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.

    
    

• 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).

  
  

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.

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 often 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 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, poor oral hygiene).

Patients who develop osteonecrosis of the jaw should receive appropriate antibiotic therapy and/or oral surgery. 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 and oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

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.

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.

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.

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

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

FOSAMAX is not indicated for use in children.

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

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.

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 has been evaluated for safety in clinical studies in approximately 7200 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

Rarely, rash and erythema have occurred.

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 P{*P=elemental phosphorus.}/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.

Post-Marketing Experience: The following adverse reactions have been reported in post-marketing use:

Hypersensitivity reactions including urticaria and rarely angioedema. As with other bisphosphonates, transient symptoms as in an acute-phase response (myalgia, malaise, asthenia and rarely, fever) have been reported with FOSAMAX, 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. Rarely, peripheral edema.

Localized osteonecrosis of the jaw (ONJ) has been reported rarely with oral bisphosphonate treatment. ONJ is generally associated with local infection, tooth extraction often with delayed healing (see Warnings and Precautions, General).

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 (see Warnings and Precautions and Dosage and Administration).

bone, joint, and/or muscle pain, rarely severe and/or incapacitating (see Warnings and Precautions); joint swelling.

dizziness, vertigo.

rash (occasionally with photosensitivity), pruritus, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

rarely uveitis, scleritis or episcleritis.

Animal studies have demonstrated that FOSAMAX 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 is not expected to interact with other drugs based on effects on protein binding, renal excretion, or metabolism of other drugs.

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. Therefore, patients must wait at least one-half hour after taking FOSAMAX 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 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 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 acetylsalicylic acid-containing products. This was not observed in a study with FOSAMAX 70 mg once weekly.

FOSAMAX 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.

Food and beverages other than plain water may markedly reduce the absorption and effectiveness of alendronate. FOSAMAX must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (see Dosage and Administration, Information to Be Provided to the Patient).

Herbal products may interfere with the absorption of alendronate. FOSAMAX must be taken at least one-half hour before any herbal products.

Interactions with laboratory tests have not been established.

Treatment of Osteoporosis in Postmenopausal Women and in Men: The recommended dosage is:

• one 70 mg tablet once weekly

  
  

  or

  
  

• one bottle of 70 mg oral solution 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 FOSAMAX. Specific retreatment data are not available, although responses to FOSAMAX were similar in patients who had received prior bisphosphonate therapy and those who had not. Retreatment with FOSAMAX 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.

Patients should be instructed that if they miss a dose of FOSAMAX 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.

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 Drug 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 Warnings and Precautions and Dosage and Administration, Information to Be Provided to the Patient).

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 FOSAMAX, there are no known or theoretical safety concerns related to FOSAMAX in patients who previously received any other antiosteoporotic or antipagetic therapy.

Treatment with FOSAMAX for longer than five years has not been studied; extension studies are ongoing.

Patients must be instructed that the expected benefits of FOSAMAX 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 FOSAMAX.

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.

Patients should be advised with respect to adequate calcium and Vitamin D intake.