Fosamax/Fosamax Plus每週福善美/ 福善美加

Fosamax/Fosamax Plus

alendronic acid

alendronic acid + colecalciferol

Manufacturer:

MSD

Distributor:

Zuellig
/
Agencia Lei Va Hong

Marketer:

A. Menarini
Full Prescribing Info
Contents
Alendronate sodium, or with colecalciferol.
Description
Fosamax: Each tablet of FOSAMAX contains 91.37 mg of alendronate sodium, which is the molar equivalent to 70 mg of free acid.
Excipients/Inactive Ingredients: Each tablet contains the following non-medicinal ingredients: Anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.
FOSAMAX tablets are gluten free.
Fosamax Plus: Each tablet of FOSAMAX PLUS contains 91.37 mg of alendronate sodium, the molar equivalent of 70 mg of free acid, and 70 or 140 mcg of colecalciferol equivalent to 2800 or 5600 International Units (IU) vitamin D3, respectively.
Excipients/Inactive Ingredients: Each tablet contains the following non-medicinal ingredients: butylated hydroxytoluene, colloidal silicon dioxide, croscarmellose sodium, gelatin, lactose anhydrous, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, modified food starch (corn), sodium aluminum silicate and sucrose.
FOSAMAX PLUS tablets are gluten free.
Summary Product Information: See Table 1.

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Action
Pharmacology: Mechanism of Action: Fosamax: FOSAMAX 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.
Fosamax Plus: FOSAMAX PLUS contains alendronate sodium, a bisphosphonate, and colecalciferol (vitamin D3).
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.
Colecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25-dihydroxyvitamin D3).
Pharmacodynamics: Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasis, 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 marrow 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. Increased bone turnover is an independent risk factor of fractures (FOSAMAX PLUS only). 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 FOSAMAX/FOSAMAX PLUS 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. 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 FOSAMAX/FOSAMAX PLUS. In osteoporosis treatment studies, FOSAMAX/FOSAMAX PLUS 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. Similar reductions in the rate of bone turnover were observed in postmenopausal women during a one-year study with FOSAMAX/FOSAMAX PLUS 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 FOSAMAX/FOSAMAX PLUS. 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 FOSAMAX/FOSAMAX PLUS 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment, however, serum phosphate returned toward pre-study levels during years three through five. In a one-year study with FOSAMAX/FOSAMAX PLUS 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 FOSAMAX/FOSAMAX PLUS 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 FOSAMAX/FOSAMAX PLUS 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 with osteoporosis receiving FOSAMAX/FOSAMAX PLUS 70 mg once weekly.
Pharmacokinetics: See Table 2.

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Absorption: Fosamax: 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%).
Fosamax Plus: The alendronate in the FOSAMAX PLUS (70 mg/2800 IU) and FOSAMAX PLUS (70 mg/5600 IU) tablets and the FOSAMAX (alendronate sodium) 70 mg tablet were found to be equally bioavailable.
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%).
Colecalciferol: Following administration of FOSAMAX PLUS (70 mg/2800 IU) after an overnight fast and two hours before a standard meal, the mean area under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3 levels) was 296.4 ng-hr/ mL. The mean maximal serum concentration (Cmax) of vitamin D3 was 14.8 nmol/L or 5.9 ng/mL, and the median time to maximal serum concentration (Tmax) was 12 hrs. Following administration of FOSAMAX PLUS (70 mg/5600 IU) after an overnight fast and two hours before a meal, the mean area under the serum-concentration-time curve (AUC0-80 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3 levels) was 490.2 ng·hr/ml. The mean maximal serum concentration (Cmax) of vitamin D3 was 30.5 nmol/L or 12.2 ng/mL and the median time to maximal serum concentration (Tmax) was 10.6 hours. The bioavailability of the vitamin D3 in FOSAMAX PLUS (70 mg/2800 IU) and FOSAMAX PLUS (70 mg/5600 IU) is similar to an equal dose of vitamin D3 administered alone.
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%.
Fosamax Plus: Colecalciferol: Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.
Metabolism: Alendronate Sodium: There is no evidence that alendronate is metabolized in animals or humans.
Colecalciferol: Fosamax Plus: Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.
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 above, it is estimated that after 10 years of oral treatment with FOSAMAX (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
Fosamax Plus: Colecalciferol: When radioactive vitamin D3 was administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4%, and the mean fecal excretion of radioactivity after 4 days was 4.9%. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of vitamin D3 in the serum following an oral dose of FOSAMAX PLUS (70 mg/2800 IU) is approximately 24 hours.
Special Populations and Conditions: Pediatrics (<18 years of age): Fosamax: The oral bioavailability in children (4 to 16 years of age) with osteogenesis imperfecta (OI) was similar to that observed in adults; however, FOSAMAX is not indicated for use in children (see Use in Children under PRECAUTIONS).
Fosamax Plus:
Alendronate pharmacokinetics have not been investigated in patients <18 years of age.
Geriatrics (≥65 years of age): Alendronate Sodium: Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly (≥65 years of age) and younger patients. No dosage adjustment of alendronate is necessary (see DOSAGE & ADMINISTRATION).
Colecalciferol: Dietary requirements of vitamin D3 may be increased in the elderly.
Gender: Bioavailability and the fraction of an IV dose of alendronate excreted in urine were similar in men and women.
Race: Pharmacokinetic differences due to race have not been studied.
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.
Colecalciferol: Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.
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]). FOSAMAX/FOSAMAX PLUS is not recommended for patients with more severe renal insufficiency (creatinine clearance < 0.58 mL/s [<35 mL/min]) due to lack of experience.
Indications/Uses
Fosamax: FOSAMAX (alendronate sodium) is indicated for: The treatment of osteoporosis in postmenopausal women.
For the treatment of osteoporosis, FOSAMAX 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.
The treatment of osteoporosis in men to reduce the incidence of fractures.
Fosamax Plus: FOSAMAX PLUS (alendronate sodium/colecalciferol) is indicated for: Treatment of osteoporosis in postmenopausal women.
The treatment of osteoporosis in men.
For the treatment of osteoporosis, the alendronate sodium component of FOSAMAX PLUS increases bone mass and can prevent 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 2.5 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture.
Patients suffering from osteoporosis are at an increased risk for vitamin D insufficiency, especially those over the age of 70 years, home bound, or chronically ill, and may need to receive vitamin D supplementation in addition to that provided in FOSAMAX PLUS (see Dosage & Administration).
An adequate calcium intake is also required.
Patients with gastrointestinal malabsorption may not adequately absorb vitamin D3 and will also require further supplementation.
FOSAMAX PLUS alone should not be used to treat vitamin D deficiency (commonly defined as 25-hydroxyvitamin D <22.5 nmol/L or 9 ng/mL).
Geriatrics (≥65 years of age): Alendronate Sodium: In clinical studies, there was no age-related difference in the efficacy or safety profiles of FOSAMAX.
Colecalciferol: Fosamax Plus: Daily requirements of vitamin D3 may be increased in the elderly.
Pediatrics (<18 years of age): Fosamax: FOSAMAX is not indicated for use in children.
Fosamax Plus:
FOSAMAX PLUS has not been studied in patients <18 years of age and should not be given to them.
Important limitations of use: The optimal duration of use has not been determined. Patients should have the need for continued therapy re-evaluated on a periodic basis (see DOSAGE & ADMINISTRATION).
Dosage/Direction for Use
Recommended Dose: Treatment of Osteoporosis in Postmenopausal Women and in Men: Fosamax: The recommended dosage is one 70 mg tablet once weekly.
The optimal duration of bisphosphonate treatment of osteoporosis has not been established.
The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of FOSAMAX on an individual patient basis.
Fosamax Plus: The recommended dosage is one tablet of FOSAMAX PLUS (70 mg/2800 IU) or FOSAMAX PLUS (70 mg/5600 IU) once weekly. The appropriate dosage of FOSAMAX PLUS must be determined by the physician based on the patient's vitamin D requirement.
All patients must receive supplemental calcium and/or vitamin D, if intake is inadequate (see Precautions).
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of FOSAMAX PLUS on an individual patient basis.
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]). FOSAMAX/FOSAMAX PLUS is not recommended for patients with more severe renal insufficiency (creatinine clearance < 0.58 mL/s [< 35 mL/min]) due to lack of experience.
Missed Dose: Patients should be instructed that if they miss a dose of FOSAMAX/FOSAMAX PLUS, they should take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.
Administration: Fosamax: FOSAMAX 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 FOSAMAX (see INTERACTIONS). Waiting less than 30 minutes will lessen the effect of FOSAMAX by decreasing its absorption into the body.
FOSAMAX should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, a FOSAMAX tablet should be swallowed with a full glass of water (200-250 mL). To facilitate gastric emptying, FOSAMAX oral solution should be followed by at least 60 mL (a quarter of a cup) of water. Patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAMAX 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 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 to FOSAMAX there are known or theoretical safety concerns related to FOSAMAX in patients who previously received any other antiosteoporotic therapy.
Fosamax Plus: FOSAMAX PLUS 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 FOSAMAX PLUS (see Interactions). Waiting less than 30 minutes will lessen the effect of FOSAMAX PLUS by decreasing its absorption into the body.
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, FOSAMAX PLUS should only be swallowed upon arising for the day with a full glass of water (200-250 mL) and patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAMAX PLUS 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 Precautions).
All patients must receive supplemental calcium and/or vitamin D, if intake is inadequate. Physicians should consider the vitamin D intake from vitamins and dietary supplements. Patients at increased risk for vitamin D insufficiency (e.g. over the age of 70 years, home bound, or chronically ill) should receive FOSAMAX PLUS (70 mg/5600 IU) and may also need additional vitamin D supplementation. For patients fifty years and over, the recommended dose is at least 800 IU per day.
Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis to FOSAMAX PLUS, there are no known or theoretical safety concerns related to FOSAMAX PLUS in patients who previously received any other antiosteoporotic therapy.
Overdosage
Alendronate Sodium: No specific information is available on the treatment of overdosage with alendronate. 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.
Colecalciferol: Fosamax Plus: Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a dose less than 10,000 IU/day. In a clinical study of healthy adults, a 4000 IU daily dose of vitamin D3 for up to five months was not associated with hypercalciuria or hypercalcemia.
Contraindications
Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see PRESENTATION AND DESCRIPTION section of the product circular.
Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
Inability to stand or sit upright for at least 30 minutes.
Hypocalcemia (see PRECAUTIONS).
Renal insufficiency with creatinine clearance < 0.58 mL/s (<35 mL/min) (see DOSAGE & ADMINISTRATION).
Special Precautions
General: To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow each tablet of FOSAMAX/FOSAMAX PLUS with a full glass of water (200-250 mL) and 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 FOSAMAX/FOSAMAX PLUS 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 FOSAMAX/FOSAMAX PLUS immediately and consult their physician.
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 receiving treatment regimens including bisphosphonates. The majority of reports occurred following tooth extractions with delayed healing and involved cancer patients treated with intravenous bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. However, some cases have also occurred in patients receiving oral bisphosphonate treatment for postmenopausal osteoporosis and other diagnoses. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection, including osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. Known risk factors for osteonecrosis of the jaw include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids, angiogenesis inhibitors, immunosuppressive drugs), poor oral hygiene, co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, diabetes mellitus), smoking, and heavy alcohol use.
Patients who develop osteonecrosis of the jaw should receive appropriate antibiotic therapy and/or oral surgery and discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. Dental surgery may exacerbate the condition. For patients requiring dental procedures (e.g. tooth extraction, dental implants), there are no definitive data available to establish whether discontinuation of bisphosphonate treatment reduces the risk of ONJ.
Clinical judgment of the treating physician and/or oral surgeon should guide the management plan, including bisphosphonate treatment, of each patient based on individual benefit/risk assessment.
The following should be considered when evaluating a patient's risk of developing ONJ: Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds).
Route of administration (higher risk for parenteral administration).
Cumulative dose of bone resorption therapy.
Co-morbid conditions (e.g. anemia, coagulopathies) and smoking.
Periodontal disease, poorly fitting dentures, history of dental disease.
Osteonecrosis of the external auditory canal: Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Musculoskeletal: In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see ADVERSE REACTIONS). However, such reports have been infrequent. This category of drugs includes FOSAMAX (alendronate sodium). Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping the medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
In placebo-controlled clinical studies of FOSAMAX, the percentages of patients with these symptoms were similar in the FOSAMAX and placebo groups.
Low-energy fractures of the subtrochanteric and proximal femoral shaft have been reported in some long-term (time to onset in the majority of reports ranged from 18 months to 10 years) alendronate-treated patients. Some were stress fractures (some of which were reported as insufficiency fractures) occurring in the absence of apparent trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. Approximately one third of these fractures were bilateral; therefore the contralateral femur should be examined in patients who have sustained a femoral shaft stress fracture. Poor healing of these fractures was also reported. Patients with suspected stress fractures should be evaluated, including evaluation for causes and risk factors of stress fractures (e.g., vitamin D deficiency, malabsorption, glucocorticoid use, lower extremity arthritis or fracture, previous stress fracture, extreme or increased exercise, diabetes mellitus, chronic alcohol abuse), and receive appropriate orthopedic care. Interruption of alendronate therapy in patients with stress fractures should be considered based on individual benefit/risk assessment.
Endocrine and Metabolism: Hypocalcemia must be corrected before initiating therapy with FOSAMAX/FOSAMAX PLUS (see CONTRAINDICATIONS). 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 FOSAMAX/FOSAMAX PLUS. 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 FOSAMAX/FOSAMAX PLUS for predisposing conditions.
Due to the positive effects of alendronate in increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur.
Fosamax Plus: Colecalciferol: FOSAMAX PLUS alone should not be used to treat vitamin D deficiency (commonly defined as 25-hydroxyvitamin D < 22.5 nmol/L or 9 ng/mL).
Patients suffering from osteoporosis are at an increased risk for vitamin D insufficiency, especially those over the age of 70 years, home bound, or chronically ill, and may need to receive vitamin D supplementation in addition to that provided in FOSAMAX PLUS (see Dosage & Administration).
Patients with gastrointestinal malabsorption syndromes may also require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Vitamin D3 supplementation may worsen hypercalcemia and/or hypercalciuria when administered to 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.
Gastrointestinal: FOSAMAX/FOSAMAX PLUS, 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 FOSAMAX/FOSAMAX PLUS 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 FOSAMAX/FOSAMAX PLUS and/or who fail to swallow it with a full glass (200-250 mL) of water, and/or who continue to take FOSAMAX/FOSAMAX PLUS 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 alendronate on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when FOSAMAX/FOSAMAX PLUS is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases (including known Barrett's esophagus), gastritis, duodenitis, or ulcers.
While no increased risk was observed in extensive clinical trials, there have been rare (post-marketing) reports of gastric and duodenal ulcers with alendronate, some severe and with complications.
Ophthalmologic: Ocular disturbances including conjunctivitis, uveitis, episcleritis and scleritis have been reported with alendronate therapy. Patients with ocular events other than uncomplicated conjunctivitis should be referred to an ophthalmologist for evaluation. If ocular inflammatory symptoms are observed, treatment may need to be discontinued.
Monitoring and Laboratory Tests: Not Applicable.
Special Populations: Use in Pregnancy: FOSAMAX/FOSAMAX PLUS has not been studied in pregnant women and should not be given to them.
Use in Lactation: FOSAMAX/FOSAMAX PLUS has not been studied in nursing mothers and should not be given to them.
Use in Children (<18 years of age): FOSAMAX/FOSAMAX PLUS has not been studied in patients <18 years of age and should not be given to them.
Use in Elderly (≥65 years of age): In clinical studies, there was no age-related difference in the efficacy or safety profiles of FOSAMAX.
Fosamax Plus: Colecalciferol: Daily requirements of vitamin D3 may be increased in the elderly.
Use In Pregnancy & Lactation
Pregnant Women: FOSAMAX/FOSAMAX PLUS has not been studied in pregnant women and should not be given to them.
Nursing Women: FOSAMAX/FOSAMAX PLUS has not been studied in nursing mothers and should not be given to them.
Adverse Reactions
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse 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.
In clinical studies, FOSAMAX 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.
Fosamax Plus has been evaluated for safety in clinical studies in approximately 7200 postmenopausal women (Fosamax Plus only)
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 FOSAMAX 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 FOSAMAX 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 FOSAMAX 10 mg/day or placebo are presented in the following table. (See Table 3.)

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One patient treated with FOSAMAX (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 FOSAMAX 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 FOSAMAX 10 mg/day was similar to that observed during the three-year placebo-controlled period. Additionally, the proportion of patients who discontinued FOSAMAX 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 FOSAMAX 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: FOSAMAX, 3.2%; placebo, 2.7%. The overall adverse experience profile was similar to that seen in other studies with FOSAMAX 5 or 10 mg/day.
In a one-year, double-blind multicenter study, the overall safety and tolerability profiles of FOSAMAX 70 mg once weekly and FOSAMAX 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 4.

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Men: In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day [n=146] and a one-year study of FOSAMAX 70 mg once weekly [n=109]), the safety profile of FOSAMAX 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 FOSAMAX 10mg/day vs. 10.5% for placebo, and 6.4% for FOSAMAX 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 FOSAMAX 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 FOSAMAX 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 FOSAMAX 5 mg/day in postmenopausal women 40-60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive FOSAMAX for either two or three years. In these studies the overall safety profiles of FOSAMAX 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 FOSAMAX 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 FOSAMAX 5 mg/day or placebo are presented in the following table: See Table 5.

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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 FOSAMAX 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 FOSAMAX 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 FOSAMAX 5 or 10 mg/day or placebo are presented in the following table: See Table 6.

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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: Fosamax Plus: In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in 175 patients taking FOSAMAX 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with FOSAMAX 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking FOSAMAX 40 mg/day (17.7% FOSAMAX 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 FOSAMAX 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 FOSAMAX 40 mg/day and 2.4% of patients treated with placebo.
In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS (70 mg/2800 IU) was similar to that of FOSAMAX 70 mg once weekly. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS (70 mg/2800 IU) administered with an additional 2800 IU vitamin D3 was similar to that of FOSAMAX PLUS (70 mg/2800 IU).
Less Common Clinical Trial Adverse Drug Reactions (<1%): Skin: rash and erythema.
Abnormal Hematologic and Clinical Chemistry Findings: 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 FOSAMAX 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
Post-Market Adverse Drug Reactions: The following adverse reactions have been reported in post-marketing use with alendronate:
Body as a Whole: hypersensitivity reactions including urticaria and angioedema; transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate typically in association with initiation of treatment; symptomatic hypocalcemia both in association with predisposing conditions and in patients without known predisposing conditions; peripheral edema.
Dental: localized osteonecrosis of the jaw (ONJ) is generally associated with local infection (including osteomyelitis) and/or tooth extraction with delayed healing (see PRECAUTIONS).
Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration; gastric or duodenal ulcers, some severe and with complications (see PRECAUTIONS and DOSAGE & ADMINISTRATION).
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and/or incapacitating; joint swelling; low-energy femoral shaft fracture (see PRECAUTIONS).
Nervous System: dizziness, vertigo, dysgeusia.
Skin: rash (occasionally with photosensitivity), pruritus, alopecia; severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: uveitis, scleritis or episcleritis; osteonecrosis of the external auditory canal (cholesteatoma).
Drug Interactions
Overview: Animal studies have demonstrated that FOSAMAX/FOSAMAX PLUS 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, FOSAMAX/FOSAMAX PLUS is not expected to interact with other drugs based on effects on protein binding, renal excretion, or metabolism of other drugs.
Drug-Drug Interactions: Alendronate Sodium: If taken at the same time it is likely that calcium supplements, antacids, other multivalent cations and other oral medications will interfere with absorption of FOSAMAX/FOSAMAX PLUS. Therefore, patients must wait at least one-half hour after taking FOSAMAX/FOSAMAX PLUS 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; no other specific drug interaction studies were performed.
Concomitant use of hormone replacement therapy (HRT [estrogen ± progestin]) and FOSAMAX/FOSAMAX PLUS was assessed in two clinical studies of one or two years' duration in postmenopausal osteoporotic women. Combined use of FOSAMAX 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: Clinical Trial Adverse Drug Reactions, Concomitant Use with Estrogen/Hormone Replacement Therapy).
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. FOSAMAX/FOSAMAX PLUS 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 FOSAMAX greater than 10 mg and ASA-containing products. This was not observed in a study with FOSAMAX 70 mg once weekly.
FOSAMAX/FOSAMAX PLUS may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a three-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 FOSAMAX 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 FOSAMAX/FOSAMAX PLUS.
Colecalciferol: Fosamax Plus: Drugs That May Impair the Absorption of Colecalciferol: Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. cholestyramine, colestipol) may impair the absorption of vitamin D.
Drugs That May Increase the Catabolism of Colecalciferol: Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.
Drug-Food Interactions: Food and beverages other than plain water may markedly reduce the absorption and effectiveness of alendronate. FOSAMAX/FOSAMAX PLUS must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (see DOSAGE & ADMINISTRATION).
Drug-Herb Interactions: Herbal products may interfere with the absorption of alendronate. FOSAMAX/FOSAMAX PLUS must be taken at least one-half hour before any herbal products.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions: No studies on the effects on the ability to drive and use machines have been performed. However, certain adverse reactions that have been reported with FOSAMAX/FOSAMAX PLUS (e.g., dizziness, vertigo, visual disturbances, and severe bone, muscle or joint pain) may affect some patients' ability to drive or operate machinery. Individual responses to FOSAMAX/FOSAMAX PLUS may vary.
ATC Classification
M05BA04 - alendronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
M05BB03 - alendronic acid and colecalciferol ; Belongs to the class bisphosphonates, combinations. Used in the treatment of bone diseases.
Presentation/Packing
Fosamax tab 70 mg (white, oval uncoated tablet with an outline of a bone image on one side and 31 on the other) x 4's. Fosamax Plus 70 mg/2,800 IU tab (white to off-white, modified capsule shaped with "710" on one side and a bone shape on the other side) 4's. 70 mg/5,600 IU tab (white to off-white, modified rectangle shaped with "270" on one side and a bone shape on the other side) x 4's.
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