses of glucocorticoids and longer durations of use associated with greater risk. A high glucocorticoid dosage generally is considered a daily dosage equivalent to more than 7.5 mg of prednisone. However, some studies have reported an increased risk of fracture with daily dosages as low as 2.5-7.5 mg of prednisolone or equivalent, while others have found no appreciable decline in bone density with prednisone dosages averaging 8 mg daily or dosages of less than 5 mg daily. Because glucocorticoid-induced osteoporosis can be effectively prevented, the American College of Rheumatology (ACR) recommends that appropriate preventive therapy be considered for patients in whom the benefits of such therapy outweigh the potential harms. ACR recommendations are based on a risk-stratification approach in which an individual's risk level for developing a fracture (low, moderate, or high) is determined based on predisposing factors including the individual's preexisting or anticipated glucocorticoid dosage. An initial clinical fracture risk assessment is recommended within 6 months of initiating long-term glucocorticoid therapy with reassessments recommended every 12 months during continued treatment. Lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) and calcium/vitamin D intake should be optimized in all patients receiving long-term (at least 3 months) glucocorticoid therapy at a daily dosage equivalent to at least 2.5 mg of prednisone. The need for additional pharmacologic therapy should be determined based on the patient's risk for fractures. ACR recommends an oral bisphosphonate in adults receiving long-term glucocorticoid therapy who are considered to be at moderate-to-high risk of fracture. Oral bisphosphonates generally are preferred because of their demonstrated benefits in reducing fracture risk as well as their safety and low cost; other options include IV bisphosphonates, teriparatide, denosumab, and raloxifene (for postmenopausal women if no other therapy is appropriate). ACR states that the available data on fracture risk and risk reduction are more limited in children and adults younger than 40 years of age; however, treatment with oral bisphosphonates and calcium/vitamin D is recommended because the possible benefits appear to outweigh the risks. For additional information on the prevention and treatment of glucocorticoid-induced osteoporosis,

Alendronate has been evaluated for the treatment of glucocorticoid-induced osteoporosis in men and women with a variety of underlying diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, inflammatory myopathy, inflammatory bowel disease, asthma) and usually with low bone mineral density (e.g., 1-2 standard deviations below the mean for healthy young adults in more than 70% of those studied) who were receiving glucocorticoid therapy (e.g., a daily dosage of at least 7.5 mg of prednisone or equivalent) in 2 placebo-controlled, double-blind, randomized studies of 1 year's duration and an extension of one of these studies for a total duration of 2 years. In these studies, therapy with alendronate 5 or 10 mg daily (given concomitantly with calcium and vitamin D supplementation) increased BMD, as determined by DXA measurements in the lumbar spine, femoral neck, trochanter bone, and total body; 2 years after initiating alendronate therapy, lumbar BMD was increased by 2.8-3.9 and trochanter BMD also was increased and femoral neck BMD maintained relative to baseline values. While patients receiving placebo lost approximately 0.4, 0.7, or 1.2% of BMD within about 1 year at the lumbar spine, trochanter bone, or femoral neck, respectively, and 0.8% with 2 years at the lumbar spine; BMD either increased or was maintained in these sites in patients receiving alendronate for such periods of time. Administration of alendronate 5 mg daily was associated with a 2.1, 1.1, or 1.2% increase in lumbar spine, trochanter bone, or femoral neck, respectively, and administration of alendronate 10 mg daily was associated with a 2.9, 2.7, or 1% increase in lumbar spine, trochanter bone, and femoral neck, respectively, after 1 year. Total body BMD was maintained with 5 mg of alendronate daily after 1 year but was increased with 5 or 10 mg of the drug daily after 2 years.

The increases in BMD in patients receiving 10 mg of alendronate daily were similar to those receiving alendronate 5 mg except in postmenopausal women not receiving estrogen replacement therapy. In these women, BMD increases (relative to placebo) at the lumbar spine were 4.1 or 1.6% in patients receiving 10 or 5 mg of alendronate daily, respectively, while at the trochanter bone, BMD increases were 2.8 or 1.7% in patients receiving 10 or 5 mg of alendronate daily, respectively; at other sites, increases in BMD were similar when using the different dosages of alendronate. In these studies, greatest increase in BMD occurred in the first year of therapy and only maintenance or smaller increases in BMD were reported in the second year of therapy with alendronate. In addition, the efficacy of alendronate reportedly was not affected by age, gender, race, underlying disease, previous duration or current dosage of corticosteroid therapy, baseline BMD, baseline bone turnover or concomitant administration of other drugs. Bone histology was normal in several patients (receiving alendronate 10 mg daily for 1 year) who underwent bone biopsy. In these studies after 1 year of therapy, patients receiving alendronate (5 or 10 mg daily), had fewer new vertebral fractures than those receiving placebo (2.3 versus 3.7%, respectively), but the difference was not significant. Analysis of pooled data indicates that after 2 years of therapy, the incidence of a new vertebral fracture was 0.7 or 6.8% in patients receiving alendronate (5 or 10 mg daily for 2 years, or 2.5 mg for 1 year followed by 10 mg for the second year) or placebo, respectively. However, these findings were based on very few fractures occurring mainly in postmenopausal women.

Paget Disease of Bone

Alendronate also is used orally in the treatment of moderate to severe Paget disease of bone (osteitis deformans). In most patients with Paget disease, only small areas of bone are involved and patients are usually asymptomatic; mild symptoms in these patients usually can be controlled with analgesics. Treatment with alendronate should be considered in patients with serum alkaline phosphatase concentrations at least twice the upper limit of normal, those who are symptomatic, or those at risk for future complications from their disease.

In clinical trials in males and females with moderate to severe Paget disease of bone (serum alkaline phosphatase concentrations at least twice the upper limit of normal), suppression of alkaline phosphatase (i.e., either normalization of serum concentrations or a decrease of at least 60% compared with baseline concentrations) after 6 months of therapy occurred in a substantially greater percentage of patients receiving alendronate (40 mg daily) than in those receiving etidronate disodium (400 mg daily) or placebo. Bone histology studies in patients with Paget disease of bone treated with alendronate 40 mg daily for 6 months indicate that bone formed during treatment with the drug is of normal quality. In placebo-controlled trials, the decreased bone turnover associated with bisphosphonate therapy has resulted in pain relief.

Retreatment with alendronate may be considered, following a 6-month posttreatment evaluation period, in patients with Paget disease of bone who have relapsed (as determined by an increase in serum alkaline phosphatase concentration). The manufacturer states that while clinical data on retreatment with alendronate currently are lacking, responses to initial therapy with the drug in patients who had or had not received prior bisphosphonate therapy have been similar.

Dosage and Administration

General

Hypocalcemia and other disturbances of bone and mineral metabolism must be corrected before alendronate therapy is initiated. Patients should receive supplemental calcium and vitamin D if their dietary intake is inadequate. Supplemental vitamin D is recommended in patients at increased risk for vitamin D insufficiency (e.g., those older than 70 years of age; those who are nursing home bound or chronically ill; patients with GI malabsorption syndrome). The recommended intake of vitamin D is 400-800 units daily; a once-weekly dose of alendronate/cholecalciferol fixed-combination preparation containing cholecalciferol 2800 or 5600 units provides the equivalent of 400 or 800 units, respectively, of vitamin D daily.

Administration

Alendronate sodium is administered orally as tablets or oral solution. The drug should be taken only upon rising for the day. Alendronate tablets and oral solution have equivalent bioavailability.

The fixed combination of alendronate sodium and cholecalciferol is administered orally as tablets.

To facilitate absorption of alendronate (alone or in fixed combination with cholecalciferol), the drug should be taken with a full glass (180-240 mL) of plain water at least 30 minutes before the first food, beverage, or other orally administered drug of the day; waiting longer than 30 minutes before eating, drinking, or ingesting another drug will improve absorption of alendronate. To facilitate gastric emptying when alendronate oral solution is given, the patient should drink at least 60 mL (2 ounces, ¼ cup) of water following administration of the drug. Because of the potential for oropharyngeal irritation or ulceration, patients should be instructed not to suck or chew alendronate tablets. Alendronate (alone or in combination with cholecalciferol) should be administered in an upright position (sitting or standing). Patients should be instructed to avoid lying down for at least 30 minutes following administration and until after the first food of the day to facilitate delivery of the drug to the stomach and minimize potential esophageal irritation.(See Upper GI Effects under Cautions: Warning/Precautions.) In addition, patients should be instructed not to take alendronate (alone or in fixed combination with cholecalciferol) at bedtime or before arising for the day.

If a patient misses a weekly dose of alendronate or alendronate/cholecalciferol, the missed dose should be taken the morning after it is remembered, followed by resumption of the regular weekly schedule. Patients should not take 2 tablets on the same day.

Dosage

Dosage of alendronate sodium, which is present as the monosodium trihydrate, is expressed in terms of alendronate.

Osteoporosis

The safety and efficacy of alendronate for the treatment of osteoporosis are based on clinical data supporting fracture reduction over 4 years of treatment. The optimal duration of bisphosphonate treatment for osteoporosis has not been established. Some evidence suggests that increased durations of bisphosphonate use may be associated with a higher risk of some adverse effects (e.g., jaw osteonecrosis). All patients receiving bisphosphonates should have periodic evaluations to determine the need for continued therapy. Discontinuance of bisphosphonate therapy may be considered after 3-5 years of use for patients who are assessed to be at low risk of fracture. Risk of fracture should be evaluated periodically in patients who discontinue therapy.

Prevention in Women

For the prevention of osteoporosis, the usual dosage of alendronate in postmenopausal women who are at risk for developing osteoporosis is 5 mg once daily as a tablet. Alternatively, these women may receive 35 mg once weekly as a tablet.

Treatment in Women and Men

For the treatment of osteoporosis in postmenopausal women, the usual dosage of alendronate is 10 mg once daily as a tablet or 70 mg once weekly as a tablet or the oral solution. If the fixed combination of alendronate and cholecalciferol is used in postmenopausal women, the usual dosage is alendronate 70 mg and cholecalciferol 5600 units once weekly; alternatively, a dosage of alendronate 70 mg and cholecalciferol 2800 units once weekly may be given.

For increasing bone mass in men with osteoporosis, the usual dosage of alendronate is 10 mg once daily as a tablet. Alternatively, a dosage of 70 mg once weekly as a tablet or the oral solution may be considered for men. If the fixed combination of alendronate and cholecalciferol is used in men with osteoporosis, the usual dosage is alendronate 70 mg and cholecalciferol 5600 units once weekly; alternatively, a dosage of alendronate 70 mg and cholecalciferol 2800 units once weekly may be given.

Glucocorticoid-induced Osteoporosis

For the treatment of glucocorticoid-induced osteoporosis, the usual dosage of alendronate in postmenopausal women receiving hormone replacement therapy (HRT), premenopausal women, and men is 5 mg once daily. In postmenopausal women who are not receiving HRT, the recommended dosage of alendronate is 10 mg once daily. Dosage recommendations for the prevention of glucocorticoid-induced osteoporosis generally are the same as those for treatment of this condition.

The manufacturer states that bone mineral density (BMD) should be measured prior to initiation of alendronate therapy and repeated after 6-12 months in patients receiving the drug for glucocorticoid-induced osteoporosis. Before initiating alendronate therapy in patients receiving long-term glucocorticoid therapy, the manufacturer recommends that gonadal hormone status be evaluated and replacement therapy given, if appropriate.

Paget Disease

For the treatment of Paget disease of bone, the usual dosage of alendronate in adults is 40 mg once daily for 6 months. Retreatment with alendronate may be considered after a 6-month posttreatment evaluation period if relapse occurs (i.e., based on increased serum alkaline phosphatase concentrations) or if initial treatment failed to normalize serum alkaline phosphatase concentrations.

Special Populations

No dosage adjustments are necessary for patients with mild to moderate renal insufficiency (creatinine clearance of 35-60 mL/minute). Safety and efficacy of alendronate and the fixed combination of alendronate and cholecalciferol have not been established in patients with severe renal insufficiency (creatinine clearance less than 35 mL/minute); use is not recommended in such patients.

Dosage modifications of alendronate based solely on age are not necessary in geriatric patients.

Cautions

Contraindications

Esophageal abnormalities that delay esophageal emptying (e.g., stricture, achalasia).

Use of alendronate oral solution is contraindicated in patients at increased risk of aspiration.

Inability to stand or sit upright for at least 30 minutes.

Hypocalcemia.

Known hypersensitivity to alendronate or any ingredient in the formulation.

Warnings/Precautions

Upper GI Effects

Because severe adverse esophageal effects including esophagitis, esophageal ulcers, perforations, and/or erosions (occasionally with bleeding and rarely followed by esophageal stricture or perforation) have been reported in patients receiving oral bisphosphonates, clinicians should be alert to any sign or symptom associated with such adverse effects.(See Cautions: Contraindications.) Patients should be instructed to discontinue alendronate and contact a clinician if dysphagia, odynophagia, new or worsening heartburn, or retrosternal pain occurs. It appears that gastric antisecretory agents (e.g., omeprazole), while beneficial in the management of esophagitis, show no benefit for treatment of alendronate-induced esophagitis. The incidence of these esophageal effects is greater in patients who do not drink a full (180-240 mL) glass of water when taking oral bisphosphonates and in those who do not avoid lying down for at least 30 minutes following administration or who continue to take the drugs after experiencing symptoms suggestive of esophageal irritation; therefore, patients should be instructed carefully about proper administration of alendronate. Alendronate should be used with caution in patients with active upper GI disease (e.g., Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, ulcers).

Gastric or duodenal ulcers, including some that were severe and with complications, have been reported in patients receiving oral bisphosphonates during postmarketing experience, although no increased risk was observed in controlled clinical trials.

Although data are conflicting, there is some evidence suggesting a possible association between use of oral bisphosphonates and an increased risk of esophageal cancer. During the period of postmarketing surveillance from October 1995 (initial marketing of alendronate) through mid-May 2008, FDA received reports of esophageal cancer in 23 patients in the US receiving alendronate (as the suspect drug in 21 cases and the concomitant drug in 2 cases); 8 deaths were reported. The histologic diagnosis was adenocarcinoma in 7 patients and squamous-cell carcinoma in 1 patient. At least 1 patient received alendronate despite having a diagnosis of Barrett's esophagus, a precursor of esophageal carcinoma. The median time from initiation of alendronate to diagnosis of esophageal cancer was 2.1 years (range 5-10 years, based on 16 patients). The most common site of cancer was the distal esophagus, with gastric involvement in some patients. Reports of esophageal cancer in the US in patients receiving other oral bisphosphonates were not found in the FDA's adverse-event reporting database at the time of analysis. However, esophageal cancer was reported in 31 patients in Europe and Japan receiving bisphosphonates, including alendronate, risedronate, ibandronate, and etidronate. Alendronate was the suspect drug in 21 of these cases, with risedronate, ibandronate, and/or etidronate identified as suspect drugs in 6 cases; a bisphosphonate was the concomitant drug in 4 cases. Six patients were reported to have adenocarcinoma, while 5 patients had squamous-cell carcinoma; 6 deaths were reported. Barrett's esophagus was reported in 3 patients and appeared to have been diagnosed near the time of diagnosis of esophageal cancer and after alendronate use. The median time from drug exposure to diagnosis of esophageal cancer was 1.3 years (range 0.3-8 years, based on 21 patients). In a large case-control study in a cohort of patients from the UK General Practice Research Database, risk of esophageal cancer was increased by 30% in patients who had at least one prescription issued for an oral bisphosphonate (alendronate, etidronate, or risedronate) compared with those not receiving such prescriptions; the risk was approximately doubled among patients who had 10 or more prescriptions issued for an oral bisphosphonate or who had an estimated duration of bisphosphonate use (calculated as the time between the first and last prescription issued during the observation period) of more than 3 years. However, another retrospective cohort study using the same database found no evidence of an increased risk of esophageal cancer in patients receiving oral bisphosphonates. Other observational studies, including a study in patients receiving long-term alendronate therapy and a cohort study of Danish patients with fractures, have shown either no risk or a reduced risk of esophageal cancer following use of oral bisphosphonates. Because of conflicting findings and limitations of currently available data, additional study is needed to determine the association, if any, between oral bisphosphonate use and esophageal cancer. FDA states that benefits of oral bisphosphonates in reducing the risk of serious fractures continue to outweigh their potential risks in patients with osteoporosis and that it is important to consider that esophageal cancer is rare, especially in women. FDA also states that there is insufficient information at this time to recommend routine endoscopic screening in asymptomatic patients receiving oral bisphosphonates. Avoidance of oral bisphosphonates in patients with Barrett's esophagus, a known precursor to esophageal adenocarcinoma, has been recommended.

Metabolic Effects

Hypocalcemia and other disturbances of bone and mineral metabolism must be corrected before alendronate therapy is initiated. Supplemental calcium and vitamin D should be administered if dietary intake is inadequate. Serum calcium and symptoms of hypocalcemia should be monitored during therapy.

Possible asymptomatic decreases in serum calcium and phosphate concentrations may occur, particularly in patients with Paget disease and in those receiving glucocorticoids; ensure adequate calcium and vitamin D intake in such patients.

The fixed combination of alendronate and cholecalciferol (vitamin D3) is not recommended for the treatment of vitamin D deficiency (i.e., 25-hydroxyvitamin D concentration below 9 ng/mL). Patients at risk for vitamin D insufficiency (e.g., GI malabsorption syndromes) may require higher doses of vitamin D supplementation; measurement of 25-hydroxyvitamin D should be considered in such patients.

Vitamin D3 supplementation may increase the risk of hypercalcemia and/or hypercalciuria in patients with diseases associated with unregulated overproduction of 1,25-dihydroxyvitamin D (e.g., leukemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.

Osteonecrosis of the Jaw

Osteonecrosis and osteomyelitis of the jaw have been reported in patients receiving bisphosphonates. Most instances have occurred in association with tooth extraction and/or local infection with delayed wound healing.

While the mechanism by which these adverse effects occur has not been elucidated, it has been suggested that suppression of bone turnover and remodeling by bisphosphonates impairs the ability to repair microfractures in the maxilla and mandible that occur with daily mastication. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), cancer, concomitant therapies (e.g., chemotherapy, glucocorticoids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Risk also may be increased with increased duration of bisphosphonate use. Discontinuance of bisphosphonate treatment may reduce the risk for osteonecrosis of the jaw in patients requiring invasive dental procedures. Clinical judgment of the treating clinician and/or oral surgeon should guide the management of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while receiving bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat osteonecrosis of the jaw may exacerbate the condition. Discontinuance of bisphosphonate therapy should be considered based on assessment of benefits and risks in individual patients.

Atypical Fracture of the Femur

Atypical, low-energy, or low-trauma femoral fractures have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from the subtrochanteric region of the hip (i.e., below the lesser trochanter) to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Such fractures generally have occurred with use of bisphosphonate therapy for more than 3 years (median 7 years in one analysis of available data). The magnitude of this risk is unclear, although such fractures appear to be rare; in addition, causality has not been established since atypical fractures also have occurred in patients not receiving bisphosphonates. Most cases of atypical femoral fractures with bisphosphonate therapy have been reported in individuals receiving treatment for osteoporosis. Such fractures most commonly occur in individuals with minimal or no trauma. Most individuals have reported prodromal symptoms presenting as dull, aching thigh pain for weeks to months prior to the occurrence of an atypical fracture. Bilateral involvement (i.e., a fracture in the contralateral limb) and evidence of delayed healing of the fracture also may be present. Concomitant use of glucocorticoid, estrogen, and proton-pump inhibitor therapy may increase the risk of an atypical fracture.

Individuals with a history of bisphosphonate exposure presenting with new thigh or groin pain should be evaluated for possible atypical femoral fracture; an assessment of the contralateral limb also should be performed to rule out possible bilateral involvement (i.e., presence of radiographic change or fracture). Interruption of bisphosphonate therapy should be considered in individuals presenting with symptoms suggestive of a possible femoral fracture following completion of a comprehensive risk-benefit assessment performed on an individualized basis. Bisphosphonate therapy should be discontinued if a femoral shaft fracture is confirmed.

Musculoskeletal Pain

Severe, occasionally incapacitating bone, joint, and/or muscle pain has been reported infrequently during postmarketing experience in patients receiving bisphosphonates, including alendronate. The time to onset of symptoms varied from 1 day to years (mean onset about 3 months) after treatment initiation. Such pain has improved following discontinuance of the drug in most patients; however, other patients have reported slow or incomplete resolution of severe musculoskeletal pain. In some patients, symptoms recurred upon subsequent rechallenge with the same drug or another bisphosphonate. The manufacturer states that alendronate should be discontinued if severe symptoms develop.

Atrial Fibrillation

While data are conflicting, a possible increased risk of atrial fibrillation has been identified with use of bisphosphonates.

Use of Fixed Combinations

When alendronate is used in fixed combination with cholecalciferol, the cautions, precautions, and contraindications associated with cholecalciferol should be considered.

Specific Populations

Pregnancy

There are no studies of alendronate in pregnant women; the drug should be used during pregnancy only if the potential benefits justify the potential risks to the mother and fetus.

Lactation

It is not known whether alendronate is distributed into human milk. Because many drugs are distributed into human milk, caution is advised when alendronate is used in nursing women.

Pediatric Use

The manufacturer states that safety and efficacy of alendronate have not been established in children. In a randomized trial in pediatric patients (4-18 years of age) with osteogenesis imperfecta, treatment with alendronate did not reduce the risk of fracture or bone pain; there was an increased incidence of vomiting in children receiving alendronate compared with placebo.

Geriatric Use

No substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults. However, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Hepatic Impairment

Alendronate has not been evaluated in patients with hepatic impairment.

Renal Impairment

Alendronate should not be used in patients with severe renal impairment (creatinine clearance less than 35 mL/minute).

Common Adverse Effects

The most common adverse effects reported in 3% or more of patients receiving alendronate in clinical studies include abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea.

Drug Interactions

Antacids or Mineral Supplements Containing Divalent Cations

Pharmacokinetic interaction (decreased alendronate absorption) is possible when alendronate is used concomitantly with antacids, mineral supplements, or oral drugs containing multivalent cations (e.g., calcium). Patients should wait at least 30 minutes after alendronate is administered to take any other oral medications.

Nonsteroidal Anti-inflammatory Agents

Concomitant use of aspirin and alendronate (at dosages greater than 10 mg daily) was associated with increased GI toxicity in clinical studies. Although adverse GI effects did not appear to be increased with concomitant use of nonsteroidal anti-inflammatory agents (NSAIAs) and lower dosages of alendronate (5 or 10 mg daily) in one study, caution is advised during such concomitant therapy.

Prednisone

No change in alendronate bioavailability was observed with concomitant use of prednisone.

Ranitidine

IV ranitidine has been shown to double alendronate bioavailability; however, the clinical importance of this interaction and whether the same effects will occur in patients receiving oral histamine H2-receptor antagonists are not known.

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