ACTONEL-35 ( Risedronate-35)
Contents : RISEDRONATE SODIUM-35
Packing : 4
Generic Name: Risedronate sodium
Dosage Form: tablets
Risedronate sodium tablets are a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Risedronate sodium tablet for oral administration contains the equivalent of 5, 30, or 35 mg of anhydrous Risedronate sodium in the form of the monohydrate. The chemical name of Risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of Risedronate sodium monohydrate is the following:
C7H10NO7P2 Na·H2O M.W. Monohydrate: 323.10
Risedronate sodium monohydrate is a white to off-white powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.
Colloidal silicon dioxide, D&C yellow #10 lake (5 mg tablets only), FD&C yellow #6 aluminum lake (35 mg tablets only), hypromellose, iron oxide red (35 mg tablets only), iron oxide yellow (5 and 35 mg tablets only), lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium stearyl fumarate, starch, and titanium dioxide.
Risedronate – Clinical Pharmacology
Mechanism of Action
Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Risedronate treatment reduces bone turnover (activation frequency, i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.
Absorption after an oral dose is relatively rapid (tmax ~1 hour) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 to 30 mg; multiple dose, from 2.5 to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Risedronate is effective when administered at least 30 minutes before breakfast.
The mean steady-state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] Risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of Risedronate in soft tissues was in the range of 0.001% to 0.01%.
There is no evidence of systemic metabolism of Risedronate.
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV = 34%) and mean total clearance is 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or 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 drug is eliminated unchanged in feces. Once Risedronate is absorbed, the serum concentration-time profile is multi-phasic, with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. This terminal half-life is hypothesized to represent the dissociation of Risedronate from the surface of bone.
Risedronate pharmacokinetics have not been studied in patients < 18 years of age. Gender Bioavailability and pharmacokinetics following oral administration are similar in men and women. Geriatric Bioavailability and disposition are similar in elderly (> 60 years of age) and younger subjects. No dosage adjustment is necessary.
Pharmacokinetic differences due to race have not been studied.
Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of Risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥ 30 mL/min.
No studies have been performed to assess Risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (< 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment. Pharmacodynamics Treatment and Prevention of Osteoporosis in Postmenopausal Women Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. 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 men and women but is more common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50 year-old women will experience an osteoporosis-related fracture during their remaining lifetimes. After experiencing 1 osteoporosis-related fracture, the risk of future fracture increases 5 fold compared to the risk among a non-fractured population. Risedronate treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Risedronate to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1 year study comparing daily versus weekly oral dosing regimens of Risedronate for the treatment of osteoporosis in postmenopausal women, Risedronate sodium tablets 5 mg daily and Risedronate sodium tablets 35 mg once a week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the Risedronate sodium tablets 5 mg daily and Risedronate sodium tablets 35 mg once a week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Risedronate sodium tablets 5 mg daily, urinary collagen cross-linked N-telopeptide was decreased by 54% and serum bone-specific alkaline phosphatase was reduced by 36%. Risedronate is not an estrogen and does not have the benefits and risks of estrogen therapy. Glucocorticoid-Induced Osteoporosis Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs in both males and females of all ages. The relative risk of a hip fracture in patients on > 7.5 mg/day prednisone is more than doubled (RR = 2.27); the relative risk of vertebral fracture is increased 5 fold (RR = 5.18). Bone loss occurs most rapidly during the first 6 months of therapy with persistent but slowing bone loss for as long as glucocorticoid therapy continues. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Risedronate decreases bone resorption without directly inhibiting bone formation.
In two 1 year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, Risedronate sodium tablets 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy.
Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget’s disease range from no symptoms to severe bone pain, bone deformity, pathological fractures, and neurological disorders. Serum alkaline phosphatase, the most frequently used biochemical marker of disease activity, provides an objective measure of disease severity and response to therapy.
In pagetic patients treated with Risedronate sodium tablets 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption). Radiographic structural changes of bone lesions, especially improvement of a majority of lesions with an osteolytic front in weight-bearing bones, were also observed after Risedronate treatment. In addition, histomorphometric data provide further support that Risedronate can lead to a more normal bone structure in these patients.
Radiographs taken at baseline and after 6 months from patients treated with Risedronate sodium tablets 30 mg daily demonstrate that Risedronate decreases the extent of osteolysis in both the appendicular and axial skeleton. Osteolytic lesions in the lower extremities improved or were unchanged in 15/16 (94%) of assessed patients; 9/16 (56%) patients showed clear improvement in osteolytic lesions. No evidence of new fractures was observed.
Treatment of Osteoporosis in Postmenopausal Women
The fracture efficacy of Risedronate sodium tablets 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Risedronate sodium tablets 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Risedronate sodium tablets 5 mg, n = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline bone mineral density (BMD) levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.
Effect on Vertebral Fractures
Fractures of previously undeformed vertebrae (new fractures) and worsening of preexisting vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (i.e., clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient’s first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Risedronate sodium tablets 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 1). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.
Table 1: The Effect of Risedronate on the Risk of Vertebral Fractures a Calculated by Kaplan-Meier methodology.
VERT NA Proportion of Patients with Fracture (%)a Absolute Risk Reduction (%) Relative Risk Reduction (%)
Placebo n = 678 Risedronate Sodium Tablets 5 mg n = 696
New and Worsening
0 to 1 Year 7.2 3.9 3.3 49
0 to 2 Years 12.8 8.0 4.8 42
0 to 3 Years 18.5 13.9 4.6 33
0 to 1 Year 6.4 2.4 4.0 65
0 to 2 Years 11.7 5.8 5.9 55
0 to 3 Years 16.3 11.3 5.0 41
VERT MN Placebo n = 346 Risedronate Sodium Tablets 5 mg n = 344 Absolute Risk Reduction (%) Relative Risk Reduction (%)
New and Worsening
0 to 1 Year 15.3 8.2 7.1 50
0 to 2 Years 28.3 13.9 14.4 56
0 to 3 Years 34.0 21.8 12.2 46
0 to 1 Year 13.3 5.6 7.7 61
0 to 2 Years 24.7 11.6 13.1 59
0 to 3 Years 29.0 18.1 10.9 49