Risedronate Sodium 129 mg; 21 mg Tablet, Film Coated, 3-count — NDC 59762-0406-3 (Billing 59762-0406-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Risedronate Sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate Sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border).

Histomorphometry in rats, dogs, and minipigs showed that Risedronate Sodium treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

12.2Pharmacodynamics Risedronate Sodium treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Risedronate Sodium 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 Sodium for the treatment of osteoporosis in postmenopausal women, Risedronate Sodium 5 mg daily and Risedronate Sodium 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 5 mg daily and Risedronate Sodium 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Risedronate Sodium 5 mg daily or Risedronate Sodium 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively.

In a 1–year study comparing Risedronate Sodium 5 mg daily versus Risedronate Sodium 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively. Osteoporosis in Men In a 2-year study of men with osteoporosis, treatment with Risedronate Sodium 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Risedronate Sodium 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Risedronate Sodium 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Risedronate Sodium 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.

Glucocorticoid-Induced Osteoporosis Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Risedronate Sodium 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 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Risedronate Sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate Sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border).

Histomorphometry in rats, dogs, and minipigs showed that Risedronate Sodium treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

12.3Pharmacokinetics Absorption Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (T max ) 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 mg to 30 mg; multiple dose, from 2.5 mg 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. Food Effect 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 Sodium is effective when administered at least 30 minutes before breakfast. Distribution The mean steady-state volume of distribution for risedronate is

13.8L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [ 14 C] 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%. Metabolism There is no evidence of systemic metabolism of risedronate.

Excretion In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 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. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%). Specific Populations Pediatric : Risedronate Sodium is not indicated for use in pediatric patients [ see Pediatric Use ( 8.4 ) ].

Gender : Bioavailability and pharmacokinetics following oral administration are similar in men and women. Geriatric : Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.

Race : Pharmacokinetic differences due to race have not been studied. Renal Impairment : 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 Sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. Hepatic Impairment : 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 (less than 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.

Drug Interactions : No specific drug-drug interaction studies were p… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Risedronate Sodium treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Risedronate Sodium 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 Sodium for the treatment of osteoporosis in postmenopausal women, Risedronate Sodium 5 mg daily and Risedronate Sodium 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 5 mg daily and Risedronate Sodium 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Risedronate Sodium 5 mg daily or Risedronate Sodium 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively.

In a 1–year study comparing Risedronate Sodium 5 mg daily versus Risedronate Sodium 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively. Osteoporosis in Men In a 2-year study of men with osteoporosis, treatment with Risedronate Sodium 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Risedronate Sodium 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Risedronate Sodium 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Risedronate Sodium 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.

Glucocorticoid-Induced Osteoporosis Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Risedronate Sodium 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 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 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. In pagetic patients treated with Risedronate Sodium 30 mg daily for 2… [Excerpted — this section continues on DailyMed.]

6.1Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Postmenopausal Osteoporosis Daily Dosing The safety of Risedronate Sodium 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis.

The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to Risedronate Sodium 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H 2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D 3 level was below normal at baseline.

The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the Risedronate Sodium 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Risedronate Sodium 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the Risedronate Sodium 5 mg group.

The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality.

Table 1 Adverse Events Occurring at a Frequency greater than or equal to 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials Body System Placebo N = 1619 5 mg Risedronate Sodium N = 1613 % % Body as a Whole Infection 29.9

31.1Back Pain 26.1

28.0Accidental Injury 16.8

16.9Pain 14.0

14.1Abdominal Pain 9.9

12.2Flu Syndrome 11.6

10.5Headache 10.8

9.9Asthenia 4.5

5.4Neck Pain 4.7

5.4Chest Pain 5.1

5.0Allergic Reaction 5.9

3.8Cardiovascular System Hypertension 9.8

10.5Digestive System Constipation 12.6

12.9Diarrhea 10.0

10.8Dyspepsia 10.6

10.8Nausea 11.2

10.5Metabolic & Nutritional Disorders Peripheral Edema 8.8

7.7Musculoskeletal System Arthralgia 22.1

23.7Arthritis 10.1

9.6Traumatic Bone Fracture 12.3

9.3Joint Disorder 5.3

7.0Myalgia 6.2

6.7Bone Pain 4.8

5.3Nervous System Dizziness 5.7

7.1Depression 6.1

6.8Insomnia 4.6

5.0Respiratory System Bronchitis 10.4

10.0Sinusitis 9.1

8.7Rhinitis 5.1

6.2Pharyngitis 5.0

6.0Increased Cough 6.3

5.9Skin and Appendages Rash 7.1

7.9Special Senses Cataract 5.7

6.5Urogenital System Urinary Tract Infection 10.4

11.1Gastrointestinal Adverse Events : The incidence of adverse events in the placebo and Risedronate Sodium 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10.0% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the Risedronate Sodium 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and Risedronate Sodium 5 mg daily groups.

Musculoskeletal Adverse Events : The incidence of adverse events in the placebo and Risedronate Sodium 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%). Laboratory Test Findings : Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/m 2 ).

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.

13.2Animal 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 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/m 2 ).