Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Aristo Pharma GmbH, Wallenroder Straße 8–10, 13435 Berlin, Germany
Pharmaco-therapeutic group: Drugs affecting bone structure and mineralization, Bisphosphonates
ATC Code: M05BA07
Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation is preserved.
In the clinical programme Risedronate sodium was studied in patients with Paget’s disease. After treatment with Risedronate sodium 30 mg/day for 2 months the following was seen:
The observed response was similar in pagetic patients regardless of whether they had previously received other treatments for Paget’s disease, or the severity of the disease.
53% of patients followed for 18 months after initiation of a single 2 month course of Risedronate sodium remained in biochemical remission.
In a trial comparing before-breakfast dosing and dosing at other times of the day in women with postmenopausal osteoporosis, lumbar spine BMD gains were statistically higher with before-breakfast dosing.
The safety and efficacy of risedronate sodium has been investigated in a 3 year study (a randomized, double-blind, placebocontrolled, multicenter, parallel group study of one-year duration followed by 2 years of open-label treatment) in paediatric patients aged 4 to less than 16 years with mild to moderate osteogenesis imperfecta. In this study, patients weighing 10-30 kg received risedronate 2.5 mg daily and patients weighing more than 30 kg received risedronate 5 mg daily.
After completion of its one-year randomized, double-blind, placebo controlled phase, a statistically significant increase in lumbar spine BMD in the risedronate group versus placebo group was demonstrated ; however an increased number of patients with at least 1 new morphometric (identified by x-ray) vertebral fracture was found in the risedronate group compared to placebo. During the one year double blind period, the percentage of patients who reported clinical fractures was 30.9% in the risedronate group and 49.0% in the placebo group.
In the open label period when all patients received risedronate(month 12 to month 36), clinical fractures were reported by 65.3% of patients initially randomized to the placebo group and by 52.9% of patients initially randomized to the risedronate group. Overall, results are insufficient to support the use of risedronate sodium in paediatric patients with mild to moderate osteogenesis imperfecta.
Absorption after an oral dose is relatively rapid (tmax ~1 hour) and is independent of dose over the range studied (2.5 to 30 mg). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women.
The mean steady state volume of distribution is 6.3 l/kg in humans. Plasma protein binding is about 24%.
There is no evidence of systemic metabolism of risedronate sodium.
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine after 28 days. Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with the difference probably attributed to clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance.
Unabsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration the concentration-time profile shows three elimination phases with a terminal half-life of 480 hours.
No dosage adjustment is necessary.
In toxicological studies in rat and dog dose dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in longer term studies in rodents, although the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2mg/kg/day in rat and 10mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Studies on genotoxicity and carcinogenesis did not show any particular risks for humans.
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