Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Merck Sharp & Dohme Limited Hertford Road, Hoddesdon Hertfordshire EN11 9BU UK
Fosamax is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. The bone formed during treatment with 'Fosamax' is of normal quality.
The effects of Fosamax on bone mass and fracture incidence in post-menopausal women were examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture Intervention Trial (FIT: n=6,459).
In the initial efficacy studies, the mean bone mineral density (BMD) increases with Fosamax 10 mg/day relative to placebo at three years were 8.8%, 5.9% and 7.8% at the spine, femoral neck and trochanter, respectively. Total body BMD also increased significantly. There was a 48% reduction in the proportion of patients treated with Fosamax experiencing one or more vertebral fractures relative to those treated with placebo. In the two-year extension of these studies BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body were maintained.
FIT consisted of two placebo-controlled studies: a three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture and a four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture, 37% of whom had osteoporosis as defined by a baseline femoral neck BMD at least 2.5 standard deviations below the mean for young, adult women. In all FIT patients with osteoporosis from both studies, Fosamax reduced the incidence of: ≥1 vertebral fracture by 48%, multiple vertebral fractures by 87%, ≥1 painful vertebral fracture by 45%, any painful fracture by 31% and hip fracture by 54%.
Overall these results demonstrate the consistent effect of Fosamax to reduce the incidence of fractures, including those of the spine and hip, which are the sites of osteoporotic fracture associated with the greatest morbidity.
The effects of Fosamax to prevent bone loss were examined in two studies of post-menopausal women aged ≤60 years. In the larger study of 1,609 women (≥6 months post-menopausal) those receiving Fosamax 5 mg daily for two years had BMD increases of 3.5%, 1.3%, 3.0% and 0.7% at the spine, femoral neck, trochanter and total body, respectively. In the smaller study (n=447), similar results were observed in women (6 to 36 months post-menopausal) treated with Fosamax 5 mg daily for three years. In contrast, in both studies, women receiving placebo lost bone mass at a rate of approximately 1% per year. The longer term effects of Fosamax in an osteoporosis prevention population are not known but clinical trial extensions of up to 10 years of continuous treatment are currently in progress.
The effects on BMD of treatment with Fosamax 10 mg once-daily and conjugated oestrogen (0.625 mg/day) either alone or in combination were assessed in a two-year study of hysterectomised, post-menopausal, osteoporotic women. At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either oestrogen or Fosamax alone (both 6.0%).
The effects on BMD when Fosamax was added to stable doses (for at least one year) of HRT (oestrogen ± progestin) were assessed in a one-year study in post-menopausal, osteoporotic women. The addition of Fosamax 10 mg once-daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
In these studies, significant increases or favourable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck and trochanter. No significant effect was seen for total body BMD.
The efficacy of Fosamax 10 mg once daily in men (ages 31 to 87; mean, 63) with osteoporosis was demonstrated in a two-year study. At two years, the mean increases relative to placebo in BMD in men receiving Fosamax 10 mg/day were: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Fosamax was effective regardless of age, race, gonadal function, baseline rate of bone turnover, or baseline BMD. Consistent with much larger studies in post-menopausal women, in these 127 men, 'Fosamax' 10 mg/day reduced the incidence of new vertebral fracture (assessed by quantitative radiography) relative to placebo (0.8% vs. 7.1%) and, correspondingly, also reduced height loss (-0.6 vs. -2.4 mm).
The efficacy of Fosamax 5 and 10 mg once-daily in men and women receiving at least 7.5 mg/day of prednisone (or equivalent) was demonstrated in two studies. At two years of treatment, spine BMD increased by 3.7% and 5.0% (relative to placebo) with Fosamax 5 and 10 mg/day respectively. Significant increases in BMD were also observed at the femoral neck, trochanter, and total body. In post-menopausal women not receiving oestrogen, greater increases in lumbar spine and trochanter BMD were seen in those receiving 10 mg Fosamax than those receiving 5 mg. Fosamax was effective regardless of dose or duration of glucocorticoid use. Data pooled from three dosage groups (5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) showed a significant reduction in the incidence of patients with a new vertebral fracture at two years (Fosamax 0.7% vs. placebo 6.8%).
Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.
Relative to an intravenous (IV) reference dose, the 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 standardised breakfast. Oral bioavailability in men (0.6%) was similar to that in women. Bioavailability was decreased similarly to an estimated 0.46% and 0.39% when alendronate was administered one hour or half an hour before a standardised 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 standardised 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 oral bioavailability of alendronate (a mean increase ranging from 20% to 44%).
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 litres in humans. Concentrations of drug in plasma following therapeutic oral doses are too low for analytical detection (<5 ng/ml). Protein binding in human plasma is approximately 78%.
There is no evidence that alendronate is metabolised in animals or humans.
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 faeces. 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 six hours following IV administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other drugs by those systems in humans.
Preclinical studies show that the drug 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 4.2 ‘Posology and method of administration’).
In test animal species the main target organs for toxicity were kidneys and gastro-intestinal tract. Renal toxicity was seen only at doses >2 mg/kg/day orally (ten times the recommended dose) and was evident only on histological examination as small widely scattered foci of nephritis, with no evidence of effect on renal function. The gastro-intestinal toxicity, seen in rodents only, occurred at doses >2.5 mg/kg/day and appears to be due to a direct effect on the mucosa. There is no additional relevant information.
Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3,256 mg/m²) and 966 mg/kg (2,898 mg/m²) (equivalent to human oral doses* of 27,600 and 48,300 mg), respectively. In males, these values were slightly higher, 626 and 1,280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4,000 mg/m²) (equivalent to a human oral dose* of 10,000 mg).
* Based on a patient weight of 50 kg.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
