Risedronate is a potent pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. Risedronate is a third generation bisphosphonate. In preclinical studies risedronate demonstrated potent anti-osteoclast and anti-resorptive activity, increasing bone mass and biomechanical strength dose-dependently. The activity of risedronate was confirmed by bone marker measurements during pharmacodynamic and clinical studies. With risedronate 5 mg daily, decreases in biochemical markers of bone turnover were observed within 1 month of treatment and reached a maximum decrease in 3-6 months, remaining stable during the course of therapy. This data demonstrates that risedronate causes a moderate reduction in bone resorption and bone turnover. The new steady state approximates the rate of bone turnover seen in pre-menopausal women. Decreases in biochemical markers of bone turnover were similar with risedronate 35 mg Once-a-Week and risedronate 5 mg daily.
In a study in men with osteoporosis, decreases in biochemical markers of bone turnover were observed at the earliest time point of 3 months and continued to be observed at 24 months.
Comparison of 5 mg daily dose and 150 mg Once-a-Month: Based on effects on mean percent change in lumbar spine BMD, risedronate sodium 150 mg (n = 561) once a month was shown to be equivalent to risedronate sodium 5 mg (n = 561) daily in a one-year, double-blind, multicentre study of postmenopausal women with osteoporosis. Both groups had statistically significant mean percent increases in lumbar spine BMD from baseline to Month 6, 12 and endpoint. The two treatment groups were also similar with regard to BMD increases at the total proximal femur and trochanter.
Comparison of 5mg daily dose and 35mg once-a-week dose: Based on a lumbar spine BMD (bone mineral density), Actonel Once-a-Week 35mg (n=485) was shown to be therapeutically equivalent to Actonel 5mg daily (n=480) in a one-year, double blind multicentre study of postmenopausal women with osteoporosis. The two treatment groups were also similar at one year with regard to BMD increases at the total proximal femur, femoral neck and trochanter.
Clinical Studies: Actonel Once-a-Month:
Treatment Osteoporosis: The clinical program involved a wide range of early and late postmenopausal women with and without fracture, including those with a history of GI disease and those using aspirin, NSAIDs, proton pump inhibitors and H2
The fracture efficacy of Actonel 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in two large, randomised, placebo-controlled, double-blind studies which enrolled a total of almost 4000 women under similar protocols. The multinational study (RVE) was conducted primarily in Europe and Australia; a second study was conducted in North America (RVN). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in the multinational study, and 2.5 in the North American study, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels also received supplemental vitamin D 500 IU/day. The number of evaluable patients treated were: RVN -5 mg risedronate n = 696; placebo n = 678; RVE-5 mg risedronate n = 344; placebo n = 346; RVN and RVE: n = 1040; placebo n = 1024.
Effect on Vertebral Fracture: The pivotal studies of Actonel in the treatment of postmenopausal osteoporosis clearly demonstrate that Actonel 5 mg daily reduces vertebral fracture incidence in patients with low bone mass and vertebral fractures, regardless of age, years since menopause, or disease severity at baseline. Actonel 5 mg daily significantly reduced the risk of new vertebral fractures in each of the two large treatment studies. In the multinational study, treatment with Actonel 5 mg daily for 3 years significantly reduced the risk of new vertebral fractures by 49% compared to treatment with placebo (p < 0.001) (Figure 1). A similar, significant reduction of 41% was seen in the North American study (p = 0.003). The effect of Actonel 5 mg daily on vertebral fracture incidence was seen as early as the end of the first year of treatment in each study. In the multinational study, the incidence of new vertebral fractures after 1 year was reduced from 13.3 to 5.6%, an absolute risk reduction of 8% and a relative risk reduction of 61% (p< 0.001). In the North American study, the incidence of new vertebral fractures after 1 year was reduced from 6.4 to 2.4%, an absolute risk reduction of 4% and a relative risk reduction of 65% (p< 0.001). At both 1 and 3 years, 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. Treatment with Actonel 5 mg daily also significantly reduced the proportion of patients experiencing new and worsening vertebral fractures in each of the studies. (See Figure 1.)
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Effect on Non-Vertebral Fractures: In a prospectively-planned analysis of pooled data from the multinational and North American studies, Actonel 5 mg daily significantly reduced the cumulative incidence of patients experiencing osteoporosis-related non-vertebral fractures (wrist, humerus, clavicle, pelvis, hip, and leg) over 3 years by 36% (p = 0.005). (See Figure 2.)
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The incidence of non-vertebral fractures in the pooled analysis (RVN and RYE) was lower in the 5 mg risedronate group than in the placebo group for all fractures at these sites combined, as well as for the wrist, humerus, pelvis, and leg separately. This difference was significant for all non-vertebral osteoporosis-related fractures (p=0.005), as well as for the humerus (p=0.024) and pelvis (p=0.044), while a trend was seen at the wrist (p=0.075) (Table 1).
These findings demonstrate a beneficial effect of risedronate in preventing non-vertebral, osteoporosis-related fractures. (See Table 1.)
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Effect on Height: In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. As shown in Figure 3, treatment with Actonel 5 mg daily was associated with a significant reduction of about 50% in the annual rate of height loss compared to treatment with placebo. (See Figure 3.)
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Effect on Bone Mineral Density: The results of four, large, randomised, placebo-controlled trials in women with postmenopausal osteoporosis demonstrate that Actonel 5 mg daily reverses the progression of disease, increasing BMD at the spine, hip, and wrist compared to the effects seen with placebo. In the large multinational vertebral fracture treatment study previously described, Actonel 5 mg daily produced increases in lumbar spine BMD which were progressive over at least 2 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points. The mean increase in BMD at the lumbar spine was 5.9%, compared to placebo at the end of 3 years. In the North American fracture trial, similarly progressive and significant increases were seen; the mean increase was 4.3%, compared to placebo. Actonel 5 mg also produced significant mean increases in BMD at the hip (femoral neck and trochanter) in each trial, compared to losses in BMD in the placebo group. The increases compared to placebo were 3.1% at the femoral neck and 6.4% at the trochanter in the multinational study, and 2.8% and 3.9%, respectively, in the North American study. Significant mean increases in the BMD of the midshaft radius, a skeletal site high in cortical bone, were also observed in each study in patients receiving Actonel treatment. These findings indicate that Actonel treatment produces positive effects at all measured skeletal sites of clinical importance for osteoporotic fractures. Positive effects of Actonel treatment on BMD were also demonstrated in each of two large, randomised, placebo-controlled trials in which almost 1200 postmenopausal women were recruited on the basis of low lumbar spine bone mass (more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture. After 1.5 to 2 years, Actonel produced significant mean increases in BMD of the lumbar spine compared to placebo (5% and 4.1% in the two studies), femoral neck (2.8% and 2.3%), and trochanter (3.3% and 3.3%) in these women with low bone mass.
Histology/Histomorphometry: Histological evaluation of 278 bone biopsy samples from 204 postmenopausal women who received Actonel or placebo once daily for 2 to 3 years (including 74 pairs of biopsies, 43 from Actonel-treated patients) showed a moderate decrease in bone turnover in Actonel-treated women. Histological assessment showed no osteomalacia, impaired bone mineralisation, or other adverse effects on bone in Actonel-treated women. These findings demonstrate that the bone formed during Actonel administration is of normal quality.
Bone Markers: In clinical studies, dose-dependent decreases in biochemical markers of bone turnover were observed with Actonel 5 mg treatment. These effects were seen within 1 month of treatment and reached a plateau, with levels about 40% below baseline values, by the sixth month of treatment which remained stable during continuous treatment for up to 3 years. These data demonstrate that 5 mg Actonel causes a moderate reduction in bone resorption without over-suppression of bone formation. This new steady-state approximates the rate of bone turnover seen in pre-menopausal women.
Combined Administration with Hormone Replacement Therapy: The effects of combining Actonel 5 mg daily with conjugated oestrogen treatment (0.625 mg daily) were compared to the effects of conjugated oestrogen alone in a 1-year, randomised, double-blind study in more than 500 postmenopausal women (mean lumbar spine BMD 1.3 SD below the pre-menopausal mean). Actonel 5 mg daily in postmenopausal women taking oestrogen produced significant mean increases from baseline in BMD of the femoral neck (2.7%) and the midshaft radius (0.7%) at 12 months. These increases were greater than the increases observed in the oestrogen alone group, and reached statistical significance in favour of the combined treatment at the femoral neck and midshaft radius.
Consistent with the changes in BM D, the reduction in bone turnover was significantly greater in the combined Actonel plus oestrogen group compared to the oestrogen alone group (40% to 47% versus 35% to 40%) and remained within the pre-menopausal range. Histologic evaluation of 93 bone biopsy samples from 61 women on oestrogen therapy who received either placebo or Actonel once daily for 1 year (including 32 pairs of biopsies, 16 from Actonel treated patients) found decreases in bone turnover in the Actonel treated patients that were consistent with the changes in bone turnover markers. Bone histology demonstrated that the bone of patients treated with Actonel plus oestrogen was of normal lamellar structure and normal mineralisation.
Endoscopic findings: Actonel Endoscopic findings from patients with moderate to severe GI complaints in both Actonel and control patients showed no evidence of treatment related gastric, duodenal or oesophageal ulcers. Duodenitis was rarely observed in the Actonel group. Four out of five patients with endoscopically-diagnosed oesophageal strictures had been taking risedronate 5 mg for more than 6 months.
35 mg Once-a-Week Dose: Actonel 35 mg Once-a-Week (n = 485) was shown to be therapeutically equivalent to Actonel 5 mg daily (n = 480) in a 1-year double-blind multicentre study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7,4.3; 95% Cl) in the 5 mg group (n = 391) and 3.9% (3.6,4.3; 95% Cl) in the 35 mg group (n = 387) and the mean difference between 5 mg daily and 35 mg Once-a-Week was 0.1% (-0.42, 0.55; 95% Cl) (see Table 2). While once a week doses of Actonel resulted in slightly smaller increases in lumbar spine BMD compared to daily doses of 5 mg after 6 months, the two regimens are equivalent after 12 months. The clinical relevance of these 6-month BMD differences is unknown. The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. This study is of 2 years' duration, the results of which will be included as soon as they are available. (See Table 2.)
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Very few patients in any treatment group had new fractured vertebrae at Month 12 (5 mg daily: 1.5%; 35 mg Once-a-Week: 1.3%). No patient had more than one new fractured vertebra. There were no statistically significant differences in the percentage of patients with new vertebral fractures among the 2 treatment groups.
150 mg Once-a-Month: Dose In a double-blind, active-controlled, multicenter study of postmenopausal women with osteoporosis, 1 year of treatment with Actonel 150 mg Once-a-Month (n = 650) was shown to be non-inferior to Actonel 5 mg daily (n =642). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3.0, 3.8; 95% Cl) in the 5 mg daily group (n = 561) and 3.5% (3.1, 3.9; 95% Cl) in the 150 mg Once-a-Month group (n = 561) with a mean difference between groups being-0.1% (-0.5, 02; 95% Cl). The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. The numbers of patients with new vertebral fractures at Month 12 and Endpoint were similar in the 150 mg Once-a-Month group and the 5 mg daily group (at Endpoint, 150 mg 1.4%; 5 mg daily 1.4%).
35mg Once-a-Week Dose Actonel Once-a-Week 35mg (n=485) was shown to be therapeutically non-inferior to Actonel 5mg daily (n=480) in a 2-year double-blind multicentre study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7,4.3; 95% Cl) in the 5mg group (n=391) and 3.9% (3.6,4.3; 95% Cl) in the 35mg group (n= 387) and the mean difference between 5mg daily and 35mg Once-a-Week 0.1 % (-0.42, 0.55; 95% Cl) (see Table 3). The weekly regimen was non inferior to the daily regimen at Month 12, the primary analysis. The month 6 and 24 analyses were consistent with the primary analysis. The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers.
The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. (See Table 3.)
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Very few patients in any treatment group had new fractured vertebrae at Month 24 (5mg daily: 3.3%; 35mg Once-a-Week: 1.4%). No patient had more than one new fractured vertebra. There were no statistically significant differences in the percentage of patients with new vertebral fractures among the 2 treatment groups.
Treatment of Osteoporosis in Men: Risedronate sodium 35mg once a week demonstrated efficacy in men with osteoporosis (age range 36 to 84 years) in a 2-year, double-blind, placebocontrolled study in 284 patients risedronate sodium 35mg n = 191). All patients received supplemental calcium and vitamin D.
Increases in BMD were observed as early as 6 months following initiation of risedronate sodium treatment. Risedronate sodium 35mg once a week produced mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo after 2 years of treatment. Antifracture efficacy was not demonstrated in this study.
The bone effect (BMD increase and BTM (bone turnover markers) decrease) of risedronate sodium is similar in males and females.
Risedronate is relatively rapidly absorbed (tmax=1 hour) throughout the upper gastrointestinal (GI) tract. Absorption is independent of dose over the range studied (single dose study, 2.5 to 30 mg; multiple dose studies, 2.5 to 5 mg daily and up to 150 mg monthly). In a 13-week pharmacokinetic study with 5 mg daily and 35 mg weekly and 50 mg weekly dosing (N~19/group), a comparison of the average serum concentration (Cavg
) for 35 mg/week and 5 mg/day was not statistically significantly different. The 95% confidence interval for Cavg
was 57.1-101.2, with a point estimate of 76.0% for the 35 mg dose compared to the 5 mg dose. Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate is administered with food. Bioavailability was similar in men and women. Although administration of risedronate either 30 minutes prior to breakfast or 2 hours after dinner reduces absorption of risedronate by 55% compared to administration in the fasting state (ie., no food or beverages for 10 hours prior to, or 4 hours after, dosing), and administration one hour prior to breakfast reduces absorption by 30%, Actonel has been shown to be effective in clinical trials when administered 30 minutes (or longer) before the first meal or beverage of the day (eg., breakfast) and also when administered 2 hours (or longer) prior to and following food or beverages at other times of the day.
The mean steady state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of risedronate is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14
C] risedronate indicate that 40-45% of the dose was distributed in the bone after 72 hours. At the same time, risedronate levels in soft tissues of rats and dogs were at least 40 and 16 times lower than those in bone respectively. The remainder of the dose was mainly excreted in the urine. This is likely to be considerably lower in humans who excrete 65% of an intravenously administered dose in the urine in 24 hours. After multiple oral dosing 1in rats, accumulation of risedronate was observed in bone but not in soft tissues.
There is no evidence of systemic metabolism of risedronate.
Approximately half the absorbed dose is excreted in the urine within 24 hours. 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min and mean total clearance is 122 mL/min. The difference primarily reflects non-renal 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. In the same pharmacokinetic study previously mentioned in the "Absorption", the percent of dose excreted in urine was measured. The point estimate for the 35 mg versus 5 mg doses was 66.8% (95%CI, 48.0-95.8). Although this was statistically significantly different, the clinical relevance is unknown. Unabsorbed risedronate is eliminated unchanged in the faeces. Following absorption, 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. Although the elimination rate from human bone is unknown, the 480 hour half-life is hypothesised to represent the dissociation of Actonel from the surface of the bone.
Paediatric: Safety and efficacy of risedronate have not been established in patients under 18 years of age.
Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.
Geriatric: Risedronate pharmacokinetics are similar in older subjects (age 45 to 76 years) with normal renal function (creatinine clearance 80 to 120 mL/min) to that observed in young subjects (age 18 to 45 years). No dosage adjustment is necessary (see Dosage & Administration).
Ethnicity: Pharmacokinetic differences due to ethnicity have not been studied.
Renal Insufficiency: Risedronate is excreted intact primarily via the kidney. There is limited clinical data in patients with severe renal impairment (creatinine clearance <30 mL/min) and therefore Actonel is not recommended for this patient group.
No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min.
Hepatic Insufficiency: No studies have been performed to assess the safety or efficacy of Actonel in patients with hepatic impairment. Risedronate is not metabolised in rat, dog, and human liver preparations. Insignificant amounts(< 0.1% of intravenous dose) of risedronate are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.