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Fosamax Plus: FOSAMAX PLUS contains alendronate sodium, a bisphosphonate, and colecalciferol (vitamin D3).
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 hydroxyapatite found in bone.
Colecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25-dihydroxyvitamin D3).
Pharmacodynamics: Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasis, 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 marrow turnover.
Osteoporosis in Postmenopausal Women: Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. Increased bone turnover is an independent risk factor of fractures (FOSAMAX PLUS only). 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.
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.
Long-term treatment of osteoporosis with FOSAMAX/FOSAMAX PLUS 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type I collagen, by approximately 50% and 70%, respectively, 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/FOSAMAX PLUS. In osteoporosis treatment studies, FOSAMAX/FOSAMAX PLUS 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase, by approximately 25 to 30%, to reach a plateau after 6 to 12 months. Similar reductions in the rate of bone turnover were observed in postmenopausal women during a one-year study with FOSAMAX/FOSAMAX PLUS 70 mg once weekly for the treatment of osteoporosis. 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/FOSAMAX PLUS. 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/FOSAMAX PLUS 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment, however, serum phosphate returned toward pre-study levels during years three through five. In a one-year study with FOSAMAX/FOSAMAX PLUS 70 mg once weekly, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to FOSAMAX/FOSAMAX PLUS but also a decrease in renal phosphate reabsorption.
Osteoporosis in Men: Even though osteoporosis is less prevalent in men than in postmenopausal women, a significant proportion of osteoporotic fractures occur in men. The prevalence of vertebral deformities appears to be similar in men and women. Treatment of men with osteoporosis with FOSAMAX/FOSAMAX PLUS 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving FOSAMAX/FOSAMAX PLUS 70 mg once weekly.
Pharmacokinetics: See Table 2.
Click on icon to see table/diagram/imageAbsorption: Fosamax: 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 of the 10 mg tablet in men was 0.59%.
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%.
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%).
Fosamax Plus: The alendronate in the FOSAMAX PLUS (70 mg/2800 IU) and FOSAMAX PLUS (70 mg/5600 IU) tablets and the FOSAMAX (alendronate sodium) 70 mg tablet were found to be equally bioavailable.
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%.
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%).
Colecalciferol: Following administration of FOSAMAX PLUS (70 mg/2800 IU) 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 (unadjusted for endogenous vitamin D3 levels) was 296.4 ng-hr/ mL. The mean maximal serum concentration (Cmax) of vitamin D3 was 14.8 nmol/L or 5.9 ng/mL, and the median time to maximal serum concentration (Tmax) was 12 hrs. Following administration of FOSAMAX PLUS (70 mg/5600 IU) after an overnight fast and two hours before a meal, the mean area under the serum-concentration-time curve (AUC0-80 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3 levels) was 490.2 ng·hr/ml. The mean maximal serum concentration (Cmax) of vitamin D3 was 30.5 nmol/L or 12.2 ng/mL and the median time to maximal serum concentration (Tmax) was 10.6 hours. The bioavailability of the vitamin D3 in FOSAMAX PLUS (70 mg/2800 IU) and FOSAMAX PLUS (70 mg/5600 IU) is similar to an equal dose of vitamin D3 administered alone.
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%.
Fosamax Plus: Colecalciferol: 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.
Colecalciferol: Fosamax Plus: 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.
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.
Fosamax Plus: Colecalciferol: 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 (70 mg/2800 IU) is approximately 24 hours.
Special Populations and Conditions: Pediatrics (<18 years of age): Fosamax: The oral bioavailability in children (4 to 16 years of age) with osteogenesis imperfecta (OI) was similar to that observed in adults; however, FOSAMAX is not indicated for use in children (see Use in Children under PRECAUTIONS).
Fosamax Plus: Alendronate pharmacokinetics have not been investigated in patients <18 years of age.
Geriatrics (≥65 years of age): Alendronate Sodium: Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly (≥65 years of age) and younger patients. No dosage adjustment of alendronate is necessary (see DOSAGE & ADMINISTRATION).
Colecalciferol: Dietary requirements of vitamin D3 may be increased in the elderly.
Gender: Bioavailability and the fraction of an IV dose of alendronate excreted in urine were similar in men and women.
Race: Pharmacokinetic differences due to race have not been studied.
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.
Colecalciferol: Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.
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 0.58 to 1 mL/s [35 to 60 mL/min]). FOSAMAX/FOSAMAX PLUS is not recommended for patients with more severe renal insufficiency (creatinine clearance < 0.58 mL/s [<35 mL/min]) due to lack of experience.
