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alendronate sodium 70 mg tab generic fosamax

Out of Stock Manufacturer VIRTUS PHARMACE 69543013104
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Uses

Osteoporosis

Alendronate is used in the treatment and prevention of osteoporosis in postmenopausal women and for the treatment of osteoporosis in men. Alendronate also is used in the treatment of corticosteroid-induced-osteoporosis.

Prevention in Postmenopausal Women

Alendronate is used for the prevention of osteoporosis in postmenopausal women. Alendronate 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.

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, 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. While the risk of postmenopausal osteoporosis 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 premature ovarian failure; a family history of osteoporosis; a small, slim body frame; endocrine disorders such as thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, insulin-dependent diabetes mellitus (type 1, IDDM); cigarette smoking; drinking excessive amounts of alcohol; a sedentary lifestyle and/or lack of physical exercise; low body weight; moderately low body mass (e.g., at least 1 standard deviation below the mean for healthy young adult women); and low dietary calcium intake. White or Asian women, particularly those who are thin or small and have a positive family history of osteoporosis, are at a higher risk for the disease than are black women. Premature ovarian failure (surgical or nonsurgical) hastens the onset of osteoporosis, and estrogen deficiency in premenopausal women (e.g., secondary to anorexia nervosa- or exercise-induced amenorrhea or to hyperprolactinemia) induces bone loss and may reduce peak bone mass.

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 bone mineral density (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.

The effect of alendronate on BMD versus that of estrogen or raloxifene remains to be established. 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.

While estrogen replacement therapy is effective for the prevention of osteoporosis in postmenopausal women, such therapy is associated with a number of adverse effects and the proportion of postmenopausal women who take estrogens for prolonged periods of time is small. Alternative agents that can be used for the prevention of osteoporosis include alendronate, raloxifene or risedronate, although experience with these drugs is not as extensive as with estrogen. The choice of alendronate, estrogen, raloxifene or risedronate for the prevention of postmenopausal osteoporosis should be individualized, taking into account differences in tolerability and safety and individual preference. In general, exercise and adequate calcium and vitamin D intake should be encouraged for all women. Whether additional preventive therapy generally should be offered to all women or just recommended for selected women at highest risk of developing osteoporosis remains to be established.

Treatment in Postmenopausal Women

Alendronate is used in the treatment of osteoporosis in postmenopausal women. Estrogen replacement therapy is effective for the treatment of osteoporosis in postmenopausal women and has been recommended as first-line therapy for women with osteoporosis. However, because results of a recent controlled study indicate that estrogen/progestin therapy is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism, recommendations on the appropriate use of such therapy are being revised. Other therapeutic modalities for the treatment of osteoporosis include calcitonin, calcium, risedronate, and vitamin D. Osteoporosis may be confirmed by the finding of a low bone mass (e.g., at least 2 or 2.5 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture. In several double-blind, placebo-controlled trials in postmenopausal women with osteoporosis (defined as lumbar spine bone mineral density values at least 2 standard deviations below premenopausal mean values), therapy with alendronate 10 mg daily for 2-3 years substantially increased bone mineral density in the lumbar spine, femoral neck, and trochanter; total body bone mineral density also increased, suggesting that bone mineral density 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 bone mineral density 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 in 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).

Corticosteroid-induced Osteoporosis

Alendronate is used in the treatment of corticosteroid-induced osteoporosis. The manufacturer recommends use of alendronate for the treatment of corticosteroid-induced osteoporosis in men and women receiving a daily dosage equivalent to at least 7.5 mg of prednisone who have low BMD. Alendronate also has been used in the prevention of corticosteroid-induced osteoporosis.

The American College of Rheumatology (ACR) currently recommends use of a bisphosphonate (i.e., alendronate, risedronate, or zoledronic acid) in conjunction with lifestyle modification and calcium and vitamin D supplementation for the prevention and treatment of corticosteroid-induced osteoporosis in select postmenopausal women and men 50 years of age or older who are initiating or currently receiving corticosteroid therapy. ACR recommendations are based on a risk-stratification approach in which an individual's clinical risk level (low, medium, or high) for developing a fracture is determined, guided in part by the FRAX risk assessment tool (which employs variables such as gender, age, race/ethnicity, and femoral neck density) and the individual's preexisting or anticipated corticosteroid dosage. In postmenopausal women or men at least 50 years of age who are considered to be at low risk of developing osteoporotic fractures, ACR recommends therapy with alendronate, risedronate, or zoledronic acid if such patients are receiving or will be receiving a daily corticosteroid dosage equivalent to at least 7.5 mg of prednisone for at least 3 months. For such patients who are considered to be at medium risk of developing fractures, ACR recommends therapy with alendronate or risedronate in those who are receiving or will be receiving a daily corticosteroid dosage equivalent to less than 7.5 mg of prednisone for at least 3 months; therapy with alendronate, risedronate, or zoledronic acid is recommended in those who are receiving or will be receiving a daily corticosteroid dosage equivalent to 7.5 mg or more of prednisone for at least 3 months. For such patients who are considered to be at high risk of developing fractures, ACR recommends therapy with a bisphosphonate (alendronate, risedronate, or zoledronic acid) in those who are receiving or will be receiving a daily corticosteroid dosage equivalent to less than 5 mg of prednisone for an actual or anticipated duration of 1 month or less. A bisphosphonate (alendronate, risedronate, or zoledronic acid) or teriparatide is recommended in high-risk patients who are receiving or will be receiving a daily corticosteroid dosage equivalent to 5 mg or more of prednisone if the duration of corticosteroid therapy is 1 month or less; a bisphosphonate or teriparatide is recommended in those who are receiving or will be receiving more than 1 month of corticosteroid therapy regardless of dosage.

ACR states that because of limited data, use of bisphosphonates for prevention or treatment of corticosteroid-induced osteoporosis in premenopausal women and men younger than 50 years of age can be recommended only in those who have a history of fragility fracture, which places them at higher risk for additional fractures. In such individuals of nonchildbearing potential, ACR recommends alendronate or risedronate therapy if a daily corticosteroid dosage equivalent to at least 5 mg of prednisone has been or will be used for 1-3 months, or zoledronic acid therapy if a daily corticosteroid dosage equivalent to at least 7.5 mg of prednisone has been or will be used for 1-3 months. In such individuals of childbearing potential, ACR recommends therapy with alendronate, risedronate, or teriparatide if a daily corticosteroid dosage equivalent to at least 7.5 mg of prednisone has been or will be used for 3 months or longer; ACR states that data are inadequate to make recommendations for individuals of childbearing potential who are or will be receiving corticosteroid therapy for 1-3 months.

Osteoporosis and related fractures are some of the most serious complications of long-term corticosteroid therapy. Bone loss is most rapid during the first 3-6 months following initiation of corticosteroid therapy and continues at a slower, more steady rate with prolonged use. The adverse skeletal effects of corticosteroids appear to be both dose and duration dependent; however, there is controversy regarding the corticosteroid dosage at which an increased risk of fracture occurs. 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. Current evidence suggests that prior or current use of oral corticosteroids can increase the risk of any type of fracture. Alternate-day regimens have not been shown to be associated with less risk of bone loss than daily regimens. Bone loss has even been associated with oral inhalation of corticosteroids. Most patients receiving long-term corticosteroid therapy will develop some degree of bone loss, and more than 25% will develop osteoporotic fracture. Vertebral fractures have been reported in 11% of asthmatic patients receiving systemic corticosteroids for at least 1 year, and corticosteroid-treated patients with rheumatoid arthritis are at increased risk of fractures of the hip, rib, spine, leg, ankle, and foot. For the management of severe osteopenia and osteoporosis occurring during long-term use of systemic corticosteroids, vitamin D analogs along with other therapies (e.g., calcium, gonadotrophic hormone replacement, bisphosphonates, weight-bearing exercise programs that maintain muscle mass) have been used for the prevention and treatment of this condition. For additional information on the minimization of risk of corticosteroid-induced bone loss, .

Bisphosphonate therapy has resulted in significant increases in BMD (most consistently in the lumbar spine) in patients with a variety of corticosteroid-treated conditions, most commonly rheumatoid arthritis or polymyalgia rheumatica, and such beneficial effects generally occurred irrespective of patient age, gender, or female menopausal status.

Alendronate has been evaluated for the treatment or prevention of corticosteroid-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 corticosteroid 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 bone mineral density (BMD), as determined by dual-energy radiographic absorption (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's Disease of Bone

Alendronate also is used orally in the treatment of moderate to severe Paget's disease of bone (osteitis deformans). In most patients with Paget's 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's 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's 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's 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

Administration

Alendronate sodium is administered orally. The drug should be taken only upon rising for the day.

Alendronate tablets and oral solution have equivalent bioavailability.

To facilitate absorption of alendronate when given as tablets, the drug should be taken with a full glass 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. Patients should be instructed to avoid lying down for at least 30 minutes following administration of alendronate to facilitate delivery of the drug to the stomach and minimize potential esophageal irritation. In addition, patients should be instructed not to take alendronate at bedtime or before arising for the day.

Since severe adverse esophageal effects including esophagitis, esophageal ulcers, perforations, and/or erosions have been reported in patients (some of whom required hospitalization) receiving oral bisphosphonates, including alendronate, clinicians should be alert to any sign or symptom associated with such adverse effects. 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. Since the incidence of these esophageal effects is greater in patients who do not drink a full (180-240 mL) glass of plain water when taking oral bisphosphonates and in those who do not avoid lying down for at least 30 minutes following administration of these drugs, patients should be instructed carefully about proper administration of alendronate and should be given a copy of the patient instructions provided by the manufacturer. In addition, alendronate is contraindicated in patients with esophageal abnormalities that delay esophageal emptying (e.g., achalasia) and in those unable to stand or sit upright for at least 30 minutes. Alendronate oral solution also is contraindicated in those with an increased risk of aspiration. Alendronate also 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, the US Food and Drug Administration (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.

Osteonecrosis and osteomyelitis of the jaw have been reported in patients, principally in those with cancer, who have received bisphosphonates. Most instances of osteonecrosis of the jaw have been observed during IV bisphosphonate therapy, but some patients have experienced this adverse effect during oral bisphosphonate therapy.

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.

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.

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

Dosage

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

Hypocalcemia must be corrected before alendronate therapy is initiated, and patients with osteoporosis or Paget's disease of bone should receive supplemental calcium and vitamin D if their daily dietary intake is inadequate. Patients with other disorders affecting mineral metabolism, such as vitamin D deficiency, should have these conditions effectively treated; serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate in such patients.

The manufacturer states that safety and efficacy of alendronate sodium in children have not been established. The manufacturer also states that safety of alendronate for treatment or prevention of osteoporosis exceeding 7 years has not been established. However, a recent long-term follow-up study found sustained therapeutic effects of alendronate in postmenopausal women over a 10-year period, and the drug was well tolerated.(See Prevention in Postmenopausal Women under Uses: Osteoporosis.)

Dosage modification of alendronate solely on the basis of age is not necessary in geriatric patients.

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. FDA is conducting an ongoing evaluation of the safety and efficacy of long-term bisphosphonate use (i.e. greater than 3 to 5 years) for the prevention and treatment of osteoporosis. All patients receiving bisphosphonates should have periodic evaluations to determine the need for continued 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. Alternatively, these women may receive 35 mg once weekly.

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. The manufacturer of alendronate states that when a woman misses a weekly dose of alendronate, 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 alendronate 70-mg tablets on the same day.

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.

Corticosteroid-induced Osteoporosis

For the prevention and treatment of corticosteroid-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. The American College of Rheumatology (ACR) recommends that therapy to prevent or treat corticosteroid-induced osteoporosis be continued as long as the patient continues to receive corticosteroid therapy.

Paget's Disease

For the treatment of Paget's 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.

Dosage in Renal and Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate renal insufficiency (creatinine clearance of 35-60 mL/minute). The safety and efficacy of alendronate sodium in patients with severe renal insufficiency (creatinine clearance less than 35 mL/minute) have not been established, and the manufacturer states that the drug is not recommended in such patients.

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