Alendronate Sodium and Cholecalciferol

FOSAMAX PLUS D contains alendronate sodium, a bisphosphonate, and cholecalciferol (vitamin D3).

Alendronate sodium is a bisphosphonate 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.

Cholecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25 dihydroxyvitamin D3).

The chemical name of cholecalciferol is (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol. The empirical formula of cholecalciferol is C27H44O and its molecular weight is 384.6. The structural formula is:

Cholecalciferol is a white, crystalline, odorless powder. Cholecalciferol is practically insoluble in water, freely soluble in usual organic solvents, and slightly soluble in vegetable oils.

FOSAMAX PLUS D for oral administration contains 91.37 mg of alendronate monosodium salt trihydrate, the molar equivalent of 70 mg of free acid, and 70 or 140 mcg of cholecalciferol, equivalent to 2800 or 5600 international units vitamin D, respectively. Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate, butylated hydroxytoluene, modified food starch, and sodium aluminum silicate.

Treatment Of Osteoporosis In Postmenopausal Women

FOSAMAX® PLUS D is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, FOSAMAX PLUS D increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies]

Treatment To Increase Bone Mass In Men With Osteoporosis

FOSAMAX PLUS D is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies].

Important Limitations Of Use

FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency.

The optimal duration of use has not been determined. The safety and effectiveness of FOSAMAX PLUS D for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Dosage Forms And Strengths

• 70 mg/2800 international units tablets are white to off-white, modified capsule-shaped tablets with code 710 on one side and an outline of a bone image on the other.
• 70 mg/5600 international units tablets are white to off-white, modified rectangle-shaped tablets with code 270 on one side and an outline of a bone image on the other.

Storage And Handling

No. 3870 — Tablets FOSAMAX PLUS D 70 mg/2800 international units are white to off-white, modified capsule-shaped tablets with code 710 on one side and an outline of a bone image on the other. They are supplied as follows:

NDC 0006-0710-44 unit of use blister packages of 4.

No. 6746 — Tablets FOSAMAX PLUS D 70 mg/5600 international units are white to off-white, modified rectangle-shaped tablets with code 270 on one side and an outline of a bone image on the other. They are supplied as follows:

NDC 0006-0270-44 unit of use blister packages of 4
NDC 0006-0270-21 unit dose packages of 20.

Store at 20-25°C (68-77°F), excursions between 15-30°C (59-86°F) are allowed. [See USP Controlled Room Temperature.] Protect from moisture and light. Store tablets in the original blister package until use.

Manuf. fot Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. By: FROSST IBERICA, S.A. 28805 Alcalá de Henares Madrid, Spain. Revised: Feb 2015

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

FOSAMAX

Treatment of Osteoporosis in Postmenopausal Women

The safety of FOSAMAX in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994); Study 3 was the three-year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027); and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to FOSAMAX. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day.

Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the FOSAMAX group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the FOSAMAX group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the FOSAMAX group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either FOSAMAX or placebo are presented in Table 1.

Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients

Rash and erythema have occurred.

Gastrointestinal Adverse Reactions: 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. In the Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline, and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. [See WARNINGS AND PRECAUTIONS]

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 less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups.

The safety of FOSAMAX 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing FOSAMAX 70 mg once weekly and FOSAMAX 10 mg daily. The overall safety and tolerability profiles of once weekly FOSAMAX 70 mg and FOSAMAX 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2.

Table 2: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients

In two studies (of one and two years' duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with FOSAMAX 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.

Osteoporosis in Men

In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day and a one-year study of once weekly FOSAMAX 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either FOSAMAX or placebo are presented in Table 3.

Table 3: Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients

In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) was similar to that of FOSAMAX once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) administered with an additional 2800 international units vitamin D3 was similar to that of FOSAMAX PLUS D (70 mg/2800 international units).

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of FOSAMAX and FOSAMAX PLUS D. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see WARNINGS AND PRECAUTIONS].

Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating [see WARNINGS AND PRECAUTIONS]; joint swelling; low-energy femoral shaft and subtrochanteric fractures [see WARNINGS AND PRECAUTIONS].

Nervous System: dizziness and vertigo.

Pulmonary: acute asthma exacerbations.

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

Special Senses: uveitis, scleritis or episcleritis.

Included as part of the PRECAUTIONS section.

Alendronate is in the group of medicines called bisphosphonates (bis FOS fo nayts). It alters the cycle of bone formation and breakdown in the body. Alendronate slows bone loss while increasing bone mass, which may prevent bone fractures.

Cholecalciferol is a form of vitamin D, and is important for the absorption of calcium from the stomach and for the functioning of calcium in the body.

Alendronate and cholecalciferol is used to treat and prevent osteoporosis.

Alendronate and cholecalciferol may also be used for purposes not listed in this medication guide.