Fosamax (Alendronate Sodium)

FOSAMAX®

MSD

Alendronate Sodium

Bone Metabolism Regulator

Action And Clinical Pharmacology: Alendronate is an aminobisphosphonate that acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Pharmacokinetics: Absorption: Relative to an i.v. reference dose, the mean oral bioavailability of alendronate in women was 0.7% for doses ranging from 5 to 40 mg when administered after an overnight fast and 2 hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women (0.78%) when administered after an overnight fast and 2 hours before breakfast.

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 2 hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Distribution: Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg i.v. administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

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

Excretion: Following a single i.v. dose of 4 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 i.v. 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 i.v. 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 alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Special Populations: Children: Alendronate pharmacokinetics have not been investigated in patients.
Gender: Bioavailability and the fraction of an i.v. dose excreted in urine were similar in men and women.

Geriatrics: Bioavailability and disposition (urinary excretion) were similar in elderly (³65 years of age) and younger patients. No dosage adjustment is necessary (see Dosage).

Race: Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative i.v. 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]). Alendronate is not recommended for patients with more severe renal insufficiency (creatinine clearance).
Hepatic Insufficiency: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary.

Drug Interactions (also see Precautions, Drug Interactions): I.V. ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown; no other specific drug interaction studies were performed.

Products containing calcium and other multivalent cations likely will interfere with absorption of alendronate.

Pharmacodynamics: 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.

Alendronate is an aminobisphosphonate 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. Alendronate thus reduces the elevated rate of bone turnover observed in postmenopausal women to approximate more closely that in premenopausal women.

Daily oral doses of alendronate (5, 20 and 40 mg for 6 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.

In long-term (2- or 3-year) osteoporosis treatment studies, alendronate 10 mg/day reduced urinary excretion of markers of bone resorption, including deoxypyridinoline and cross-linked N-telopeptides of type I collagen, by approximately 50 to 60% to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as 1 month and at 3 to 6 months reached a plateau that was maintained for the entire duration of treatment with alendronate. In osteoporosis treatment studies, alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and total serum alkaline phosphatase, by approximately 50% and 25 to 30%, respectively, to reach a plateau after 6 to 12 months. In osteoporosis prevention studies, alendronate 5 mg/day decreased these markers by approximately 40% and 15%, respectively. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate 10 mg, but no further decreases were observed for the 3-year duration of the studies. Similar reductions were observed with alendronate 5 mg/day. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate but also a decrease in renal phosphate reabsorption.

Paget’s Disease of Bone: Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget’s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

Alendronate decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate 40 mg once daily for 6 months produced highly significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

Indications And Clinical Uses: Osteoporosis: For the treatment and prevention of osteoporosis in postmenopausal women. For the treatment of osteoporosis, alendronate increases bone mass and prevents fractures, including those of the hip, wrist, and spine (vertebral compression fractures).

Osteoporosis may be confirmed by the finding of low bone mass (e.g., at least 2.0 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture.

For the prevention of osteoporosis, alendronate may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture.

Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass; thin body build; Caucasian or Asian race; and family history of osteoporosis. The presence of such risk factors may be important when considering the use of alendronate for prevention of osteoporosis.

Paget’s Disease of Bone: For the treatment of Paget’s disease of bone. Treatment is indicated in patients having serum alkaline phosphatase at least 2 times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease.

Contra-Indications: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes; hypersensitivity to any component of this product; hypocalcemia (see Precautions); renal insufficiency with creatinine clearance.
Manufacturers’ Warnings In Clinical States: Alendronate, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions 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 signalling a possible esophageal reaction and patients should be instructed to discontinue alendronate immediately and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking alendronate and/or who fail to swallow it with a full glass of water, and/or who continue to take alendronate after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see Dosage).

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 alendronate is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers.

Precautions: To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed to swallow alendronate with a full glass of water 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 alendronate at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate immediately and consult their physician.

While no increased risk was observed in extensive clinical trials, there have been rare (postmarketing) reports of gastric and duodenal ulcers, some severe and with complications. However, a causal relationship has not been established.

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

Hypocalcemia must be corrected before initiating therapy with alendronate (see Contraindications). Other disturbances of mineral metabolism (such as vitamin D deficiency) should be treated.

Paget’s Disease of Bone: Due to the positive effects of alendronate to increase bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget’s disease, in whom the pretreatment rate of bone turnover may be greatly elevated. Adequate calcium and vitamin D nutrition must be ensured to provide for these enhanced needs.

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

Children: Alendronate has not been studied in patients
Pregnancy: Alendronate has not been studied in pregnant women and should not be given to them.

Lactation: Alendronate has not been studied in nursing mothers and should not be given to them.

Men: Safety and effectiveness in male osteoporosis have not been established.

Drug Interactions: If taken at the same time it is likely that calcium supplements, antacids, and other oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking alendronate before taking any other oral medication.

I.V. 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.

A number of postmenopausal women in the osteoporosis trials received estrogen (intravaginal, transdermal, or oral) while taking alendronate. No adverse experiences attributable to their concomitant use were identified.

However, the effectiveness of the concomitant use of hormone replacement therapy and alendronate in postmenopausal women has not been established. Specific interaction studies were not performed. Alendronate was used in studies of treatment (10 mg/day) and prevention (5 mg/day) of osteoporosis in postmenopausal women with a wide range of commonly prescribed drugs without evidence of clinical adverse reactions.

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving therapy with dosages of alendronate greater than 10 mg/day and ASA-containing compounds.

Alendronate may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2 027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

Animal studies have demonstrated that alendronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected. Although alendronate is bound approximately 78% to plasma protein in humans, its plasma concentration is so low after oral dosing that only a small fraction of plasma-binding sites is occupied, resulting in a minimal potential for interference with the binding of other drugs. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other drugs by those systems in humans. In summary, alendronate is not expected to interact with other drugs based on effects on protein binding, renal excretion, or metabolism of other drugs.

Adverse Reactions: Clinical Studies: In clinical studies, alendronate was generally well tolerated. Side effects, which usually were mild, generally did not require discontinuation of therapy.

Alendronate has been evaluated for safety in clinical studies in more than 3 800 postmenopausal women.

Treatment of Osteoporosis in Postmenopausal Women: In 2 large, 3-year, placebo-controlled, double-blind, multicenter studies (U.S. and Multinational) of virtually identical design, with a total of 994 postmenopausal women, the overall safety profiles of alendronate 10 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6.0% of 397 patients treated with placebo.

Adverse experiences reported by the investigators as possibly, probably, or definitely drug-related in ³1% of patients treated with either alendronate 10 mg/day or placebo are presented in Table II.

Rarely, rash and erythema have occurred.

One patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant ASA developed an anastomotic ulcer with mild hemorrhage, which was considered drug-related. ASA and alendronate were discontinued and the patient recovered.

In the Vertebral Fracture Study of the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 7.6% of 1 022 patients treated with alendronate 5 mg/day for 2 years and 10 mg/day for the third year and 9.4% of 1 005 patients treated with placebo. Similarly, discontinuations due to upper gastrointestinal adverse experiences were comparable: alendronate, 2.6%; placebo, 2.6%. The overall adverse experience profile was similar to that seen in other studies with alendronate 5 or 10 mg/day.

Prevention of Osteoporosis in Postmenopausal Women: The safety of alendronate in postmenopausal women 40 to 60 years of age has been evaluated in 3 double-blind, placebo-controlled studies involving over 1 400 patients randomized to receive alendronate for either 2 or 3 years. In these studies the overall safety profiles of alendronate 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 7.5% of 642 patients treated with alendronate 5 mg/day and 5.7% of 648 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ³1% of patients treated with either alendronate 5 mg/day or placebo are presented in Table III.

Paget’s Disease of Bone: In clinical studies (Paget’s disease and osteoporosis), adverse experiences reported in 175 patients taking alendronate 40 mg/day for 3 to 12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking alendronate 40 mg/day (17.7% alendronate vs 10.2% placebo). Isolated cases of esophagitis and gastritis resulted in discontinuation of treatment.

Additionally, musculoskeletal pain (bone, muscle or joint), which has been described in patients with Paget’s disease treated with other bisphosphonates, was reported by the investigators as possibly, probably, or definitely drug-related in approximately 6% of patients treated with alendronate 40 mg/day vs approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 6.4% of patients with Paget’s disease treated with alendronate 40 mg/day and 2.4% of patients treated with placebo.

Postmarketing Experience: The following adverse reactions have been reported in postmarketing use:

Body as a Whole: hypersensitivity reactions including urticaria and rarely angioedema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, and oropharyngeal ulceration. Some of these have been serious and required hospitalization. Rarely, gastric or duodenal ulcers, some severe and with complications, although a causal relationship has not been established (see Warnings, Precautions and Dosage).

Laboratory Tests: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18 and 10%, respectively, of patients taking alendronate vs approximately 12 and 3% of those taking placebo. However, the incidences of decreases in serum calcium to
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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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.

Dosage And Administration: Alendronate 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 alendronate (see Precautions, Drug Interactions). Waiting less than 30 minutes will lessen the effect of alendronate by decreasing its absorption into the body.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, alendronate should only be swallowed upon arising for the day with a full glass of water (200 to 250 mL) and patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences (see Warnings).

All patients must receive supplemental calcium and vitamin D, if dietary intake is inadequate.

Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis or Paget’s disease to alendronate, there are no known or theoretical safety concerns related to alendronate in patients who previously received any other antiosteoporotic or antipagetic therapy.

Treatment with alendronate for longer than 4 years has not been studied; extension studies are ongoing.

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]).

Treatment of Osteoporosis in Postmenopausal Women: The recommended dosage is 10 mg once a day.

Prevention of Osteoporosis in Postmenopausal Women: The recommended dosage is 5 mg once a day.

Paget’s Disease of Bone: The recommended treatment regimen is 40 mg once a day for 6 months.

Retreatment of Paget’s Disease: In clinical studies in which patients were followed every 6 months, relapses during the 12 months following therapy occurred in 9% (3 out of 32) of patients who responded to treatment with alendronate. Specific retreatment data are not available, although responses to alendronate were similar in patients who had received prior bisphosphonate therapy and those who had not. Retreatment with alendronate may be considered, following a 6-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.

Information to be Provided to the Patient: Patients must be instructed that the expected benefits of alendronate may only be obtained when each tablet is swallowed with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed to swallow alendronate with a full glass of water 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 alendronate at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate immediately and consult their physician.

Availability And Storage: 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 5 mg as alendronate sodium. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Blister packages of 30.

10 mg: Each white, round, uncoated tablet, with an embossed bone image on each side and FOSAMAX engraved on one side and MRK 936 on the other, contains: alendronate 10 mg as alendronate sodium. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Blister packages of 30.

40 mg: Each white, triangle-shaped, uncoated tablet, with FOSAMAX on one side and MRK 212 on the other, contains: alendronate 40 mg as alendronate sodium. Nonmedicinal ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Blister packages of 30.

Store at room temperature (15 to 30°C).

FOSAMAX® MSD Alendronate Sodium Bone Metabolism Regulator

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