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Fosamax®

(Alendronate Sodium Tablets)


DESCRIPTION
CLINICAL PHARMACOLOGY
ANIMAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED


Description

FOSAMAX (alendronate sodium) is an aminobisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.

The empirical formula of alendronate sodium is C4H12NNaO7P2•3H2O and its formula weight is 325.12. The structural formula is:

Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.

Tablets FOSAMAX for oral administration contain 6.53, 13.05 or 52.21 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5.0, 10.0 and 40.0 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.

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Clinical Pharmacology

Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Pharmacokinetics
Absorption

Relative to an intravenous (IV) 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 two 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 two 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 IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

Metabolism

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

Excretion

Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min, and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the 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.

Special Populations

Pediatric: Alendronate pharmacokinetics have not been investigated in patients <18 years of age.

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

Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly (65 years of age) and younger patients. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).

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

Renal Insufficiency: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative IV doses of 35 mg/kg in young male rats. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). FOSAMAX is not recommended for patients with more severe renal insufficiency (creatinine clearance <35 mL/min) due to lack of experience.

Hepatic Insufficiency: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary.

Drug Interactions (also see PRECAUTIONS, Drug Interactions)

Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown; no other specific drug interaction studies were performed.

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

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)

Renal Clearance (mL/min)
(n=6)

71

(64, 78)

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 (spinal) 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. Alendronate is not an estrogen and does not have the benefits and risks of estrogen replacement therapy.

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.

In long-term (two- or three-year) osteoporosis treatment studies, FOSAMAX 10 mg/day reduced urinary excretion of markers of bone resorption, including deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50-60% 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 total serum alkaline phosphatase, by approximately 50% and 25-30%, respectively, to reach a plateau after 6 to 12 months. In osteoporosis prevention studies FOSAMAX 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 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, but no further decreases were observed for the three-year duration of the studies. Similar reductions were observed with FOSAMAX 5 mg/day. 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.

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 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, FOSAMAX induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

Clinical Studies
Treatment of osteoporosis in postmenopausal women
Effect on bone mineral density

The efficacy of FOSAMAX 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration. These included two large three-year, multicenter studies of virtually identical design, one performed in the United States (U.S.) and the other in 15 different countries (Multinational), which enrolled 478 and 516 patients, respectively. The following graph shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving FOSAMAX 10 mg/day relative to placebo-treated patients at three years for each of these studies.

Increase in BMD
FOSAMAX 10 mg/day in Two Studies at Three Years

Graph -1

Highly significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received FOSAMAX 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See figures below for lumbar spine results.) Thus, FOSAMAX appears to reverse the progression of osteoporosis. FOSAMAX was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).

Time Course of Effect of FOSAMAX 10 mg/day Versus Placebo:
Lumbar Spine BMD Percent Change From Baseline

Graph 2-3

In patients with postmenopausal osteoporosis treated with FOSAMAX for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. These data indicate that continuous daily treatment with FOSAMAX is required to maintain the effect of the drug.

Effect on fracture incidence

To assess the effects of FOSAMAX on vertebral fracture incidence, the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of FOSAMAX (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a significant 48% reduction in the proportion of patients treated with FOSAMAX experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received FOSAMAX had a statistically significant smaller loss in stature than those who received placebo (–3.0 mm vs. –4.6 mm). Furthermore, of patients who sustained any vertebral fracture, those treated with FOSAMAX experienced less height loss (5.9 mm vs. 23.3 mm) due to a reduction in both the number and severity of fractures.

The Vertebral Fracture Study of the Fracture Intervention Trial (FIT) included results from 2027 patients who had at least one baseline vertebral (compression) fracture. The results of this study demonstrated the reduction in fracture incidence due to FOSAMAX. In this three-year, randomized, double-blind, placebo-controlled study, 1022 patients received FOSAMAX and 1005 patients received placebo. Treatment with FOSAMAX resulted in statistically significant and clinically meaningful reductions in the proportion of patients experiencing fractures as shown in the table below.


Effect of FOSAMAX on Fracture Incidence Over Three Years
in the Vertebral Fracture Study of FIT


 

% of Patients

Reduction (%) in

FOSAMAX Placebo Fracture Incidence

Patients with:      
> 1 new vertebral fracture 8.0 15.0 47
> 2 new vertebral fractures 0.5 4.9 90
> 1 painful vertebral fracture 2.3 5.0 55
Hip fractures 1.1 2.2 51
Wrist (forearm) fracture 2.2 4.1 48

Furthermore, treatment with FOSAMAX significantly reduced the incidence of total hospitalizations (24.9% vs. 30.4%).

The reduction in the incidence of vertebral fractures (FOSAMAX versus placebo) in the Vertebral Fracture Study of FIT (in which all women had at least one baseline vertebral fracture) was consistent with that in the combined U.S. and Multinational (U.S./Mult) treatment studies (see above), in which 80% of the women did not have a vertebral fracture at baseline. During these three-year studies, treatment with FOSAMAX reduced the proportion of women experiencing at least one new vertebral fracture in both study populations by approximately 50% (FIT: 47% reduction, p<0.001; U.S./Mult: 48% reduction, p = 0.034). Similarly, FOSAMAX reduced the proportion of women experiencing multiple (two or more) new vertebral fractures by approximately 90% in both studies (p<0.001). Thus, FOSAMAX reduces the incidence of fractures whether or not patients have experienced a previous vertebral fracture.

The two figures below display the cumulative incidence of patients with hip and wrist fractures over 3 years in the Vertebral Fracture Study of FIT. In both figures, the cumulative incidence of patients with these types of fracture is lower with FOSAMAX compared with placebo at all time points. FOSAMAX reduced the proportion of women experiencing hip fracture by 51% and wrist fracture by 48%. Proportionately similar reductions of hip and wrist fractures were seen in pooled earlier osteoporosis treatment studies.

Cumulative Incidence of Patients with Hip and Wrist Fractures
FIT
(Vertebral Fracture Study)

Graph 4-5

Overall, these results demonstrate the efficacy of FOSAMAX to reduce the incidence of fractures at the spine, hip and wrist, which are the three most common sites of osteoporotic fracture.

Bone histology

Bone histology in 270 postmenopausal patients with osteoporosis treated with FOSAMAX at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with FOSAMAX is of normal quality.

Prevention of osteoporosis in postmenopausal women

Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40-60 years of age. One thousand six hundred nine patients (FOSAMAX 5 mg/day; n = 498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (FOSAMAX 5 mg/day; n = 88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, FOSAMAX 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see figures below). In addition, FOSAMAX 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. FOSAMAX 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.

Change in BMD from Baseline
2-Year Study

Change in BMD from Baseline
3-Year Study

Graph 6-7

Bone histology was normal in the 28 patients biopsied at the end of three years who received FOSAMAX at doses of up to 10 mg/day.

Paget’s disease of bone

The efficacy of FOSAMAX 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget’s disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. The following figure shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.

Effect on Serum Alkaline Phosphatase of FOSAMAX 40 mg/day
Versus Placebo or Etidronate 400 mg/day

At six months the suppression in alkaline phosphatase in patients treated with FOSAMAX was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline 60%) occurred in approximately 85% of patients treated with FOSAMAX in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. FOSAMAX was similarly effective irrespective of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).

Bone histology was evaluated in 33 patients with Paget’s disease treated with FOSAMAX 40 mg/day for 6 months. As in patients treated for osteoporosis (see Clinical Studies, Treatment of osteoporosis in postmenopausal women, Bone histology), FOSAMAX did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with FOSAMAX, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with FOSAMAX is of normal quality.

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Animal Pharmacology

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

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Indicatons and Usage

FOSAMAX 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, wrist, and spine (vertebral compression fractures). Osteoporosis may be confirmed by the finding of low bone mass (for example, at least 2 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture. (See CLINICAL PHARMACOLOGY, Pharmacodynamics.)
  • 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 (for example, at least 1 standard deviation below the mean for healthy young adult women); 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.

FOSAMAX is indicated for the treatment of Paget's disease of bone.

  • Treatment is indicated in patients with Paget's disease of bone having 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.

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Contraindications

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

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

  • Hypersensitivity to any component of this product

  • Hypocalcemia (see PRECAUTIONS, General)

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Warnings

FOSAMAX, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding, 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 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 FOSAMAX and/or who fail to swallow it with a full glass (6-8 oz) 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). In patients who cannot comply with dosing instructions due to mental disability, therapy with FOSAMAX should be used under appropriate supervision.

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).

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Precautions

General

There have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in pre-marketing clinical trials.

FOSAMAX is not recommended for patients with renal insufficiency (creatinine clearance <35 mL/min). (See DOSAGE AND ADMINISTRATION.)

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

Hypocalcemia must be corrected before initiating therapy with FOSAMAX (see CONTRAINDICATIONS). Other disturbances of mineral metabolism (such as vitamin D deficiency) should also be effectively treated. Presumably due to the effects of FOSAMAX on 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. Adequate calcium and vitamin D intake should be ensured to provide for these enhanced needs.

Information for Patients

Patients should be instructed that the expected benefits of FOSAMAX 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 FOSAMAX (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption).

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed to swallow FOSAMAX with a full glass of water (6-8 oz) 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 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 and consult their physician.

Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist.

Physicians should instruct their patients to read the patient package insert before starting therapy with FOSAMAX and to reread it each time the prescription is renewed.

Drug Interactions (also see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions)

Estrogen

The safety and effectiveness of the concomitant use of hormone replacement therapy and FOSAMAX in postmenopausal women has not been established.

Calcium Supplements/Antacids

It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of FOSAMAX. Therefore, patients must wait at least one-half hour after taking FOSAMAX before taking any other drug.

Aspirin

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

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

FOSAMAX may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n = 2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking FOSAMAX 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 FOSAMAX.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.5 to 4 times the 10 mg human dose based on surface area, mg/m2.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 1 and 3 times the 10 mg human dose based on surface area.

Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate was weakly positive at concentrations 5 mM in the presence of cytotoxicity.

Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (four times the 10 mg human dose based on surface area).

Pregnancy
Pregnancy Category C:

Reproduction studies in rats showed decreased postimplantation survival at 2 mg/kg/day and decreased body weight gain in normal pups at 1 mg/kg/day. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at 10 mg/kg/day in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. The above doses ranged from 1 times (1 mg/kg) to 9 times (10 mg/kg) the 10 mg human dose based on surface area, mg/m2. No similar fetal effects were seen when pregnant rabbits were treated at doses up to 35 mg/kg/day (50 times the 10 mg human dose based on surface area, mg/m2).

Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day (13 times the 10 mg human dose based on surface area) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day (0.5 times the recommended human dose) when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with 15 mg/kg/day for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; calcium supplementation IV prevented maternal, but not fetal deaths.

There are no studies in pregnant women. FOSAMAX should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FOSAMAX is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

Of the patients receiving FOSAMAX in the two large osteoporosis treatment studies and Paget’s disease studies (see CLINICAL PHARMACOLOGY, Clinical Studies), 45% and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Use in Men

Safety and effectiveness in male osteoporosis have not been established.

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Adverse Reactions

ADVERSE REACTIONS

Clinical Studies

In clinical studies adverse experiences associated with FOSAMAX usually were mild, and generally did not require discontinuation of therapy

FOSAMAX has been evaluated for safety in approximately 3800 postmenopausal women in clinical studies.

Treatment of osteoporosis

In two large, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational), 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 reported 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.


Drug-Related** Adverse Experiences
Reported in >1% of Patients


Gastrointestinal

FOSAMAX
10 mg/day
%
(n = 196)
_______________

Placebo

%
(n = 397)
_______________

abdominal pain
nausea
dyspepsia
constipation
diarrhea
flatulence
acid regurgitation
esophageal ulcer
vomiting
dysphagia
abdominal distention
gastritis
6.6
3.6
3.6
3.1
3.1
2.6
2.0
1.5
1.0
1.0
1.0
0.5
4.8
4.0
3.5
1.8
1.8
0.5
4.3
0.0
1.5
0.0
0.8
1.3
Musculoskeletal    
musculoskeletal (bone, muscle
or joint) pain
muscle cramp


4.1
0.0


2.5
1.0

Nervous System/Psychiatric    
headache
dizziness

2.6
0.0

1.5
1.0

Special Senses    
taste perversion

0.5

1.0


** Considered possibly, probably, or definitely drug related as assessed by the investigators

Rarely, rash and erythema have occurred.

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

The adverse experience profile was similar for the 401 patients treated with either 5 or 20 mg doses of FOSAMAX in the United States and Multinational studies.

In the Vertebral Fracture Study of the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 7.6% of 1022 patients treated with FOSAMAX 5 mg/day for 2 years and 10 mg/day for the third year and 9.4% of 1005 patients treated with placebo. Similarly, discontinuations due to upper gastrointestinal adverse experiences were comparable: FOSAMAX, 2.6%; placebo, 2.6%. The overall adverse experience profile was similar to that seen in other studies with FOSAMAX 5 or 10 mg/day.

Prevention of osteoporosis

The safety of FOSAMAX 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. The 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.


Drug-Related** Adverse Experiences
Reported in >1% of Patients


Gastrointestinal

FOSAMAX
5 mg/day
%
(n = 642)
_______________

Placebo

%
(n = 648)
_______________

abdominal pain
acid regurgitation
diarrhea
dyspepsia
nausea

1.7
1.4
1.1
1.9
1.4
3.4
2.5
1.7
1.7
1.4

** Considered possibly, probably, or definitely drug related as assessed by the investigators

Paget’s disease of bone

In clinical studies (osteoporosis and Paget's disease), 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). One case of esophagitis and two cases of gastritis resulted in discontinuation of treatment.

Additionally, musculoskeletal (bone, muscle or joint) pain, 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.

Laboratory Test Findings

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/dL (0.65 mM) were similar in both treatment groups.

Post-Marketing Experience

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

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

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers and oropharyngeal ulceration. Rarely, gastric or duodenal ulcers, some severe and with complications have been reported (see WARNINGS, PRECAUTIONS, General and Information for Patients, and DOSAGE AND ADMINISTRATION).

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Overdosage

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2).

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.

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Dosage and Administration

FOSAMAX must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (see PRECAUTIONS, Information for Patients). Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of FOSAMAX (see PRECAUTIONS, Drug Interactions). Waiting less than 30 minutes, or taking FOSAMAX with food, beverages (other than plain water) or other medications will lessen the effect of FOSAMAX by decreasing its absorption into the body.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, FOSAMAX should only be swallowed upon arising for the day with a full glass of water (6-8 oz) and 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).

Patients should receive supplemental calcium and vitamin D, if dietary intake is inadequate (see PRECAUTIONS, General).

No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). FOSAMAX is not recommended for patients with more severe renal insufficiency (creatinine clearance <35 mL/min) due to lack of experience.

Treatment of osteoporosis in postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is 10 mg once a day.

Prevention of osteoporosis in postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is 5 mg once a day.

Safety of treatment or prevention of osteoporosis with FOSAMAX for longer than four years has not been studied; extension studies are ongoing.

Paget’s disease of bone

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.

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How Supplied

No. 3759 — Tablets FOSAMAX, 5 mg, are white, round, uncoated tablets with an outline of a bone image on one side and code MRK 925 on the other. They are supplied as follows:

NDC 0006-0925-31 unit-of-use bottles of 30

NDC 0006-0925-58 unit-of-use bottles of 100.

No. 3600 — Tablets FOSAMAX, 10 mg, are white, round, uncoated tablets with a bone image and code MRK 936 on one side and a bone image and FOSAMAX on the other. They are supplied as follows:

NDC 0006-0936-31 unit-of-use bottles of 30

(6505-01-424-1106, 10 mg 30's)

NDC 0006-0936-58 unit-of-use bottles of 100

NDC 0006-0936-28 unit dose packages of 100

(6505-01-424-1113, 10 mg 100's)

NDC 0006-0936-82 bottles of 1000.

NDC 0006-0936-72 carton of 25 UNIBLISTER™ cards of 31 tablets each.

No. 3592 — Tablets FOSAMAX, 40 mg, are white, triangular-shaped, uncoated tablets with code MRK 212 on one side and FOSAMAX on the other. They are supplied as follows:

NDC 0006-0212-31 unit-of-use bottles of 30

(6505-01-424-1111, 40 mg 30's).

Storage

Store in a well-closed container at room temperature, 15-30C (59-86F).

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Issued July 1997

FOSAMAX is a registered trademark of Merck & Co., Inc.





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