Actonel
Россия
  • Россия
  • Украина

Actonel - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Osteoporosis, Paget's Disease, Prevention of Osteoporosis
Class: Bisphosphonates
Form: Tablets
Ingredients: Risedronate Sodium, Crospovidone, Ferric Oxide (5, 35 & 75 Mg), Hydroxypropyl Cellulose, Hypromellose, Indigo Carmine (150 Mg), Lactose Monohydrate (5, 30 & 35 Mg), Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Silicon Dioxide And Titanium Dioxide, Edetate Disodium, Ferric Oxide Yellow, Magnesium Stearate, Methacrylic Acid Copolymer Dispersion, Polysorbate 80, Silicified Microcrystalline Cellulose, Simethicone, Sodium Starch Glycolate, Stearic Acid, Talc And Triethyl Citrate

Pharmaceutical information

Drug Substance

Proper Name: risedronate sodium hemi-pentahydrate
Chemical Name: Phosphonic acid, [1-hydroxy-2-(3-pyridinyl)ethylidene]bis-, monosodium salt.
Molecular Formula: C7H10NO7P2Na·2.5H2O
Structural Formula:



Molecular Weight: Anhydrous: 305.10
Hemi-pentahydrate: 350.13
Solubility: Risedronate sodium is soluble in pH 7.0 potassium phosphate dibasic solution, 0.1 N sodium hydroxide, and water; very slightly soluble in 0.1 N hydrochloric acid, practically insoluble in ethanol, and insoluble in isopropanol.
Solution pH: The pH of a 1.0% aqueous solution of risedronate sodium is 4.15.
Dissociation Constants: The five pKa values for risedronate sodium are as follows: pK1 = 1.6 ± 0.2, pK2 = 2.2 ± 0.2, pK3 = 5.9 ± 0.1, pK4 = 7.1 ± 0.1 and pK5 = 11.7 ± 0.3.
Description: Risedronate sodium is a fine white to off-white crystalline powder. Risedronate sodium is present in the form of hemi-pentahydrate with small amounts of monohydrate.

Clinical Trials

Treatment of Osteoporosis in Postmenopausal Women

Study Demographics and Trial Design

Table 1 Summary of Patient Demographics for Clinical Trials of ACTONEL or ACTONEL DR in the Treatment of Osteoporosis in Postmenopausal Women
Study
Number
Trial
Designa
Dosage Duration Patients
N = number
Age Range (Age Mean) Daily
Supplement**
Vitamin D
1
VERT-MN
R, PC, DB, MC, PG 2.5 mg/day
5 mg/day
Placebo
2 years
3 years
3 years
1226 48-85
(71.0)
≤500 IU
2
VERT-NA
R, PC, DB, MC, PG 2.5 mg/day
5 mg/day
Placebo
1 year
3 years
3 years
2458 28-85
(68.6)
≤500 IU
3 R, PC, DB, MC, PG 2.5 mg/day
5 mg/day
Placebo
2 years 543 45-80
(64.7)
-
4 R, PC, DB, MC, PG 2.5 mg/day
5 mg/day
Placebo
12 – 18 months 648 39-80
(62.5)
-
5 R, AC, DB, MC, PG 5 mg/day
35 mg/week*
50 mg/week*
12 months 1456 48-95
(67.9)
≤500 IU
6 R, AC, DB, MC, PG 5 mg/day
35 mg/week*†
24 months 922 50-87
(65.7)
800-1000 IU
7 R, AC, DB, MC, PG 5 mg/day
75 mg x 2 days/month*
12 months 1229 50-86
(64.6)
400-800 IU
8 R, AC, DB, MC, PG 5 mg/day
150 mg once/month*
13 months 1292 50-88
(64.9)
400-500 to
1000 IU
a R: randomized; AC: active-controlled; PC: placebo-controlled; DB: double-blind; MC: multicentre; PG: parallel-group
* Placebo other days of treatment. † 35 mg enteric-coated following breakfast and before breakfast.
** Patients in these studies were supplemented with 1000 mg elemental calcium/day

In Studies 1 and 2, 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 Study 1, and 2.5 in Study 2, with a broad range of baseline BMD levels. All fractures (symptomatic/painful/clinical vertebral fractures and asymptomatic/nonpainful/silent vertebral fractures) were systematically captured and measured by annual radiographs.

In Studies 3 to 5 postmenopausal women were recruited on the basis of low lumbar spine bone mass (i.e., more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture.

In Studies 5 to 8, patients had either lumbar spine bone mass more than 2.5 SD below the premenopausal mean, or lumbar spine bone mass more than 2.0 SD below, and a prevalent vertebral fracture.

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, NSAIDs or drugs usually used for the treatment of peptic ulcers were not specifically excluded from participating in the ACTONEL daily, weekly or monthly or ACTONEL DR weekly dosing osteoporosis studies.

Study Results

Results of Studies 1 and 2

The pivotal studies of ACTONEL (risedronate sodium) 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. When measured by annual radiographs, the effect of ACTONEL 5 mg daily on vertebral fracture incidence was seen at the first year of treatment in each study. In the North American study, treatment with ACTONEL 5 mg daily for 1 year significantly reduced the risk of new vertebral fractures by 65% compared to treatment with placebo (p < 0.001). In the Multinational study, a similar significant reduction of 61% was seen (p = 0.001). Treatment with ACTONEL 5 mg daily also significantly reduced the proportion of patients experiencing new and worsening vertebral fractures in each of the studies. Figures 1 and 2 below display the cumulative incidence of vertebral and nonvertebral fractures (i.e., hip, wrist, humerus, clavicle, pelvis and leg). In both figures, the cumulative incidence of these types of fractures is lower with ACTONEL compared with placebo at all time points, consistent with the positive effect of ACTONEL on bone strength.

Table 2 Effect of ACTONEL on Fracture, Height and Bone Mineral Density in the Treatment of Osteoporosis in Postmenopausal Women
Endpoints ACTONEL
5 mg
Placebo Mean
Difference
from
Placebo
Relative
Risk
Reduction
%
p-value
Study 1: VERT-MN
Cumulative incidence of new vertebral
fracture over 3 years (% of patients) 18.1 29.0 49 <0.001
Median annual height changea (mm/yr) -1.33 -2.4 0.003
Mean increase in BMD (%)
6 months Lumbar Spine 3.3 -0.1 3.4 <0.001
36 months Lumbar Spine 7.1 1.3 5.9 <0.001
Femoral Neck 2.0 -1.0 3.1 <0.001
Trochanter 5.1 -1.3 6.4 <0.001
36 months Midshaft Radius 0.5 -1.9 2.4 <0.001
Study 2: VERT-NA
Cumulative incidence of new vertebral
Fracture over 3 years (% of patients) 11.3 16.3 41 0.003
Median annual height changea (mm/yr) -0.67 -1.14 0.001
Mean increase in BMD (%)
6 months Lumbar Spine 2.7 0.4 2.2 <0.001
36 months Lumbar Spine 5.4 1.1 4.3 <0.001
Femoral Neck 1.6 -1.2 2.8 <0.001
Trochanter 3.3 -0.7 3.9 <0.001
36 months Midshaft Radius 0.2 -1.4 1.6 <0.001
Prospectively Combined Studies 1 and 2: VERT-MN and VERT-NA
Cumulative incidence of non-vertebral
fractureb over 3 years (% of patients) 7.1 11.0 36 0.005
a Measured by stadiometer
b Osteoporosis-related non-vertebral fractures (hip, wrist, humerus, clavicle, pelvis, and leg)

Figure 1 Cumulative New Vertebral Fracture Incidence in Postmenopausal Women with Osteoporosis



Figure 2 Cumulative Incidence of Osteoporosis-Related Non-vertebral Fractures Studies 1 and 2 Combined



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.

ACTONEL 5 mg daily produced increases in lumbar spine BMD which 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 (12, 18, 24 and 36 months).

Results of Studies 3 and 4

Table 3 Effect of ACTONEL on Bone Mineral Density in the Treatment of Osteoporosis in Postmenopausal Women
Endpoints ACTONEL 5 mg Daily
Mean Increase
in BMD
%
Placebo
Mean Increase
in BMD
%
Mean Difference
from Placebo
%
Study 3
6 months Lumbar Spine 3.3 0.4 2.8**
24 months Lumbar Spine 4.1 0.0 4.1**
Femoral Neck 1.3 -1.0 2.3*
Trochanter 2.7 -0.6 3.3**
Study 4
6 months Lumbar Spine 3.3 0.7 2.6**
18 months Lumbar Spine 5.2 0.3 5.0**
Femoral Neck 3.1 0.2 2.8**
Trochanter 4.8 1.4 3.3**
vs. placebo: *p<0.01; **p<0.001

In Studies 3 and 4, ACTONEL 5 mg daily produced significant mean increases in BMD of the lumbar spine compared to placebo at 6 months in women with low bone mass. Compared to placebo after 1.5 to 2 years, further significant mean increases in BMD were seen at the lumbar spine, femoral neck and trochanter.

The results of four large, randomized, placebo-controlled trials (Studies 1 to 4) in women with postmenopausal osteoporosis separately and together 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.

Results of Study 5

Table 4 Comparison of ACTONEL Once–a-Week vs. Daily Dosing in the Treatment of Osteoporosis in Postmenopausal Women – Primary Efficacy Analysis of Completers
Endpoints ACTONEL 5 mg
Daily
Mean Increase in BMD
%
(95% Confidence Interval)
ACTONEL 35 mg
Once-a-Week
Mean Increase in BMD
%
(95% Confidence Interval)
n = 391 n = 387
12 months Lumbar Spine 4.0
(3.7, 4.3)
3.9
(3.6, 4.3)

The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. There were also no statistically significant differences between the two treatment groups at 1 year in regards to BMD increases from baseline at other skeletal sites (total proximal femur, femoral neck and femoral trochanter). Based on these BMD outcomes, ACTONEL 35 mg Once-a-Week was concluded to be non-inferior to ACTONEL 5 mg daily.

In trials with ACTONEL 5 mg daily, changes in BMD of this magnitude were associated with a significant decrease in fracture incidence relative to placebo (see Table 2). This is further supported by the fact that within the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily, no statistically significant differences amongst these treatment groups were seen with respect to the number of patients with at least 1 new fractured vertebra at 1 year. ACTONEL 35 mg taken once a week is similar in safety and efficacy to ACTONEL 5 mg daily for the treatment of postmenopausal osteoporosis.

Results of Study 6

Table 5 Comparison of ACTONEL DR Weekly vs. ACTONEL Daily Dosing in the Treatment of Osteoporosis in Postmenopausal Women – Primary Efficacy Analysis*
Endpoints ACTONEL 5 mg
Daily
Mean Increase in BMD
%
(95% Confidence Interval)
ACTONEL DR 35 mg
Weekly following breakfast
Mean increase in BMD
%
(95% Confidence Interval)
n=307 n=307
12 months* Lumbar Spine 3.1**
(2.7, 3.5)
3.3**
(2.9, 3.7)
24 months† Lumbar Spine 4.1**
(3.7, 4.6)
5.2**
(4.7, 5.7)
*Last available observation on or prior to month 12,
†Last available observation on or prior to month 24
** Indicates a statistically significant difference from baseline determined from 95% CI unadjusted for multiple comparisons.

In a 2-year, double-blind, multicentre study of postmenopausal women with osteoporosis, ACTONEL DR 35 mg weekly was statistically shown to be non-inferior to ACTONEL 5 mg administered daily. At all time points, increases in BMD were statistically significant (p<0.05) compared to baseline for all sites measured.

At 1 year, ACTONEL DR 35 mg weekly was shown to be non-inferior to the ACTONEL 5 mg daily regimen for the primary efficacy variable of percent change from baseline of lumbar spine BMD. The two treatment groups were also similar with regard to percent change from baseline BMD at the total proximal femur, greater trochanter and femoral neck.

At 2 years, there were statistically significant greater increases (p<0.05; unadjusted for multiple comparisons) in mean percent change from baseline BMD at the total proximal femur for ACTONEL DR 35 mg weekly following breakfast (2.8) compared to ACTONEL 5 mg daily (2.2). This statistically significant difference at 2 years was also observed at the lumbar spine (see Table 10). The treatment groups were similar with regard to percent change from baseline BMD at the femoral neck.

At 2 years, a statistically significant greater (p<0.05) percentage of patients in the ACTONEL DR 35 mg weekly group (89%) were considered responders (i.e., change from baseline in lumbar spine >0%) compared to the ACTONEL 5 mg group (82%).

Results of Study 7

Table 6 Comparison of ACTONEL on Two Consecutive Days Per Month vs. Daily Dosing in the Treatment of Osteoporosis in Postmenopausal Women – Primary Efficacy Analysis*
Endpoints ACTONEL 5 mg
Daily
Mean Increase in BMD
%
(95% Confidence Interval)
ACTONEL 75 mg
Monthly Duet
Mean Increase in BMD
%
(95% Confidence Interval)
N = 527 n = 524
12 months Lumbar Spine 3.6
(3.3, 3.9)
3.4
(3.1, 3.7)
* The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy population analysis.

In the first year of a 2-year, double-blind, multicentre study of postmenopausal women with osteoporosis, ACTONEL 75 mg monthly duet, given on two consecutive days per month was shown to be non-inferior to ACTONEL 5 mg daily.

ACTONEL 75 mg on two consecutive days per month was statistically shown to be non-inferior to the ACTONEL 5 mg daily regimen for the primary efficacy variable of percent change from baseline to 1 year in lumbar spine BMD. The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The incidences of vertebral and non-vertebral fractures, reported as adverse events, were similar in the two treatment groups. ACTONEL 75 mg taken on two consecutive days per month is similar in safety and efficacy to ACTONEL 5 mg daily for the treatment of postmenopausal osteoporosis. The safety and efficacy of ACTONEL 75 mg, on two consecutive days per month, has not yet been assessed beyond one year of treatment.

Results of Study 8

Table 7 Comparison of ACTONEL Once-a-Month vs. Daily Dosing in the Treatment of Osteoporosis in Postmenopausal Women – Primary Efficacy Analysis
Endpoints ACTONEL 5 mg
Daily Mean Increase in BMD
%
(95% Confidence Interval)
ACTONEL 150 mg
Once-a-Month
Mean Increase in BMD
%
(95% Confidence Interval)
n = 561 n = 578
12 months (using LOCF*) Lumbar Spine 3.4
(3.0, 3.8)
3.5
(3.1, 3.9)
* LOCF: last observation carried forward

In the first year of a 2-year, double-blind, multicentre study of postmenopausal women with osteoporosis, ACTONEL 150 mg Once-a-Month was shown to be non-inferior to ACTONEL 5 mg daily. ACTONEL 150 mg Once-a-Month was statistically shown to be non-inferior to the ACTONEL 5 mg daily regimen for the primary efficacy variable of percent change from baseline to 1 year in increasing lumbar spine BMD. The two treatment groups were similar with regard to BMD increases at the lumbar spine, total proximal femur, femoral neck and femoral trochanter. The incidence of vertebral and non-vertebral fractures, reported as adverse events, was similar in the two treatment groups. ACTONEL 150 mg Once-a-Month is similar in safety and efficacy to ACTONEL 5 mg daily for the treatment of postmenopausal osteoporosis. The safety and efficacy of ACTONEL 150 mg Once-a-Month is currently being assessed beyond one year of treatment.

Histology/Histomorphometry

Histomorphometric evaluation of 278 bone biopsy samples from 204 postmenopausal women who received ACTONEL 5 mg or placebo once daily for 2 to 3 years (including 74 pairs of biopsies, 43 from ACTONEL-treated patients) showed a moderate and expected decrease in bone turnover in ACTONEL-treated women.

Histologic assessment showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in ACTONEL-treated women. These findings demonstrate that the bone formed during ACTONEL administration is of normal quality.

Prevention of Osteoporosis in Postmenopausal Women

Study Demographics and Trial Design

Table 8 Summary of Patient Demographics for Clinical Trials of ACTONEL in the Prevention of Osteoporosis in Postmenopausal Women
Study
Number
Trial
Design
Dosage Duration Patients
N = number
Age Range
(Age
Mean)
Daily Supplement
Elemental
Calcium
Vitamin D
9 R, PC,
DB, MC,
PG
2.5 mg/day
5 mg/day
2 years 383 42-63
(52.7)
1000 mg -
10 R, DB,
PC, MC,
PG
35 mg/week
Placebo
1 year 28 44-64
(53.6)
1000 mg 400 IU
R: randomized; PC: placebo-controlled; DB: double-blind; MC: multicentre; PG: parallel-group

Women in Study 9 were within 3 years of menopause and all patients in this study received supplemental calcium 1000 mg/day. Study 10 included women who were 0.5 to 5 years postmenopausal without osteoporosis. All patients were supplemented with 1000 mg elemental calcium and 400 IU vitamin D per day.

Results of Study 9

Table 9 Effect of ACTONEL 5 mg Daily on Bone Mineral Density in Postmenopausal Women without Osteoporosis
Endpoints ACTONEL 5 mg
Mean Increase in BMD
%
Placebo
Mean Increase in BMD
%
Mean Difference
from Placebo
%
24 months Lumbar Spine 2.0 -2.5 4.5*
Femoral Neck 1.0 -2.3 3.3*
Trochanter 2.3 -2.0 4.3*
* vs. placebo: p<0.001

Increases in BMD were observed as early as 3 months following initiation of ACTONEL treatment. Prevention of spinal bone loss was observed in the vast majority of women who received ACTONEL treatment. In contrast, most placebo-treated women experienced significant and progressive bone loss, despite receiving supplemental calcium 1000 mg/day. ACTONEL 5 mg daily was similarly effective in patients with lower baseline BMD (i.e., more than 1 SD below the premenopausal mean) and in those with higher BMD.

Results of Study 10

Table 10 Effect of ACTONEL 35 mg Once-a-Week on Bone Mineral Density in Postmenopausal Women without Osteoporosis
Endpoints ACTONEL 35 mg
Once-a-Week
Mean Increase in BMD
%
Placebo
Mean Increase in BMD
%
Mean Difference
from Placebo
%
6 months Lumbar Spine 1.7 -0.5 2.2*
Trochanter 1.0 -0.4 1.3*
Femoral Neck 0.4 -1.0 1.4*
12 months Lumbar Spine 1.9 -1.1 3.0*
Trochanter 1.0 -0.7 1.7*
Femoral Neck 0.3 -1.0 1.3**
vs. placebo: *p≤0.0001; ** p=0.0041

Combined Administration with Hormone Replacement Therapy

Study Demographics and Trial Design

Table 11 Summary of Patient Demographics for Clinical Trials of ACTONEL in Combined Administration with Hormone Replacement Therapy
Study
Number
Trial
Design
Dosage Duration Patients
N = number
Age Range
(Age Mean)
Gender
11 R, PC, DB,
MC, PG
Stratified
ACTONEL 5 mg/day and conjugated estrogen 0.625 mg/day
Placebo and conjugated estrogen 0.625 mg/day
1 year 524 37-82
(58.9)
Postmenopausal
female
R: randomized; PC: placebo-controlled; DB: double-blind; MC: multicentre; PG: parallel-group

For inclusion in Study 11 women had a mean lumbar spine BMD 1.3 SD below the pre-menopausal mean and had recently initiated conjugated estrogen treatment (i.e., not taken estrogen for more than 1 month in the past year).

Results of Study 11

Table 12 Effect of ACTONEL on Bone Mineral Density in Combination Therapy with Conjugated Estrogen
Endpoints ACTONEL 5 mg Daily and
Conjugated Estrogen
Mean increase in BMD
Conjugated Estrogen

Mean increase in BMD
12 months Lumbar Spine 5.2 4.6
Femoral Neck 2.7* 1.8
Trochanter 3.7 3.2
Midshaft Radius 0.7* 0.4
All values represent significant (p≤0.05) change vs. baseline.
vs. conjugated estrogen alone: *p≤0.05

Consistent with the changes in BMD, the reduction in bone turnover, as measured by urinary deoxypyridinoline/creatinine, was significantly greater in the combined ACTONEL 5 mg daily plus estrogen group compared to the estrogen alone group (45-50% vs. 40%) and remained within the premenopausal range.

Histomorphometric evaluation of 93 bone biopsy samples from 61 women on estrogen therapy who received either placebo or ACTONEL 5 mg 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 BTMs. Bone histology demonstrated that the bone of patients treated with ACTONEL plus estrogen was of normal lamellar structure and normal mineralization.

Treatment of Osteoporosis in Men, to Improve Bone Mineral Density

Study Demographics and Trial Design

Table 13 Summary of Patient Demographics for Clinical Trial of ACTONEL in Treatment of Osteoporosis in Men, to Improve Bone Mineral Density
Study
Number
Trial
Design
Dosage Duration Patients
N = number
Age Range
(Age Mean)
Daily Supplement
Elemental
Calcium
Vitamin
D
12 R, DB,
PC, MC,
PG
ACTONEL
35 mg/day
Placebo
2 year 191
93
36-84
(60.8)
1000 mg 400-500
IU
R: randomized ; DB: double-blind; PC: placebo-controlled; MC: multicentre; PG: parallel-group

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, NSAIDs, or drugs traditionally used for the treatment of peptic ulcers were not specifically excluded from participating in the 2-year male osteoporosis study.

Results of Study 12

ACTONEL 35 mg Once-a-Week demonstrated efficacy in men with osteoporosis, as measured by change in BMD. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400-500 IU/day. ACTONEL 35 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo in a 2 year study (lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total hip, 1.5%). Statistically significant increases in lumbar spine BMD were observed within 6 months following initiation of ACTONEL treatment. Lumbar spine BMD percent change from baseline at Months 6, 12 and 24 showed that the ACTONEL 35 mg Once-a-Week group had a statistically significant increase in mean percent change from baseline versus placebo at all time points (see Figure 3).

Figure 3 Mean Percent Change from Baseline in Lumbar Spine BMD at all Time Points(Intent-to-Treat Population)



Glucocorticoid-Induced Osteoporosis

Study Demographics and Trial Design

Table 14 Summary of Patient Demographics for Clinical Trials of ACTONEL in the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis
Study Number Trial Design Dosage Duration Patients
N = number
Age Range
(Age Mean)
Gender
13
Recent GC
DB, PC 5 mg/day
Placebo
1 year 228 18-85
(59.5)
Men and
women
14
Long-term GC
DB, PC 5 mg/day
Placebo
1 year 290 19-85
(58.4)
Men and
women
GC: glucocorticoid; DB: double-blind; PC: placebo-controlled

In Study 13, each patient had initiated glucocorticoid therapy (> 7.5 mg/day of prednisone or equivalent) within the previous 3 months for rheumatic, skin and pulmonary diseases. The mean lumbar spine BMD was normal at baseline. All patients in this study received supplemental calcium 500 mg/day.

Long-term use in Study 14 was defined as > 6 months of glucocorticoids 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 supplemental vitamin D 400 IU/day.

Results of Studies 13 and 14

Table 15 Change in Bone Mineral Density at 12 months from Baseline in Patients taking Glucocorticoid Therapy
Endpoints ACTONEL 5 mg
Mean Change in
BMD
%
Placebo
Mean Change in
BMD
%
Least Squares
Mean Difference
from Placebo
%
Study 13: Recent GC
N = 58-60 N = 56-57
Lumbar Spine 0.6 -2.8 3.8**
Femoral Neck 0.8 -3.1 4.1**
Trochanter 1.4 -3.1 4.6**
Study 14: Long-term GC
N = 77-79 N = 66-67
Lumbar Spine 2.9 0.4 2.7**
Femoral Neck 1.8 -0.3 1.9**
Trochanter 2.4*** 1.0 1.4*
GC: glucocorticoid; *p≤0.01 vs. placebo; **p≤0.001 vs. placebo; ***p≤0.05 vs. baseline

By the third month of treatment, and continuing through treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck and trochanter, while BMD was maintained or increased in the ACTONEL 5 mg group. At each skeletal site there were statistically significant differences between the ACTONEL 5 mg group and the placebo group at all time points (Months 3, 6, 9, 12). The treatment differences increased with continued treatment. The results at these skeletal sites were also statistically significant when the subgroups of men and postmenopausal women were analyzed separately.

ACTONEL was effective and prevented bone loss regardless of underlying disease, age, gender, glucocorticoid dose or baseline BMD.

Vertebral Fractures

Vertebral fractures were monitored for safety in the two placebo-controlled studies.

Table 16 Incidence of Vertebral Fracture in Patients Initiating or Continuing Glucocorticoid Therapy
Endpoints ACTONEL 5 mg Daily Placebo
N % of patients N % of patients
Study 13: Recent GC 53 6 52 17
Study 14: Long-term GC 58 5 59 15
Combined Studies 13 and 14 111 5* 111 16
vs. placebo: *p≤0.05

The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to a relative risk reduction of 70%.

Histology/Histomorphometry

Histomorphometric evaluation of 70 bone biopsy samples from 48 patients on glucocorticoid therapy who received either placebo or ACTONEL 5 mg daily for 1 year (including 22 pairs of biopsies, 16 from ACTONEL-treated patients) indicated that ACTONEL reduces bone resorption and produces a mild-to-moderate decrease in the rate of bone turnover. The rate of bone formation was preserved or increased and there was no evidence of impaired mineralization. The structure of the cortical bone (cortical thickness and porosity) was maintained in the ACTONEL-treated patients; cortical porosity increased, however, in the placebo group. These findings indicate that bone formed during ACTONEL treatment is of normal quality.

Bone histology demonstrated that bone formed during treatment with ACTONEL was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed.

Paget’s Disease of Bone

Study Demographics and Trial Design

Table 17 Summary of Patient Demographics for Clinical Trials in the Treatment of Paget’s Disease of Bone
Study
Number
Trial Design Dosage and Duration Patients
N = number
Age Range
(Age Mean)
Gender
15 DB, AC ACTONEL 30 mg
for 2 months
Didronel 400 mg for
6 months
123 34-85
(66.8)
Men and women
16 AC Risedronate 10, 20
or 30 mg for 28 days
62 (67.7) Men and women
17 OL Risedronate 30 mg 162 (68.4) Men and women
18 OL Risedronate 30 mg 13 (68.2) Men and women
19 OL Risedronate 30 mg 20 (74.0) Men and women
20 OL Risedronate 30 mg 73 (69) Men and women
DB: double-blind; AC: active-controlled; OL: open-label

Patients in Study 15 had moderate-to-severe Paget's disease (i.e., serum alkaline phosphatase levels of at least two times the upper limit of normal). The efficacy of ACTONEL 30 mg daily was demonstrated in six clinical studies involving over 390 male and female patients.

Results of Study 15

Figure 4 below shows that at Day 180, 77% (43/56) of ACTONEL-treated patients achieved normalization of serum alkaline phosphatase levels compared to 10.5% of patients treated with Didronel (p < 0.001). For 33 of these 43 patients (77%), the remission (i.e., normalization of serum alkaline phosphatase) induced by ACTONEL treatment was maintained through at least 300 days of post-treatment observation.

Figure 4 Percent of Patients with Normalized Serum Alkaline Phosphatase vs. Time



During the first 180 days of the active-controlled study, 85% (51/60) of ACTONEL-treated patients demonstrated a ≥ 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 < 0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 5 below) reveal that the onset of the effect of ACTONEL is significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only 6% seen with Didronel treatment at the same time point (p < 0.001).

Figure 5 Mean Percent from Baseline in Serum Alkaline Phosphatase Excess by Visit Study RPD-001694



Response to ACTONEL therapy was independent of age, gender, or race and was similar in patients with mild to very severe Paget's disease. Table 18 below shows the maximum mean percent reduction from baseline in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.

Table 18 Maximum Percent Reduction from Baseline in Total Serum Alkaline Phosphatase (AP) Excess by Disease Severity – 30 mg ACTONEL
Subgroup:
Baseline Disease Severity (AP)
N Baseline Serum AP
(U/L)*
Mean Maximum %
Reduction
>2, <3x ULN 32 271.6 ± 5.3 -90.2
≥ 3, <7x ULN 14 475.3 ± 28.8 -90.4
≥7x ULN 17 1611.3 ± 231.5 -80.9
* values shown are mean ± SEM; ULN: upper limit of normal

Results of Study 16

Response to ACTONEL was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, four out of five patients (80%) previously non-responsive to complete courses of anti-pagetic therapy (calcitonin, Didronel, clodronate) responded to treatment with ACTONEL 30 mg daily (defined by at least a 30% change from baseline). Of these four patients, all achieved at least 90% reduction from baseline in serum alkaline phosphatase excess with three patients achieving normalization of serum alkaline phosphatase levels. ACTONEL does not impair mineralization. Histology data showed that the bone formed during ACTONEL treatment was lamellar and of normal quality.

Radiographs taken at baseline and after 6 months from patients treated with ACTONEL 30 mg daily demonstrate that ACTONEL is highly effective in decreasing the extent of osteolysis across all anatomical sites including the appendicular and axial skeleton. Importantly, osteolytic lesions in the lower extremities improved or were unchanged in 15/16 (94%) of assessed patients; 9/15 (60%) patients showed clear improvement in osteolytic lesions. No evidence of new fractures was observed.

Detailed Pharmacology

There are extensive preclinical data to support that bone produced during ACTONEL (risedronate sodium) treatment at therapeutic doses is of normal quality, consistent with clinical experience. Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized animals, increasing bone mass and biomechanical strength dose-dependently. Risedronate treatment maintained the positive correlation between BMD and bone strength. In intact dogs, risedronate induced positive bone balance at the level of the basic multicellular unit.

Long-term oral administration of risedronate to ovariectomized rats (up to 2.5 mg/kg/day for 12 months) and ovariectomized minipigs (up to 2.5 mg/kg/day for 18 months) did not impair bone structure, mineralization, or biomechanical strength. These doses were 5 times the optimal antiresorptive dose for these species. Normal lamellar bone was formed in these animals. Risedronate treatment did not impair the normal healing of radial fractures in adult dogs. 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 (5 mg/kg/day, subcutaneously), which was > 3000 times the lowest antiresorptive dose (1.5 μg/kg/day).

Toxicology

Acute Toxicity

Lethality after single oral doses was seen in female rats at 903 mg/kg (5826 mg/m2) and male rats at 1703 mg/kg (10967 mg/m2). The minimum lethal dose in mice, rabbits, and dogs was 4000 mg/kg (10909 mg/m2), 1000 mg/kg (10870 mg/m2), and 128 mg/kg (2560 mg/m2), respectively. These values represent 140 to 620 times the human 30 mg dose based on surface area, mg/m2.

Chronic Toxicity

In a 1-year daily repeat dose toxicity study in dogs, the limiting toxicity of risedronate was observed at 8 mg/kg/day (160 mg/m2) and consisted of liver, testicular, renal, and gastrointestinal changes. Gastrointestinal effects at 16 mg/kg (111 mg/m2) were the first limiting toxicity in rats in a 26-week study. These doses are equivalent to approximately 6.25 to 9 times the human 30 mg dose based on surface area, mg/m2. In 6 month and 1-year monthly repeat dose toxicity studies in dogs, the limiting systemic toxicity of risedronate was observed at 32 mg/kg (640 mg/m2) and consisted of liver, testicular, and renal toxicities. Gastric lesions were observed at 16 mg/kg (320 mg/m2). These doses are equivalent to approximately 3.5 and 7 times the human 150 mg dose based on surface area, mg/m2.

A 13-week oral dog study was performed to evaluate the gastric and lower gastrointestinal toxicity and toxicokinetics of risedronate (8 and 16 mg/kg) when dosed with or without EDTA (2.5 and 12.5 mg/kg) following 14 once-weekly oral doses. No additional GI toxicity was observed with the addition of either dose of EDTA to either dose of risedronate. No new organs of toxicity were identified when dogs were treated with risedronate in combination with EDTA (vs risedronate alone). Treatment with EDTA alone was not associated with any treatment-related changes.

Co-administration of EDTA with 8 and/or 16 mg/kg risedronate was associated with potentiation of risedronate-mediated histologic alterations in the liver, kidneys, and testes (incidence and/or severity). Potentiation of toxicity was more evident at 12.5 mg/kg EDTA when compared with 2.5 mg/kg EDTA. With respect to expected pharmacological effects (e.g. increased bone), 12.5 mg/kg EDTA potentiated the severity of rib hypertrophy and the incidence of increased bone in nasal turbinates when administered in combination with 8 and 16 mg/kg risedronate (vs risedronate alone). These findings may be related to the observed increase in exposure noted when risedronate was administered in combination with EDTA.

Carcinogenicity

Three carcinogenicity studies in two species (mouse and rat) have been completed. All studies clearly showed dose-dependent bone pharmacologic effects. Risedronate was not carcinogenic in male or female rats dosed daily by gavage for 104 weeks at doses up to 24 mg/kg/day (12 times the human 30 mg dose based on surface area, mg/m2). Similarly, there was no evidence of a carcinogenic potential in male or female mice dosed daily by gavage for 80 weeks at doses up to 32 mg/kg/day (5 times the human 30 mg dose based on surface area, mg/m2).

Mutagenesis

In a series of seven in vitro and in vivo mutagenicity assays, risedronate was not genotoxic. An in vitro chromosomal aberration assay in Chinese hamster ovary cells was weakly positive at highly cytotoxic doses (> 675 μg/mL). However, when the assay was repeated at doses exhibiting increased cell survival (300 μg/mL), risedronate was negative.

Reproduction

In female rats, ovulation was inhibited at an oral dose of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). Decreased implantation was noted in female rats treated with doses ≥ 7 mg/kg/day (approximately 2.3 times the 30 mg/day human dose based on surface area, mg/m2). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (approximately 13 times the 30 mg/day human dose based on surface area, mg/m2). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 8 times the 30 mg/day human dose based on surface area, mg/m2). These findings tended to increase in severity with increased dose and exposure time.

Survival of neonates was decreased in rats treated during gestation with oral doses ≥ 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). Body weight was decreased in neonates from dams treated with 80 mg/kg (approximately 26 times the 30 mg/day human dose based on surface area, mg/m2). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7.1 mg/kg/day (approximately 2.3 times the 30 mg/day human dose based on surface area, mg/m2). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses ≥ 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m2). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses ≥ 3.2 mg/kg/day (approximately 1 time the 30 mg/day human dose based on surface area, mg/m2). The relevance of this finding to human use of ACTONEL is unclear. No significant fetal ossification effects were seen in rabbits treated with oral doses up to 10 mg/kg/day during gestation (approximately 6.7 times the 30 mg/day human dose based on surface area, mg/m2). However, in rabbits treated with 10 mg/kg/day, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.

Similar to other bisphosphonates, treatment during mating and gestation with doses as low as 3.2 mg/kg/day (approximately 1 time the 30 mg/day human dose based on surface area, mg/m2) has resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.