Apo-Alendronate

Apo-Alendronate

alendronic acid

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Alendronate sodium.
Description
Each tablet of APO-ALENDRONATE contains 13.05 or 91.35 mg of alendronate monosodium salt trihydrate, which is the molar equivalent to 10 or 70 mg, respectively, of alendronate.
Excipients/Inactive Ingredients: Magnesium stearate, mannitol and microcrystalline cellulose.
Action
Pharmacology: Pharmacodynamics: APO-ALENDRONATE (alendronate sodium) is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
Pharmacokinetics: Absorption: Relative to an intravenous (IV) reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men was 0.59%.
A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).
Distribution: Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.
Metabolism: There is no evidence that alendronate is metabolized in animals or humans.
Excretion: Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the previous text, it is estimated that after 10 years of oral treatment with alendronate (10 mg daily), the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
Special Populations: Pediatric: Alendronate pharmacokinetics have not been investigated in patients <18 years of age.
Gender: Bioavailability and the fraction of an IV dose excreted in urine were similar in men and women.
Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly (>65 years of age) and younger patients. No dosage adjustment is necessary (see DOSAGE & ADMINISTRATION).
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative IV doses of 35 mg/kg in young male rats. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.
No dosage adjustment is necessary for patients with mild-to-moderate renal insufficiency [creatinine clearance 0.58 to 1 mL/s (35 to 60 mL/min)]. APO-ALENDRONATE is not recommended for patients with more severe renal insufficiency [creatinine clearance <0.58 mL/s (<35 mL/min)] due to lack of experience.
Hepatic Insufficiency: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary.
Drug Interactions (see Interactions): Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown; no other specific drug interaction studies were performed.
Products containing calcium and other multivalent cations likely will interfere with absorption of alendronate. (See Table 1.)

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Pharmacodynamics: Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.
Osteoporosis in Postmenopausal Women: Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.
Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.
Long-term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type I collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with alendronate. In osteoporosis treatment studies, alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase, by approximately 25 to 30%, to reach a plateau after 6 to 12 months. In osteoporosis prevention studies, alendronate 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during a one year study with alendronate 70 mg once weekly for the treatment of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.
As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate. In the long term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment, however, serum phosphate returned toward prestudy levels during years three through five.
Similar reductions were observed with alendronate 5 mg/day. In a one-year study with alendronate 70 mg once weekly, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate but also a decrease in renal phosphate reabsorption.
Osteoporosis in Men: Even though osteoporosis is less prevalent in men than in postmenopausal women, a significant proportion of osteoporotic fractures occur in men. The prevalence of vertebral deformities appears to be similar in men and women. Treatment of men with osteoporosis with alendronate 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men receiving alendronate 70 mg once weekly.
Glucocorticoid-Induced Osteoporosis: Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation.
In clinical studies of up to two years' duration, alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type 1 collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).
Paget's Disease of Bone: Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
Alendronate decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.
Indications/Uses
APO-ALENDRONATE (alendronate sodium) is indicated for: The treatment and prevention of osteoporosis in postmenopausal women: For the treatment of osteoporosis, APO-ALENDRONATE increases bone mass and prevents fractures, including those of the hip and spine (vertebral compression fractures).
Osteoporosis may be confirmed by the finding of low bone mass (for example, at least 2.0 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture.
For the prevention of osteoporosis, APO-ALENDRONATE may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture.
Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass; thin body build; Caucasian or Asian race; and family history of osteoporosis. The presence of such risk factors may be important when considering the use of APO-ALENDRONATE for prevention of osteoporosis.
The treatment of osteoporosis in men to reduce the incidence of fractures.
The treatment and prevention of glucocorticoid-induced osteoporosis in men and women.
The treatment of Paget's disease of bone in men and women.
Treatment is indicated in patients with Paget's disease of bone having serum alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease.
The optimal duration of use of bisphosphates for the treatment of osteoporosis has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
Dosage/Direction for Use
Administration: APO-ALENDRONATE (alendronate sodium) must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only. Other beverages (including mineral water), food, and some medications are known to reduce the absorption of APO-ALENDRONATE (see Interactions). Waiting less than 30 minutes will lessen the effect of APO-ALENDRONATE by decreasing its absorption into the body.
APO-ALENDRONATE should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an APO-ALENDRONATE tablet should be swallowed with a full glass of water (200-250 mL). Patients should not lie down for at least 30 minutes and until after their first food of the day. APO-ALENDRONATE should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences (see DOSAGE & ADMINISTRATION and PRECAUTIONS).
All patients must receive supplemental calcium and Vitamin D, if dietary intake is inadequate.
Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis or Paget's disease to alendronate, there are no known or theoretical safety concerns related to APO-ALENDRONATE in patients who previously received any other antiosteoporotic or antipagetic therapy.
Treatment with alendronate for longer than five years has not been studied; extension studies are ongoing.
Recommended Dose: Treatment of Osteoporosis in Postmenopausal Women and in Men: The recommended dosage is one 70 mg tablet once weekly or one 10 mg tablet once daily.
Prevention of Osteoporosis in Postmenopausal Women: The recommended dosage is 5 mg once a day.
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis in Men and Women: The recommended dosage is 5 mg once a day, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is 10 mg once a day.
Paget's Disease of Bone in Men and Women: The recommended treatment regimen is 40 mg once a day for six months.
Retreatment of Paget's Disease: In clinical studies in which patients were followed every six months, relapses during the 12 months following therapy occurred in 9% (3 out of 32) of patients who responded to treatment with alendronate. Specific retreatment data are not available, although responses to alendronate were similar in patients who had received prior bisphosphonate therapy and those who had not.
Retreatment with APO-ALENDRONATE may be considered, following a six-month post-treatment evaluation period, in patients who have relapsed based on increases in serum alkaline phosphatase (which should be measured periodically). Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
Dosage Adjustment: No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency [creatinine clearance 0.58 to 1 mL/s (35 to 60 mL/min)]. APO-ALENDRONATE is not recommended for patients with more severe renal insufficiency (creatinine clearance <0.58 mL/s [<35 mL/min]) due to lack of experience.
Information to be Provided to the Patients: Patients must be instructed that the expected benefits of APO-ALENDRONATE may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate.
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow each tablet of APO-ALENDRONATE with a full glass of water. Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take APO-ALENDRONATE at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking APO-ALENDRONATE immediately and consult their physician.
Missed Dose: Patients should be instructed that if they miss a dose of APO-ALENDRONATE 70 mg once weekly, they should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.
Patients should be advised with respect to adequate calcium and Vitamin D intake.
Overdosage
No specific information is available on the treatment of overdosage with APO-ALENDRONATE (alendronate sodium). Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Dialysis would not be beneficial.
Contraindications
Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; Inability to stand or sit upright for at least 30 minutes; Hypersensitivity to any component of this product; Hypocalcemia (see PRECAUTIONS); Renal insufficiency with creatinine clearance <0.58 mL/s (<35 mL/min) (see DOSAGE & ADMINISTRATION).
Special Precautions
APO-ALENDRONATE (alendronate sodium), like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate. 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 APO-ALENDRONATE immediately 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 alendronate and/or who fail to swallow it with a full glass of water, and/or who continue to take alendronate 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 & ADMINISTRATION).
Because of possible irritant effects of APO-ALENDRONATE on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when APO-ALENDRONATE is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers.
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow each tablet of APO-ALENDRONATE (alendronate sodium) with a full glass of water. Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take APO-ALENDRONATE at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems.
Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking APO-ALENDRONATE immediately and consult their physician.
Patients should be instructed that if they miss a dose of APO-ALENDRONATE 70 mg once weekly, they should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.
While no increased risk was observed in extensive clinical trials, there have been rare (postmarketing) reports of gastric and duodenal ulcers, some severe and with complications. However, a causal relationship has not been established.
Causes of osteoporosis other than estrogen deficiency, aging and glucocorticoid use should be considered.
Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of cases occurred after tooth extractions with delayed healing. Many had signs of local infection including osteomyelitis. Some of these cases occurred in patients receiving oral treatment for postmenopausal osteoporosis and other diagnoses. Patients who develop osteonecrosis of the jaw should receive appropriate antibiotic therapy and/or oral surgery.
A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
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 impact 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 a femur fracture. Subjects 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.
Endocrine and Metabolism: Hypocalcemia must be corrected before initiating therapy with APO-ALENDRONATE (see CONTRAINDICATION). Other disorders affecting mineral metabolism (such as Vitamin D deficiency) should be treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with APO-ALENDRONATE. Symptomatic hypocalcemia has been reported rarely, both in patients with predisposing conditions and patients without known predisposing conditions. Patients should be advised to report to their physicians any symptoms of hypocalcemia, such as paresthesias or muscle spasms. Physicians should carefully evaluate patients who develop hypocalcemia during therapy with APO-ALENDRONATE for predisposing conditions.
Due to the positive effects of APO-ALENDRONATE to increase 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.
Use in pregnancy: Alendronate has not been studied in pregnant women and should not be given to them.
Use in lactation: Alendronate has not been studied in nursing mothers and should not be given to them.
Use in children: Alendronate has not been studied in patients <18 years of age and should not be given to them.
Use in elderly: In clinical studies, there was no age-related difference in the efficacy or safety profiles of alendronate.
Use In Pregnancy & Lactation
Use in Obstetrics: Alendronate has not been studied in pregnant women and should not be given to them.
Use in Nursing Mothers: Alendronate has not been studied in nursing mothers and should not be given to them.
Adverse Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Clinical Studies: In clinical studies, alendronate was generally well tolerated. In studies of up to five years in duration, side effects, which usually were mild, generally did not require discontinuation of therapy.
Alendronate has been evaluated for safety in clinical studies in approximately 7200 postmenopausal women.
Treatment of Osteoporosis: Postmenopausal Women: In two, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational) of virtually identical design, with a total of 994 postmenopausal women, the overall safety profiles of alendronate 10 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6.0% of 397 patients treated with placebo.
Adverse experiences considered by the investigators as possibly, probably, or definitely drug-related in >1% of patients treated with either alendronate 10 mg/day or placebo are presented in the following table. (See Table 2.)

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Less Common Clinical Adverse Reactions (<1%): Rarely, rash and erythema have occurred.
One patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant acetylsalicylic acid (ASA) developed an anastomotic ulcer with mild hemorrhage, which was considered drug-related. ASA and alendronate were discontinued and the patient recovered.
In the two-year extension (treatment years 4 and 5) of the previously mentioned studies, the overall safety profile of alendronate 10 mg/day was similar to that observed during the three-year placebo-controlled period. Additionally, the proportion of patients who discontinued alendronate 10 mg/day due to any clinical adverse experience was similar to that during the first three years of the study.
In the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with alendronate 5 mg/day for two years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo.
Discontinuations due to upper gastrointestinal adverse experiences were: alendronate, 3.2%; placebo, 2.7%. The overall adverse experience profile was similar to that seen in other studies with alendronate 5 or 10 mg/day.
In a one-year, double-blind multicenter study, the overall safety and tolerability profiles of alendronate 70 mg once weekly and alendronate 10 mg daily were similar. The adverse experiences considered by the investigators as possibly, probably, or definitely drug-related in >1% of patients in either treatment group are presented in the following table: See Table 3.

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Men: In two, placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate 10 mg/day (n=146) and a one-year study of alendronate 70 mg once weekly (n=109)), the safety profile of alendronate was generally similar to that seen in postmenopausal women. The rates of discontinuation of therapy due to any clinical adverse experience were 2.7% for alendronate 10 mg/day vs 10.5% for placebo and 6.4% for alendronate 70 mg once weekly vs 8.6% for placebo.
Other studies in men and women: In a ten-week endoscopy study in men and women (n=277; mean age: 55) no difference was seen in upper gastrointestinal tract lesions between alendronate 70 mg once weekly and placebo.
In an additional one-year study in men and women (n=335; mean age: 50) the overall safety and tolerability profiles of alendronate 70 mg once weekly were similar to that of placebo and no difference was seen between men and women.
Prevention of Osteoporosis in Postmenopausal Women: 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 1400 patients randomized to receive alendronate 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 experience occurred in 7.5% of 642 patients treated with alendronate 5 mg/day and 5.7% of 648 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in >1% of patients treated with either alendronate 5 mg/day or placebo are presented in the following table: See Table 4.

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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.
Treatment and Prevention of 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 or 10 mg/day were generally similar to that of placebo. Adverse experiences reported 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 the following table: See Table 5.

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The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies was consistent with that observed in the first year.
Paget's Disease of Bone: In clinical studies (Paget's disease and osteoporosis), adverse experiences 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 experiences in patients taking alendronate 40 mg/day (17.7% alendronate vs 10.2% placebo). Isolated cases of esophagitis and gastritis resulted in discontinuation of treatment.
Additionally, musculoskeletal pain (bone, muscle or joint), which has been described in patients with Paget's disease treated with other bisphosphonates, was reported 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 experience occurred in 6.4% of patients with Paget's disease treated with alendronate 40 mg/day and 2.4% of patients treated with placebo.
Post-Marketing Experience: The following adverse reactions have been reported in post-marketing use: Body as a Whole: Hypersensitivity reactions including urticaria and rarely angioedema. As with other bisphosphonates, transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever) have been reported with alendronate, typically in association with initiation of treatment.
Rarely, symptomatic hypocalcemia has occurred, both in association with predisposing conditions and in patients without known predisposing conditions.
Gastrointestinal: Esophagitis, esophageal erosions, esophageal ulcers, rarely esophageal stricture or perforation, and oropharyngeal ulceration. Some of these have been serious and required hospitalization. Rarely, gastric or duodenal ulcers, some severe and with complications, although a causal relationship has not been established (see Dosage & Administration and Precautions).
Skin: Rash (occasionally with photosensitivity), pruritus, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: Rarely uveitis, rarely scleritis.
Osteonecrosis of the jaw: Osteonecrosis of the jaw has been reported in patients receiving treatment regimens including bisphosphonates (see PRECAUTIONS). Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to determine if these events are related to alendronate or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, head and neck radiotherapy, corticosteroid), to patient's underlying disease or to other co-morbid risk factors (e.g., anemia, infection, preexisting oral disease).
Laboratory Tests: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18 and 10%, respectively, of patients taking alendronate versus approximately 12 and 3% of those taking placebo. However, the incidences of decreases in serum calcium to <8.0 mg/dL (2.0 mM) and serum phosphate to <2.0 mg P1/dL (0.65 mM) were similar in both treatment groups.
In a small, open label study, at higher doses (80 mg/day) some patients had elevated transaminases. However, this was not observed at 40 mg/day. No clinically significant toxicity was associated with these laboratory abnormalities.
Rare cases of leukemia have been reported following therapy with other bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.
1P: Elemental phosphorus.
Drug Interactions
Overview: Animal studies have demonstrated that alendronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected. Although alendronate is bound approximately 78% to plasma protein in humans, its plasma concentration is so low after oral dosing that only a small fraction of plasma-binding sites is occupied, resulting in a minimal potential for interference with the binding of other drugs. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other drugs by those systems in humans. In summary, APO-ALENDRONATE is not expected to interact with other drugs based on effects on protein binding, renal excretion, or metabolism of other drugs.
Drug-Drug Interactions: If taken at the same time it is likely that calcium supplements, antacids, and other oral medications will interfere with absorption of APO-ALENDRONATE. Therefore, patients must wait at least one-half hour after taking APO-ALENDRONATE before taking any other oral medication.
Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
Concomitant use of hormone replacement therapy (HRT [estrogen±progestin]) and alendronate was assessed in two clinical studies of one or two years' duration in postmenopausal osteoporotic women. Combined use of alendronate and HRT resulted in greater increases in bone mass, together with greater decreases in bone turnover, than seen with either treatment alone. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments (see ADVERSE REACTIONS). The studies were too small to detect antifracture efficacy, and no significant differences in fracture incidence among the treatment groups were found.
Specific interaction studies were not performed. Alendronate was used in osteoporosis studies in men, postmenopausal women, and glucocorticoid users, with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions.
In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving daily therapy with dosages of alendronate greater than 10 mg and acetylsalicylic acid-containing products. This was not observed in a study with alendronate 70 mg once weekly.
Alendronate may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with APO-ALENDRONATE.
Storage
Store below 25°C.
ATC Classification
M05BA04 - alendronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Presentation/Packing
Tab 10 mg (white, round, biconvex, engraved "APO" on one side and "10" on the other) x 3 x 10's. 70 mg (white, oval, biconvex, engraved "APO" on one side and "ALE70" on one side) x 4's.
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