Risedronate Sodium (risedronate sodium 75 mg) Dailymed

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice. 

Mutagenesis Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage. 

Impairment of Fertility In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time. 

Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m²). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

13.2 Animal Toxicology and/or Pharmacology

Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose.

In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose.

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that risedronate sodium tablets administered at the therapeutic dose is unlikely to induce osteomalacia.

Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m²).

14 Clinical Studies

14.1 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 BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low 25-hydroxyvitamin D₃ levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 international units/day.

Effect on Vertebral Fractures Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (that is, 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 3). 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 3 The Effect of Risedronate SodiumTablets on the Risk of Vertebral Fractures

	Proportion of Patients with Fracture (%) Calculated by Kaplan-Meier methodology.
VERT MN	PlaceboN = 678	Risedronate Sodium Tablets 5 mgN = 696	Absolute Risk Reduction(%)	Relative Risk Reduction(%)
New and Worsening
0 - 1 Year	7.2	3.9	3.3	49
0 - 2 Years	12.8	8.0	4.8	42
0 - 3 Years	18.5	13.9	4.6	33
New
0 - 1 Year	6.4	2.4	4.0	65
0 - 2 Years	11.7	5.8	5.9	55
0 - 3 Years	16.3	11.3	5.0	41
VERT MN	PlaceboN = 346	Risedronate Sodium Tablets 5 mgN = 344	Absolute Risk Reduction(%)	Relative Risk Reduction(%)
New and Worsening
0 - 1 Year	15.3	8.2	7.1	50
0 - 2 Years	28.3	13.9	14.4	56
0 - 3 Years	34.0	21.8	12.2	46
New
0 - 1 Year	13.3	5.6	7.7	61
0 - 2 Years	24.7	11.6	13.1	59
0 - 3 Years	29.0	18.1	10.9	49

Effect on Osteoporosis-Related Nonvertebral FracturesIn VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related nonvertebral fractures. Risedronate sodium tablets 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.

  

Effect on Bone Mineral Density The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that risedronate sodium tablets 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), risedronate sodium tablets 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.

Table 4 Mean Percent Increase in BMD from Baseline in Patients Taking Risedronate Sodium Tablets 5 mg or Placebo at Endpoint^a

	VERT MNb		VERT NAb		BMD MNc		BMD NAc
	PlaceboN = 323	5 mgN = 323	PlaceboN = 599	5 mgN = 606	PlaceboN = 161	5 mgN = 148	PlaceboN = 191	5 mgN = 193
Lumbar Spine	1.0	6.6	0.8	5.0	0.0	4.0	0.2	4.8
Femoral Neck	-1.4	1.6	-1.0	1.4	-1.1	1.3	0.1	2.4
Femoral Trochanter	-1.9	3.9	-0.5	3.0	-0.6	2.5	1.3	4.0
Midshaft Radius	-1.5*	0.2*	-1.2*	0.1*	ND		ND

<sup>a The endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last post-baseline BMD value prior to the study's last time point is used. b The duration of the studies was 3 years. c The duration of the studies was 1.5 to 2 years. * BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, N = 222; 5 mg, N = 214) and VERT NA (placebo, N = 310; 5 mg, N = 306). ND = analysis not done

Risedronate sodium tablets 35 mg once-a-week (N = 485) was shown to be non-inferior to risedronate sodium tablets 5 mg daily (N = 480) in a 1-year, double-blind, multicenter 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% confidence interval [CI]) in the 5 mg daily group (N = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg once-a-week group (N = 387) and the mean difference between 5 mg daily and 35 mg once-a-week was 0.1% (-0.4, 0.6; 95% CI). 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. 

In a double-blind, multicenter study of postmenopausal women with osteoporosis, treatment with risedronate sodium tablets 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to risedronate sodium tablets 5 mg daily (N = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.6% (3.3, 3.9; 95% CI) in the 5 mg daily group (N = 527) and 3.4% (3.1, 3.7; 95% CI) in the 75 mg two days per month group (N = 524) with a mean difference between groups being 0.2% (-0.2, 0.6; 95% CI). 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. 

Risedronate sodium tablets 150 mg once-a-month (N = 650) was shown to be non-inferior to risedronate sodium tablets 5 mg daily (N = 642) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. The primary efficacy analysis was conducted in all randomized patients with baseline and post-baseline lumbar spine BMD values (modified intent-to-treat population) using last observation carried forward. The mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3.0, 3.8; 95% CI) in the 5 mg daily group (N = 561), and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once-a-month group (N = 578) with a mean difference between groups being -0.1% (-0.5, 0.3; 95% CI). The results of the completers analysis were consistent with the primary efficacy analysis. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. 

Histology/Histomorphometry Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily  risedronate sodium tablets (2.5 mg or 5 mg) for 2 to 3 years. Histologic evaluation (N = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in risedronate sodium-treated women. These findings demonstrate that bone formed during risedronate sodium tablets administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 21 treated with placebo and 23 patients treated with  risedronate sodium tablets 5 mg. Mineralizing surface decreased moderately in risedronate sodium-treated patients (median percent change: placebo, -21%;  risedronate sodium tablets 5 mg, -74%), consistent with the known effects of treatment on bone turnover.

Effect on Height In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both risedronate sodium and placebo-treated groups lost height during the studies. Patients who received risedronate sodium tablets had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -2.4 mm/yr in the placebo group compared to -1.3 mm/yr in the  risedronate sodium tablets 5 mg daily group. In VERT NA, the median annual height change was -1.1 mm/yr in the placebo group compared to -0.7 mm/yr in the  risedronate sodium tablets 5 mg daily group.</sup>

14.2 Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of  risedronate sodium tablets 5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a 2-year, double-blind, placebo-controlled study of 383 postmenopausal women (age range 42 to 63 years) within three years of menopause (risedronate sodium tablets 5 mg, N = 129). All patients in this study received supplemental calcium 1000 mg/day. Increases in BMD were observed as early as 3 months following initiation of  risedronate sodium tablets treatment.  Risedronate sodium tablets 5 mg daily produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2).  Risedronate sodium tablets 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both risedronate sodium and placebo-treated women following 1 year of treatment.



 

The safety and effectiveness of  risedronate sodium tablets 35 mg once-a-week for the prevention postmenopausal osteoporosis were demonstrated in a 1-year, double-blind, placebo-controlled study of 278 patients ( risedronate sodium tablets 35 mg, N = 136). All patients were supplemented with 1000 mg elemental calcium and 400 international units vitamin D per day. The primary efficacy measure was the percent change in lumbar spine BMD from baseline after 1 year of treatment using LOCF (last observation carried forward).  Risedronate sodium tablets 35 mg once-a-week resulted in a statistically significant mean difference from placebo in lumbar spine BMD of +2.9% (least square mean for placebo -1.05%; risedronate +1.83%).  Risedronate sodium tablets 35 mg once-a-week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of +1.5% (placebo -0.53%; risedronate +1.01%), femoral neck of +1.2% (placebo -1.00%; risedronate +0.22%), and trochanter of +1.8% (placebo -0.74%; risedronate +1.07%).

Combined Administration with Hormone Replacement Therapy The effects of combining  risedronate sodium tablets 5 mg daily with conjugated estrogen 0.625 mg daily (N = 263) were compared to the effects of conjugated estrogen alone (N = 261) in a 1-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 5. 

Table 5 Percent Change from Baseline in BMD After 1 Year of Treatment

	Estrogen 0.625 mgN = 261	Risedronate sodium tablets 5 mg +Estrogen 0.625 mgN = 263
Values shown are mean (±SEM) percent change from baseline.
Lumbar Spine	4.6 ± 0.20	5.2 ± 0.23
Femoral Neck	1.8 ± 0.25	2.7 ± 0.25
Femoral Trochanter	3.2 ± 0.28	3.7 ± 0.25
Midshaft Radius	0.4 ± 0.14	0.7 ± 0.17
Distal Radius	1.7 ± 0.24	1.6 ± 0.28

Histology/Histomorphometry Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received  risedronate sodium tablets 5 mg plus estrogen or estrogen-alone once daily for 1 year. Histologic evaluation (N = 47) demonstrated that the bone of patients treated with risedronate sodium tablets plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with risedronate sodium tablets plus estrogen and 12 treated with estrogen-alone. Mineralizing surface decreased in both treatment groups (median percent change: risedronate sodium tablets plus estrogen, -79%; estrogen-alone, -50%), consistent with the known effects of these agents on bone turnover.

14.3 Men with Osteoporosis

The effects of  risedronate sodium tablets 35 mg once-a-week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (Risedronate Sodium Tablets, N = 192). The patients had a mean age of 61 years (range 36 to 84 years) and 95% were Caucasian. At baseline, mean lumbar spine T-score was -3.2 and mean femoral neck T-score was -2.4. All patients in the study had either, 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or 2) a BMD T-score less than or equal to -1 at the femoral neck and less than or equal to -2.5 at the lumbar spine. All patients were supplemented with calcium 1000 mg/day and vitamin D 400 to 500 international units/day.  Risedronate sodium tablets 35 mg once-a-week produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter, and total hip compared to placebo after 2 years of treatment (treatment difference: lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total proximal femur, 1.5%).

14.4 Glucocorticoid-Induced Osteoporosis

Bone Mineral Density

Two 1-year, double-blind, placebo-controlled trials in patients who were taking greater than or equal to 7.5 mg/day of prednisone or equivalent demonstrated that risedronate sodium tablets 5 mg daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing  glucocorticoid therapy. The efficacy of risedronate sodium tablets therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.

The prevention study enrolled 228 patients (risedronate sodium tablets 5 mg, N = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T-score - 0.7). All patients in this study received supplemental calcium 500 mg/day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the risedronate sodium tablets 5 mg group. At each skeletal site there were statistically significant differences between the placebo group and the risedronate sodium tablets 5 mg group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the risedronate sodium tablets 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and risedronate sodium tablets 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. Risedronate sodium was effective at the lumbar spine, femoral neck, and trochanter regardless of age (less than 65 vs. greater than or equal to 65), gender, prior and concomitant glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

The treatment study of similar design enrolled 290 patients (risedronate sodium tablets 5 mg, N = 100) (19 to 85 years of age) with continuing, long-term (greater than or equal to 6 months) use of glucocorticoids (mean duration of use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.63 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400 international units/day.

After 1 year of treatment, the BMD of the placebo group was within 1% of baseline levels at the lumbar spine, femoral neck, and trochanter. Risedronate sodium tablets 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between risedronate sodium tablets and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. Risedronate sodium tablets were similarly effective on lumbar spine BMD regardless of age (less than 65 vs. greater than or equal to 65), gender, or pre-study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

Figure 3 Change in BMD from Baseline Patients Recently Initiating Glucocorticoid Therapy



Figure 4 Change in BMD from Baseline Patients on Long-Term Glucocorticoid Therapy



Vertebral Fractures

In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at 1 year was reduced from 17% in the placebo group to 6% in the risedronate sodium tablets group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the risedronate sodium tablets group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (that is, clinical fractures).

Figure 5 Incidence of Vertebral Fractures in Patients Initiating or Continuing Glucocorticoid Therapy



Histology/Histomorphometry

Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received placebo or daily risedronate sodium tablets (2.5 mg or 5 mg) for 1 year. Histologic evaluation (N = 33) showed that bone formed during treatment with risedronate sodium tablets was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 10 patients treated with risedronate sodium tablets 5 mg. Mineralizing surface decreased 24% (median percent change) in these patients. Only a small number of placebo-treated patients had both baseline and post-treatment biopsy samples, precluding a meaningful quantitative assessment.

14.5 Treatment of Paget's Disease

The efficacy of risedronate sodium tablets was demonstrated in 2 clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget’s disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with risedronate sodium tablets 30 mg daily for 2 months or Didronel (etidronate disodium) 400 mg daily for 6 months. At Day 180, 77% (43/56) of risedronate sodium-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel (p less than 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of risedronate sodium-treated patients and 14% (4/29) of Didronel-treated patients with available data remained in biochemical remission.

During the first 180 days of the active-controlled study, 85% (51/60) of risedronate sodium -treated patients demonstrated a greater than or equal to 75% reduction from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint of the normal range) with 2 months of treatment compared to 20% (12/60) in the Didronel-treated group with 6 months of treatment (p less than 0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 6) were significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only a 6% reduction seen with Didronel treatment at the same time point (p less than 0.01).

Figure 6 Mean Percent Change from Baseline in Serum Alkaline Phosphatase Excess by Visit

 

Response to risedronate sodium therapy was similar in patients with mild to very severe Paget’s disease. Table 6 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.

Table 6 Mean Percent Reduction from Baseline at Day 180 in Total Serum Alkaline Phosphatase Excess by Disease Severity

	Risedronate Sodium Tablets 30 mg			Didronel 400 mg
Subgroup:Baseline DiseaseSeverity (AP)	n	Baseline SerumAP (U/L)Values shown are mean ± SEM; ULN = upper limit of normal.	Mean % Reduction	n	BaselineSerumAP (U/L)	Mean % Reduction
greater than 2, less than 3x ULN	32	271.6 ± 5.3	-88.1	22	277.9 ± 7.45	-44.6
greater than or equal to 3, less than 7x ULN	14	475.3 ± 28.8	-87.5	25	480.5 ± 26.44	-35.0
greater than or equal to 7x ULN	8	1336.5 ± 134.19	-81.8	6	1331.5 ± 167.58	-47.2

Response to risedronate sodium therapy was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, 4 patients previously non-responsive to 1 or more courses of anti-pagetic therapy (calcitonin, Didronel) responded to treatment with risedronate sodium tablets 30 mg daily (defined by at least a 30% change from baseline). Each of these patients achieved at least 90% reduction from baseline in serum alkaline phosphatase excess, with 3 patients achieving normalization of serum alkaline phosphatase levels.

Histomorphometry of the bone was studied in 14 patients with bone biopsies: 9 patients had biopsies from pagetic bone lesions and 5 patients from non-pagetic bone. Bone biopsy results in non-pagetic bone did not reveal osteomalacia, impairment of bone remodeling, or induction of a significant decline in bone turnover in patients treated with risedronate sodium tablets.

See FDA-Approved patient labeling (Medication Guide)

Instruct patients to read the Medication Guide before starting therapy with risedronate sodium tablets and to re-read it each time the prescription is renewed.

Instruct patients that Atelvia and risedronate sodium tablets contain the same active ingredient and if they are taking Atelvia, they should not take risedronate sodium tablets [see Warnings and Precautions (5.1)].

Instruct patients to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, risedronate sodium tablets should be taken at least 30 minutes before the first food or drink of the day other than water.

Instruct patients to take risedronate sodium tablets while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 ounces) to facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation.

Instruct patients not to lie down for 30 minutes after taking the medication [see Warnings and Precautions (5.1)].

Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal irritation.

Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing risedronate sodium tablets. 

Instruct patients about missing risedronate sodium tablets doses as follows: 

• If a dose of risedronate sodium tablets 35 mg once-a–week is missed, they should take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-week, as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.
• If one or both tablets of  risedronate sodium tablets 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away, the patient should be instructed as follows:
  • If both tablets are missed, take one risedronate sodium 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning.
  • If only one risedronate sodium 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered.
  • Patients should then return to taking their  risedronate sodium tablets 75 mg on two consecutive days per month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days.

• 
  If one or both tablets of  risedronate sodium tablets 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days, patients should wait until their next month’s scheduled doses and then continue taking  risedronate sodium tablets 75 mg on two consecutive days per month as originally scheduled.
  

• 
  If the dose of risedronate sodium tablets 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away, the patient should be instructed to take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their risedronate sodium tablets 150 mg once-a-month as originally scheduled. Patients should not take more than one 150 mg tablet within 7 days.
  

• 
  If the dose of risedronate sodium tablets 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days, patients should wait until their next month’s scheduled dose and then continue taking risedronate sodium tablets 150 mg once-a-month as originally scheduled.
  

Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.3)]. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist.

Instruct patients to take calcium supplements or calcium-, aluminum-, and magnesium-containing medications at a different time of the day than risedronate sodium tablets as these medications may interfere with the absorption of risedronate sodium tablets. 

Remind patients to give all of their healthcare providers an accurate medication history. Instruct patients to tell all of their healthcare providers that they are taking risedronate sodium tablets. Patients should be instructed that any time they have a medical problem they think may be from risedronate sodium tablets, they should talk to their doctor.

All registered trademarks in this document are the property of their respective owners.

APOTEX INC.

Risedronate Sodium Tablets, USP

35 mg, 75 mg, 150 mg

Manufactured by:	Manufactured for:
Apotex Inc.	Apotex Corp.
Toronto, ON	Weston, Florida
Canada M9L 1T9	33326, USA

Revised: January 2020

Revision: 12