Fosamax

Drug Interactions

Drug-Herb Interactions

Drug-Food Interactions

Drug-Drug Interactions

Drug-Laboratory Interactions

Overview

Information for the Patient

Fosamax

Dosage and Administration

Recommended Dose

Dosage Adjustment

Administration

Missed Dose

Adverse Reactions

Gastrointestinal

Dental

Post-Market Adverse Drug Reactions

Abnormal Hematologic and Clinical Chemistry Findings

Clinical Trial Adverse Drug Reactions

Special Senses

Other Studies in Men and Women

Body as a Whole

FOSAMAX

Drug-related^a Adverse Experiences Reported in ≥1% of Patients—Prevention of Osteoporosis

FOSAMAX

Drug-related^a Adverse Experiences Reported in ≥1% of Patients Treated for Osteoporosis

Nervous System

Musculoskeletal

Treatment of Osteoporosis

Concomitant Use with Estrogen/Hormone Replacement Therapy

Men

Paget's Disease of Bone

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Skin

FOSAMAX

Drug-related^a Adverse Experiences Reported in ≥1% of Patients—Treatment and Prevention of Glucocorticoid-induced Osteoporosis

Indications and Clinical Use

FOSAMAX (alendronate sodium) is indicated for:

• The treatment and prevention 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.

    
    

  • For the prevention of osteoporosis, FOSAMAX 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 FOSAMAX 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.

    Overdosage

    For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.

    
    

    No specific information is available on the treatment of overdosage with FOSAMAX. 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.

    Dosage Forms, Composition and Packaging

    10 mg

    Each white, oval, wax-polished tablet, with MRK engraved on one side and 936 on the other, contains: alendronate monosodium salt trihydrate 13.05 mg, which is the molar equivalent to 10 mg of free acid. Nonmedicinal ingredients: anhydrous lactose, carnauba wax, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Gluten-free. Blister packages of 28.

    Oral Solution

    Each bottle of clear, colorless oral solution with a raspberry flavor contains: alendronate monosodium salt trihydrate 91.35 mg, which is the molar equivalent to 70 mg of free acid. Nonmedicinal ingredients: artificial raspberry flavor, citric acid anhydrous, purified water, sodium citrate dihydrate and sodium saccharin. Added as preservatives are sodium propylparaben and sodium butylparaben. Gluten-free. Single-dose bottles, cartons of 4.

    40 mg

    Each white, triangle-shaped, uncoated tablet, with FOSAMAX on one side and MSD 212 on the other, contains: alendronate monosodium salt trihydrate 52.21 mg, which is the molar equivalent to 40 mg of free acid. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Gluten-free. Blister packages of 28.

    5 mg

    Each white, round, uncoated tablet, with an outline of a bone image on one side and MRK 925 on the other, contains: alendronate monosodium salt trihydrate 6.53 mg, which is the molar equivalent to 5 mg of free acid. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Gluten-free. Blister packages of 28.

    Tablets

    
    
    

    70 mg

    Each white, oval, uncoated tablet, with an outline of a bone image on one side and 31 on the other, contains: alendronate monosodium salt trihydrate 91.37 mg, which is the molar equivalent to 70 mg of free acid. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Gluten-free. Blister packages of 4.

    
    
    

    Warnings and Precautions

    Geriatrics

    In clinical studies, there was no age-related difference in the efficacy or safety profiles of FOSAMAX.

    Special Populations

    
    
    

    Gastrointestinal

    FOSAMAX, 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 FOSAMAX. 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 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 and/or who fail to swallow it with the recommended amount of water, and/or who continue to take FOSAMAX after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see Dosage and Administration).

    
    

    Because of possible irritant effects of FOSAMAX on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when FOSAMAX is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, 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, some severe and with complications.

    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. 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 alendronate-treated patients. Some were stress fractures (also known as insufficiency fractures) occurring in the absence of 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. Patients with suspected stress fractures should be evaluated, including evaluation for causes of stress fractures (e.g., vitamin D deficiency, malabsorption, glucocorticoid use, lower extremity arthritis or 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.

    Osteonecrosis of the Jaw

    Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer 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 (e.g., cancer, chemotherapy, head and neck radiotherapy, corticosteroids, periodontal disease, poor oral hygiene).

    
    

    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.

    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 with a full glass of water. To facilitate gastric emptying, patients should drink at least 60 mL (a quarter of a cup) of water after taking FOSAMAX oral solution. 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 FOSAMAX 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 immediately and consult their physician.

    
    

    Causes of osteoporosis other than estrogen deficiency, aging and glucocorticoid use should be considered.

    Monitoring and Laboratory Tests

    Not applicable.

    Endocrine and Metabolism

    Hypocalcemia must be corrected before initiating therapy with FOSAMAX (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. 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 for predisposing conditions.

    
    

    Due to the positive effects of FOSAMAX in increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.

    
    

    Ensuring adequate calcium and Vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids.

    Pediatrics (<18 years of age)

    FOSAMAX is not indicated for use in children.

    Pregnant Women

    FOSAMAX has not been studied in pregnant women and should not be given to them.

    Nursing Women

    FOSAMAX has not been studied in nursing mothers and should not be given to them.

    
    
    

    Storage and Stability

    Tablets: Store at room temperature (15-30°C).

    
    

    Oral Solution: Store at 25°C, excursions permitted to 15-30°C. Do not freeze.

    Action and Clinical Pharmacology

    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%.

    Special Populations and Conditions

    
    
    

    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% (see Table 5).

    
    

    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
    
    Summary of Pharmacokinetic Parameters in the Normal Population

    
    

    	Mean	90% Confidence Interval
    Absolute bioavailability of 5 mg tablet, taken 2 hours before first meal of the day	0.63% (females)	(0.48, 0.83)
    Absolute bioavailability of 10 mg tablet, taken 2 hours before first meal of the day	0.78% (females)	(0.61, 1.04)
    	0.59% (males)	(0.43, 0.81)
    Absolute bioavailability of 40 mg tablet, taken 2 hours before first meal of the day	0.60% (females)	(0.46, 0.78)
    Absolute bioavailability of 70 mg tablet, taken 2 hours before first meal of the day	0.57% (females)	(0.44, 0.73)
    Renal Clearance mL/s (mL/min) (n=6)	1.18 (71)	(1.07, 1.3) (64,78)

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    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 FOSAMAX 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 FOSAMAX 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 FOSAMAX. In osteoporosis treatment studies, FOSAMAX 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, FOSAMAX 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 FOSAMAX 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. 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 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 FOSAMAX 5 mg/day. In a one-year study with FOSAMAX 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 but also a decrease in renal phosphate reabsorption.

    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.

    Gender

    Bioavailability and the fraction of an IV dose excreted in urine were similar in men and women.

    Metabolism

    There is no evidence that alendronate is metabolized in animals or humans.

    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.

    Pediatrics

    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 Warnings and Precautions, Special Populations, Pediatrics (<18 years of age)).

    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, FOSAMAX 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, FOSAMAX 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).

    Geriatrics

    Bioavailability and disposition (urinary excretion) were similar in elderly (≥65 years of age) and younger patients. No dosage adjustment is necessary (see Dosage and Administration).

    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.

    Mechanism of Action

    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.

    Race

    Pharmacokinetic differences due to race have not been studied.

    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 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 70 mg once weekly.

    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 is not recommended for patients with more severe renal insufficiency (creatinine clearance <0.58 mL/s [<35 mL/min]) due to lack of experience.

    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.

    
    

    FOSAMAX decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, FOSAMAX 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, FOSAMAX induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

    
    
    

    Contraindications

    Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging.

    
    

  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.

    
    

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

    
    

  • Patients at increased risk of aspiration should not receive FOSAMAX oral solution.

    
    

  • Hypocalcemia (see Warnings and Precautions).

    
    

  • Renal insufficiency with creatinine clearance <0.58 mL/s [<35 mL/min] (see Dosage and Administration).