FDA clears Merck's Fosamax as the first nonhormonal drug to treat osteoporosis in women after menopause.

WEST POINT, Pa.--(BUSINESS WIRE)--Oct. 2, 1995--Merck & Co. Inc. Monday announced that the U.S. Food and Drug Administration has cleared for marketing Fosamax (alendronate sodium) to treat osteoporosis in women after menopause.

Fosamax, a breakthrough prescription medicine, builds healthy bone, restoring some of the bone lost as a result of osteoporosis. Fosamax is a new treatment choice and the first nonhormonal medicine for women after menopause who have this bone-weakening disease, which leads to osteoporotic fractures in more than one in three women over age 50.

"Until recently, the only treatments for osteoporosis, a potentially painful, disabling and sometimes life-threatening disease, were hormonal. Finally, there is a new treatment choice women can discuss with their physicians," said Ethel Siris, M.D., director of osteoporosis programs at the Center for Women's Health, Columbia-Presbyterian Medical Center, New York, and a clinical investigator for Fosamax. "Fosamax is a highly effective treatment that increased the amount of bone in women in clinical trials. As a result, Fosamax also reduced the risk of new spinal fractures. This treatment should help the 20 million American women with osteoporosis remain active, strong and independent throughout their lives."

The FDA clearance of Fosamax is based on efficacy data from five clinical trials involving 1,827 women after menopause with osteoporosis in 16 countries who were followed for at least two years. The women ranged in age from 41 to 85, with an average age of 64.3.

In individuals with osteoporosis, bone loss can lead to spinal fractures, which can gradually collapse the bones of the spine and cause height loss, pain and a deformed back (dowager's hump). -0- Fosamax -- pronounced FOS-sah-max -- is the Merck registered trademark for alendronate sodium. -0-

Results from two three-year pivotal trials with 994 postmenopausal women with osteoporosis supported the conclusion that Fosamax built healthy bone. In patients treatedwith Fosamax, a progressive increase in bone mineral density (a measure of bone strength) occurred at the spine (8.2 percent) and hip (7.2 percent), compared with patients treated with placebo, in whom bone mineral density decreased by between 0.65 and 1.16 percent.

Fosamax also significantly increased bone mineral density at other sites, suggesting that the gains in bone mineral density at the spine and hip did not occur because of a loss of bone mineral density elsewhere in the skeleton.

While the studies were not designed to detect fracture risk, further analysis supports that Fosamax reduced by nearly half (48 percent) the number of women who suffered new spinal fractures compared with women treated with placebo. Treatment with Fosamax also led to a 63 percent reduction in the total number of new spinal fractures. Patients who fracture a bone in their spine are more likely to fracture another than patients who have no spinal fractures.

In the trials, women treated with Fosamax lost an average of 3.0 mm in height, compared with women on placebo who lost an average of 4.6 mm -- a 35 percent reduction in overall height loss. In women with at least one new spinal fracture, those treated with Fosamax lost an average of 5.9 mm (less than a quarter-inch) while women on placebo lost an average of 23.3 mm (approximately one inch) in height. This results from a reduction in both the number and severity of fractures.

Side Effects Generally Mild

Side effects observed in clinical trials were generally mild and generally have not caused patients to stop taking Fosamax. Of patients taking placebo, 6.0 percent (24 of 397) discontinued treatment due to adverse experiences, compared with 4.1 percent (8 of 196) taking Fosamax 10 mg. The most commonly reported drug-related side effects in patients taking Fosamax were abdominal and musculoskeletal pain. Less frequently reported were other digestive disturbances such as nausea, heartburn, and irritation or pain of the esophagus. Patients with low levels of calcium in their blood, severe kidney disease or who are pregnant or nursing should not take Fosamax. As with other drugs in its class, caution should be used when Fosamax is given to patients with active upper gastrointestinal problems.

The safety of treatment with Fosamax for longer than four years has not been studied; extension studies are ongoing.

The recommended dosage of Fosamax is 10 mg once daily for treatment of osteoporosis in women after menopause. Fosamax must be taken at least one-half hour before the first food, beverage or medication of the day with a full glass of plain water only to ensure adequate absorption. Patients should not lie down for at least 30 minutes after taking Fosamax.

Osteoporosis: One of America's Most Prevalent Diseases

Fosamax is indicated for the treatment of osteoporosis in postmenopausal women. Osteoporosis is a progressive disease of the skeleton caused by an imbalance in the body's bone-rebuilding cycle. Osteoporosis is characterized by low bone mass, which results in bones that are prone to fracture, or by the presence or history of an osteoporotic fracture. Bone mass is closely related to bone strength; the greater the bone mass, the stronger the bones and the less likely they are to fracture. A woman's bones can become so fragile that even bending to pick up a newspaper can cause bones in the spine to fracture.

Osteoporosis affects more than 25 million Americans, 80 percent of them women. Each year, osteoporosis causes more than 1.3 million fractures, including 500,000 spinal fractures, 250,000 hip fractures and 240,000 wrist fractures. The disease costs the U.S. healthcare system more than $10 billion annually, primarily due to these fractures of the hip, wrist and spine.

"Because women with osteoporosis may find it difficult to conduct normal daily activities, such as getting in and out of a car or getting dressed, many women can feel isolated and dependent on others," said Deborah T. Gold, Ph.D., assistant professor of medical sociology at Duke University Medical Center and an expert in the psychological and social effects of osteoporosis. "Few people realize that chronic pain due to osteoporotic fractures can physically limit a woman's life and affect her socially and emotionally."

Osteoporosis: Typically Without Symptoms for Many Years

Because bone loss occurs without symptoms, osteoporosis often goes unrecognized. In many cases, it is not diagnosed until after one or several fractures have occurred. However, several types of tests, all of which are quick, painless and non-invasive, can detect low bone mass.

"Contrary to popular belief, osteoporosis is not just a disease of elderly women, but can affect women at any age, even those who exercise regularly and take calcium," said Dr. Siris. "All women who are past menopause or who have had a total hysterectomy should talk to their doctor to evaluate their personal risk for osteoporosis and determine if a bone mass measurement would be helpful. Those who already have the disease should talk to their doctor about treatments and other measures to prevent fractures."

Bone Loss Accelerates at Menopause

Bone is constantly being rebuilt (or remodeled) throughout life in a process in which old bone tissue is broken down (or resorbed) by cells called osteoclasts and replaced with new bone tissue by cells called osteoblasts. In healthy young adults, the overall rate of remodeling is usually in balance so that the amount of bone lost is about equal to the amount that is replaced.

However, after menopause, more bone is broken down than is replaced, causing bone loss to occur and bones to become weaker. This is due to a drop in the level of estrogen. In the first five years after menopause, women may lose as much as 25 percent of their bone mass. In fact, menopause is the single most important risk factor for osteoporosis in women.

"Fosamax builds healthy bone; it inhibits bone breakdown, decreasing the amount of bone lost. The effect of continuous treatment with Fosamax is a net increase in bone mass in women with osteoporosis after menopause," said Laurence J. Hirsch, M.D., executive director of clinical research, Merck Research Laboratories. "To date, a progressive increase in bone mass has been observed for at least three years in the clinical trials of Fosamax."

Fosamax Also Cleared for Treatment of Paget's Disease of Bone

The FDA also cleared Fosamax for the treatment of Paget's disease of bone, a chronic disorder that affects up to 1.3 million Americans and may result in enlarged and deformed bones in one or more regions of the skeleton. In patients with Paget's disease of bone, excessive remodeling causes the bone to be enlarged but fragile, and may result in bone pain, deformities, fractures and, in some cases, arthritis and neurological complications.

In patients taking Fosamax 40 mg a day, most side effects were similar to those seen in the treatment of postmenopausal women with osteoporosis. However, there was an apparent increase in upper gastrointestinal experiences and musculoskeletal pain.

The recommended dosage of Fosamax for Paget's disease of bone is 40 mg once daily for six months. Patients should be periodically evaluated to determine their response to therapy.

Merck's catalog price to pharmacies for a 10 mg tablet of Fosamax (the recommended daily dose for treatment of osteoporosis in postmenopausal women) will be $1.39. Merck estimates that the retail price for 10 mg will be between $1.65 and $1.80 a day ($50 to $55 monthly, $600 to $660 annually), which includes markups of 20 to 30 percent that are based on historical audit data. Prices at the retail level are established by pharmacies, not by Merck, and can vary.

Fosamax was licensed to Merck & Co. Inc. by Istituto Gentili SPA of Pisa, Italy, in 1988 and is approved in 18 other countries. The New Drug Application for Fosamax was submitted to the FDA on March 31, 1995.

Merck has entered into a promotion agreement with Wyeth-Ayerst Laboratories, a division of American Home Products Corp., under which Wyeth-Ayerst will promote Fosamax to obstetricians and gynecologists in the United States. Merck will concentrate its promotional and educational efforts on other key specialty groups, such as endocrinologists, rheumatologists, and orthopedic surgeons, and primary-care physicians.

Merck & Co. Inc. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health. -0- Full prescribing information for Fosamax is attached.

FOSAMAX (ALENDRONATE SODIUM TABLETS) DESCRIPTION

FOSAMAX(a) (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 C4H12NNaO7P23H2O 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 either 13.05 mg or 52.21 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 10.0 mg and 40.0 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.

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 administr ation 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. Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

In a trial in elderly patients given 5 mg of alendronate (n = 86) 30 minutes before breakfast, similar bone mineral density changes were noted when compared to the pivotal trials, in which one of the treatment arms was 5 mg alendronate administered 60 minutes before breakfast.

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 phamacokinetics 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 likely will interfere with absorption of alendronate. -0-

Summary of Pharmacokinetic Parameters in the Normal Population

                                    Mean        90% ConfidenceInterval
Absolute bioavailability of
10 mg tablet, taken 2 hours
before first meal of the day       0.78%          (0.61, 1.04)
                                  (females)

                                   0.59%          (0.43, 0.81)
                                   (males)

Absolute bioavailability of
40 mg tablet, taken 2 hours
before first meal of
the day                            0.60%          (0.46, 0.78)
                                 (females)

Renal Clearance (mL/min)             71           (64, 78)
(n=6)-0- 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 am ong 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, hi p, 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 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) 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. 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 addition, the markers of bone formation, serum osteocalcin and alkaline phosphatase, we re also reduced by approximately 50% and 25 to 30%, respectively, to a plateau after 6 to 12 months. 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. 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.

Pagets disease

Pagets 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 Pagets 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 Osteoporosis in postmenopausal women

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.

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).

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 effects of treatment withdrawal were assessed in a study that included patients treated with FOSAMAX for one or two years. Following discontinuation, neither further increases in bone mass nor accelerated rate of bone loss was noted. These data indicate that continuous daily treatment with FOSAMAX is required to maintain the effect of the drug.

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.

Pagets disease

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 Pagets 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.

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 Pagets disease treated with FOSAMAX 40 mg/day for 6 months. As in patients treated for osteoporosis (see Clinical Studies, Osteoporosis in postmenopausal women), FOSAMAX did not impair mineralization, and the e xpected 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.

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.

INDICATIONS AND USAGE FOSAMAX is indicated for the treatment of: o Osteoporosis in postmenopausal women

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.) o Pagets disease of bone

Treatment is indicated in patients with Pagets 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. CONTRAINDICATIONS o Hypersensitivity to any component of this product o Hypocalcemia (see PRECAUTIONS, General) PRECAUTIONS General

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

As with other bisphosphonates, caution should be used when FOSAMAX is given to patients with active upper gastrointestinal problems, such as dysphagia, symptomatic esophageal diseases, gastritis, duodenitis, or ulcers.

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 Pagets 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 taken with plain water the first thing in the morning at least 30 minutes before the first food, beverage, or medication of the day. Patients should also be instructed that waiting longer than 30 minutes will improve the absorption of FOSAMAX. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of FOSAMAX (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption).

Patients should be instructed to take FOSAMAX with a full glass of water (6 8 oz.) and not to lie down for at least 30 minutes following administration to facilitate delivery to the stomach and reduce the potential for esophageal irritation.

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

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

Concomitant use of hormone replacement therapy and FOSAMAX in the treatment of osteoporosis in postmenopausal women is not recommended because of lack of clinical experience.

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.

NSAIDS/Aspirin

The risk of upper gastrointestinal adverse events associated with NSAIDS does not appear to be greater with concomitant treatment with FOSAMAX 10 mg/day. However, in patients receiving concomitant therapy with doses of FOSAMAX greater than 10 mg/day and aspirin-containing compounds, the incidence of upper gastrointestinal adverse events was increased.

Other

Although specific interaction studies were not performed, FOSAMAX 10 mg/day was used in postmenopausal osteoporosis studies with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions. These included antacids, anticholinergics, aspirin-containing compounds, benzodiazepines, beta-blockers, calcium channel blockers, diuretics, gastric acid secretion inhibitors, glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDS), sedative hypnotics, thiazides, thyroid hormones, vasoconstrictors, and vasodilators.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Harderian gland (a retroorbital 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 ar ea).

Pregnancy Pregnancy Category C:

Reproduction studies in rats showed decreased postimplantation