Risedronate Sodium

Risedronate sodium, USP is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Inactive Ingredients: All dose strengths contain: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol and titanium dioxide. Dose strength-specific ingredients include: 75 mg-red iron oxide and triacetin; 150 mg-FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs and minipigs showed that risedronate treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

12.2 Pharmacodynamics

Risedronate treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of risedronate to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a one-year study comparing daily versus weekly oral dosing regimens of risedronate for the treatment of osteoporosis in postmenopausal women, risedronate 5 mg daily and risedronate 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 5 mg daily and risedronate 35 mg once a week groups, respectively. When postmenopausal women with osteoporosis were treated for one year with risedronate 5 mg daily or risedronate 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 one-year study comparing risedronate 5 mg daily versus risedronate 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.

12.3 Pharmacokinetics

Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately one 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.

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 one hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Risedronate is effective when administered at least 30 minutes before breakfast.

The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [¹⁴C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.

There is no evidence of systemic metabolism of risedronate.

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%).

Risedronate is not indicated for use in pediatric patients [see Pediatric Use (8.4) ].

Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.

Pharmacokinetic differences due to race have not been studied.

Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance 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.

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.

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450) [see Drug Interactions (7) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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.

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 3,500 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 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 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in two large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4,000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (risedronate 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (risedronate 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.

Fractures of previously undeformed vertebrae (new fractures) and worsening of preexisting vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (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 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 1). The reduction in risk seen in the subgroup of patients who had two or more vertebral fractures at study entry was similar to that seen in the overall study population.

In 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 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.

The results of four randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that risedronate 5 mg daily increases BMD at the spine, hip and wrist compared to the effects seen with placebo. Table 2 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 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 2. Mean Percent Increase in BMD from Baseline in Patients Taking Risedronate 5 mg or Placebo at EndpointThe 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.

ND = analysis not done
	VERT MNThe duration of the studies was 3 years.		VERT NAThe duration of the studies was 3 years.		BMD MNThe duration of the studies was 1.5 to 2 years.		BMD NAThe duration of the studies was 1.5 to 2 years.
	Placebo	5 mg	Placebo	5 mg	Placebo	5 mg	Placebo	5 mg
	n = 323	n = 323	n = 599	n = 606	n = 161	n = 148	n = 191	n = 193
Lumbar Spine	1	6.6	0.8	5	0	4	0.2	4.8
Femoral Neck	-1.4	1.6	-1	1.4	-1.1	1.3	0.1	2.4
Femoral Trochanter	-1.9	3.9	-0.5	3	-0.6	2.5	1.3	4
Midshaft Radius	-1.5BMD 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).	0.2BMD 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).	-1.2BMD 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).	0.1BMD 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		ND

Risedronate 35 mg once a week (n = 485) was shown to be non-inferior to risedronate 5 mg daily (n = 480) in a one-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 one year were 4% (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 two 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 75 mg two consecutive days per month (n = 616) was shown to be non-inferior to risedronate 5 mg daily (n = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at one 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 two treatment groups were also similar with regard to BMD increases at other skeletal sites.

Risedronate 150 mg once a month (n = 650) was shown to be non-inferior to risedronate 5 mg daily (n = 642) in a one-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 one year were 3.4% (3, 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 two treatment groups were also similar with regard to BMD increases at other skeletal sites.

Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily risedronate (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-treated women. These findings demonstrate that bone formed during risedronate 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 5 mg. Mineralizing surface decreased moderately in risedronate-treated patients (median percent change: placebo, -21%; risedronate 5 mg, -74%), consistent with the known effects of treatment on bone turnover.

In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both risedronate and placebo-treated groups lost height during the studies. Patients who received risedronate 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 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 5 mg daily group.

14.2 Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of risedronate 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 3 years of menopause (risedronate 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 treatment. Risedronate 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 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than one 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 and placebo-treated women following one year of treatment.

The safety and effectiveness of risedronate 35 mg once a week for the prevention postmenopausal osteoporosis were demonstrated in a one-year, double-blind, placebo-controlled study of 278 patients (risedronate 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 one year of treatment using LOCF (last observation carried forward). Risedronate 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 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%; risedronate +0.22%) and trochanter of + 1.8% (placebo -0.74%; risedronate +1.07%).

The effects of combining risedronate 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 one-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 3.

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received risedronate 5 mg plus estrogen or estrogen-alone once daily for one year. Histologic evaluation (n = 47) demonstrated that the bone of patients treated with risedronate 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 plus estrogen and 12 treated with estrogen-alone. Mineralizing surface decreased in both treatment groups (median percent change: risedronate plus estrogen, -79%; estrogen-alone, -50%), consistent with the known effects of these agents on bone turnover.

16 HOW SUPPLIED/STORAGE AND HANDLING

Risedronate Sodium Tablets, USP are available containing 75 mg or 150 mg risedronate sodium, USP.

The 75 mg tablets are pink film-coated, round, unscored tablets debossed with M on one side of the tablet and 727 on the other side. They are available as follows:

NDC 0378-4727-90
unit of use blister card containing 2 tablets

NDC 0378-4727-94
carton of 10 cards each containing 2 tablets

The 150 mg tablets are light blue film-coated, round, unscored tablets debossed with M over RE on one side of the tablet and 150 on the other side. They are available as follows:

NDC 0378-4150-32
unit of use blister card containing 1 tablet

NDC 0378-4150-97
carton of 10 cards each containing 1 tablet

NDC 0378-4150-53
unit of use blister card containing 3 tablets

NDC 0378-4150-93
carton of 10 cards each containing 3 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

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

Instruct patients that risedronate sodium delayed-release tablets and risedronate sodium tablets contain the same active ingredient and if they are taking risedronate sodium delayed-release tablets, 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 lie down for 30 minutes after taking the medication [see Warnings and Precautions (5.1) ].

Instruct patients not 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 tablet doses as follows:

• •If one or both tablets of risedronate sodium 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 75 mg tablets 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 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 75 mg tablets on two consecutive days per month as originally scheduled.
• •If the dose of risedronate sodium 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 150 mg tablet 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 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 150 mg tablet 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.

MEDICATION GUIDE
RISEDRONATE SODIUM TABLETS, USP
(ris″ e droe′ nate soe′ dee um)
75 mg and 150 mg

Read the Medication Guide that comes with risedronate sodium tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. Talk to your doctor if you have any questions about risedronate sodium tablets, there may be new information about it.

What is the most important information I should know about risedronate sodium tablets?

Risedronate sodium tablets can cause serious side effects including:

• 1.Esophagus problems
• 2. Low calcium levels in your blood (hypocalcemia)
• 3.Severe jaw bone problems (osteonecrosis)
• 4.Bone, joint or muscle pain
• 5.Unusual thigh bone fractures
  
  
• 1. Esophagus problems. Some people who take risedronate sodium tablets may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation or ulcers of the esophagus which may sometimes bleed.
  • • It is important that you take risedronate sodium tablets exactly as prescribed to help lower your chance of getting esophagus problems. (See the section “How should I take risedronate sodium tablets?”)
  • • Stop taking risedronate sodium tablets and call your doctor right away if you get chest pain, new or worsening heartburn or have trouble or pain when you swallow.
• 2. Low calcium levels in your blood (hypocalcemia).
  Risedronate sodium tablets may lower the calcium levels in your blood. If you have low blood calcium before you start taking risedronate sodium tablets, it may get worse during treatment. Your low blood calcium must be treated before you take risedronate sodium tablets. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:
  • •Spasms, twitches or cramps in your muscles
  • •Numbness or tingling in your fingers, toes or around your mouth
•  Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take risedronate sodium tablets. Take calcium and vitamin D as your doctor tells you to.
• 3. Severe jaw bone problems (osteonecrosis).
  Severe jaw bone problems may happen when you take risedronate sodium tablets. Your doctor should examine your mouth before you start risedronate sodium tablets. Your doctor may tell you to see your dentist before you start risedronate sodium tablets. It is important for you to practice good mouth care during treatment with risedronate sodium tablets.
• 4. Bone, joint or muscle pain.
  Some people who take risedronate sodium tablets develop severe bone, joint or muscle pain.
• 5. Unusual thigh bone fractures.
  Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin or thigh.

Call your doctor right away if you have any of these side effects.

What are risedronate sodium tablets?

Risedronate sodium tablets are a prescription medicine used to:

• •Treat or prevent osteoporosis in women after menopause. Risedronate sodium tablets help increase bone mass and help reduce the chance of having a spinal or non-spinal fracture (break).

It is not known how long risedronate sodium tablets work for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if risedronate sodium tablets are still right for you.

Risedronate sodium tablets are not for use in children.

Who should not take risedronate sodium tablets?

Do not take risedronate sodium tablets if you:

• •Have certain problems with your esophagus, the tube that connects your mouth with your stomach
• •Cannot stand or sit upright for at least 30 minutes
• •Have low levels of calcium in your blood
• •Are allergic to risedronate sodium tablets or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking risedronate sodium tablets?

Before you start risedronate sodium tablets, be sure to talk to your doctor if you:

• •Have problems with swallowing
• •Have stomach or digestive problems
• •Have low blood calcium
• •Plan to have dental surgery or teeth removed
• •Have kidney problems
• •Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)
• •Are pregnant, or plan to become pregnant. It is not known if risedronate sodium tablets can harm your unborn baby.
• •Are breast-feeding or plan to breast-feed. It is not known if risedronate sodium passes into your milk and may harm your baby.

Especially tell your doctor if you take:

• •antacids
• •aspirin
• •Non-steroidal Anti-Inflammatory (NSAID) medicines

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Certain medicines may affect how risedronate sodium tablets work.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take risedronate sodium tablets?

• •Take risedronate sodium tablets exactly as your doctor tells you. Your doctor may change your dose of risedronate sodium tablets if needed.
• • Risedronate sodium tablets work only if taken on an empty stomach.
• •Take one risedronate sodium tablet, after you get up for the day and before taking your first food, drink or other medicine.
• •Take risedronate sodium tablets while you are sitting or standing.
• • Do not chew or suck on a tablet of risedronate sodium.
• •Swallow the risedronate sodium tablet with a full glass (6 to 8 ounces) of plain water only.
• •Do not take risedronate sodium tablets with mineral water, coffee, tea, soda or juice.

After swallowing the risedronate sodium tablet, wait at least 30 minutes:

• •Before you lie down. You may sit, stand or walk, and do normal activities like reading.
• •Before you take your first food or drink except for plain water.
• •Before you take other medicines, including antacids, calcium and other supplements and vitamins.

Do not lie down for at least 30 minutes after you take risedronate sodium tablets and after you eat your first food of the day.

If you miss a dose of risedronate sodium tablets, do not take it later in the day. Take your missed dose the next morning and then return to your normal schedule. Do not take two doses at the same time.

If you miss more than two doses of risedronate sodium tablets in a month, call your doctor for instructions.

If you take too much risedronate sodium, call your doctor. Do not try to vomit. Do not lie down.

What are the possible side effects of risedronate sodium tablets?

Risedronate sodium tablets may cause serious side effects:

• •See “What is the most important information I should know about risedronate sodium tablets?”

The most common side effects of risedronate sodium tablets are:

• •pain, including back and joint pain
• •stomach area (abdominal) pain
• •heartburn

You may get allergic reactions, such as hives, swelling of your face, lips, tongue or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of risedronate sodium tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store risedronate sodium tablets?

• •Store risedronate sodium tablets at 20° to 25°C (68° to 77°F).

Safely throw away medicine that is out of date or no longer needed.

Keep risedronate sodium tablets and all medicines out of the reach of children.

General information about the safe and effective use of risedronate sodium tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use risedronate sodium tablets for a condition for which it was not prescribed. Do not give risedronate sodium tablets to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about risedronate sodium tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about risedronate sodium tablets that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in risedronate sodium tablets?

Active ingredient: risedronate sodium, USP

Inactive ingredients in all dose strengths: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol and titanium dioxide

Inactive ingredients specific to a dose strength: 75 mg-red iron oxide and triacetin; 150 mg-FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

^* The brands listed are trademarks of their respective owners.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

FEBRUARY 2014
RISE:R1

PRINCIPAL DISPLAY PANEL – 75 mg

NDC 0378-4727-94     Two Consecutive Days a Month

Risedronate
Sodium
Tablets, USP
75 mg

PHARMACIST: Dispense the accompanying
Medication Guide to each patient.

Rx only     10 Packs (2 Tablets per Pack)

Each film-coated tablet contains:
Risedronate sodium, USP 75 mg

Usual Dosage: See accompanying prescribing information.

Keep this and all medication out of the reach of children.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

M4727:20C:R1