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Fosamax Plus
(alendronate sodium/cholecalciferol)


THERAPEUTIC CLASS
FOSAMAX PLUS contains alendronate sodium and cholecalciferol (vitamin D3).
Alendronate Sodium
Alendronate sodium is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydoxyapatite found in bone.
Cholecalciferol
Cholecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25-dihydroxyvitamin D3)

INDICATIONS
FOSAMAX PLUS is indicated
For the treatment of osteoporosis in postmenopausal women to increase bone mass, prevent fractures, including those of the hip and spine (vertebral compression fractures). Osteoporosis may be confirmed by the finding of low bone mass or by the presence or history of osteoporotic fracture.
Treatment of osteoporosis in men to prevent fractures.

CLINICAL PHARMACOLOGY
Mechanism of Action

Alendronate Sodium
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, where it is no longer 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.


Cholecalciferol
Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver Conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.

 

Vitamin D3 is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in secondary hyperparathyroidism, hypophosphatemia, proximal muscle weakness and osteomalacia, further increasing the risk of falls and fractures in osteoporotic individuals.


Pharmacokinetics

Absorption

Alendronate Sodium
Relative to an intravenous (IV) reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability in men (0.6%) was similar to that in women.


The alendronate in the FOSAMAX PLUS tablet and the FOSAMAX 70 mg tablet is bioequivalent.

 

Bioavailability was decreased similarly (by approximately 40%) whether alendronate was administered one or one-half hour before a standardized breakfast. In osteoporosis studies, FOSAMAX was effective when administered at least 30 minutes before the first food or beverage of the day.


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 healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).


Cholecalciferol
Following administration of FOSAMAX PLUS after an overnight fast and two hours before a standard meal, the mean area under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3 was 296.4 ng-hr/mL. The mean maximal serum concentration (Cmax) of vitamin D3 was 5.9 ng/mL, and the median time to maximal serum concentration (Tmax) was 12 hrs. The bioavailability of the 2800 IU vitamin D3 in FOSAMAX PLUS is similar to 2800 IU vitamin D3 administered alone.


Distribution

Alendronate Sodium
Studies in 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 for analytical detection (less than 5 ng/mL). Protein binding in human plasma is approximately 78%.


Cholecalciferol
Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.


Metabolism

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


Cholecalciferol
Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.


Elimination

Alendronate Sodium
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, reflecting release of alendronate from the skeleton.


Cholecalciferol
When radioactive vitamin D3 was administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4%, and the mean fecal excretion of radioactivity after 4 days was 4.9%. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of vitamin D3 in the serum following an oral dose of FOSAMAX PLUS is approximately 24 hours.


Characteristics in Patients
Preclinical studies show that the alendronate that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after chronic dosing with cumulative IV doses up to 35 mg/kg in animals. 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 (see DOSAGE AND ADMINISTRATION).

 

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