The safety and effectiveness of Actonel (Risedronate sodium) for the treatment of osteoporosis are based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

Actonel (Risedronate sodium) should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, Actonel (Risedronate sodium) should be swallowed while the patient is in an upright position and with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication [ ].

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate [ ]. Calcium supplements and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of Actonel (Risedronate sodium) and should be taken at a different time of the day. Actonel (Risedronate sodium) is not recommended for use in patients with severe renal impairment (creatinine clearance

Actonel (Risedronate sodium) , like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Actonel (Risedronate sodium) is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [ ].

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Actonel (Risedronate sodium) and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient []. In patients who cannot comply with dosing instructions due to mental disability, therapy with Actonel (Risedronate sodium) should be used under appropriate supervision.

There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including Actonel (Risedronate sodium) . Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment [ ].

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions
Hypersensitivity and skin reactions have been reported rarely, including angioedema, generalized rash and bullous skin reactions, some severe.

Gastrointestinal Adverse Events
Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [ ].

Musculoskeletal Pain
Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [ ].

Eye Inflammation
Reactions of eye inflammation including iritis and uveitis have been reported rarely.

Jaw Osteonecrosis
Osteonecrosis of the jaw has been reported rarely [ ].

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (e.g., Cytochrome P450).

Pregnancy Category C: There are no adequate and well-controlled studies of Actonel (Risedronate sodium) in pregnant women. Actonel (Risedronate sodium) should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

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.

In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Actonel (Risedronate sodium) is unclear.

No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 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 of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

Actonel (Risedronate sodium) is not indicated for use in pediatric patients.

The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In Actonel (Risedronate sodium) -treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.

The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in ≥10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Actonel (Risedronate sodium) and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m).

Actonel (Risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Actonel (Risedronate sodium) tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is CHNOPNa •2.5 HO. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:

Risedronate sodium 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.

All dose strengths contain: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

Dose strength-specific ingredients include: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake.

Actonel (Risedronate sodium) treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Actonel (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 Actonel (Risedronate sodium) for the treatment of osteoporosis in postmenopausal women, Actonel (Risedronate sodium) 5 mg daily and Actonel (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 Actonel (Risedronate sodium) 5 mg daily and Actonel (Risedronate sodium) 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Actonel (Risedronate sodium) 5 mg daily or Actonel (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 Actonel (Risedronate sodium) 5 mg daily versus Actonel (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 Actonel (Risedronate sodium) 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Actonel (Risedronate sodium) 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Actonel (Risedronate sodium) 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Actonel (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. Actonel (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, Actonel (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 Actonel (Risedronate sodium) 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption).

Absorption
Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at ~ 1 hour (T) 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 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. Actonel (Risedronate sodium) is effective when administered at least 30 minutes before breakfast.

Distribution
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 [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
Gender:
Geriatric:
Race:
Renal Impairment:
Hepatic Impairment:

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: bacterial mutagenesis in and (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (>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). 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.

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 Actonel (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).

The fracture efficacy of Actonel (Risedronate sodium) 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Actonel (Risedronate sodium) 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Actonel (Risedronate sodium) 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 D levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.

Effect on Vertebral Fractures
Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (i.e., 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. Actonel (Risedronate sodium) 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 (). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.

Effect on Osteoporosis-Related Nonvertebral Fractures
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. Actonel (Risedronate sodium) 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. shows the overall results as well as the results at the individual skeletal sites for the combined studies.

Effect on Bone Mineral Density
The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Actonel (Risedronate sodium) 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. 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), Actonel (Risedronate sodium) 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.

Actonel (Risedronate sodium) 35 mg once-a-week (N = 485) was shown to be non-inferior to Actonel (Risedronate sodium) 5 mg daily (N = 480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7, 4.3; 95% confidence interval [CI]) in the 5 mg daily group (N = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg once-a-week group (N = 387) and the mean difference between 5 mg daily and 35 mg once-a-week was 0.1% (-0.4, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

In a double-blind, multicenter study of postmenopausal women with osteoporosis, treatment with Actonel (Risedronate sodium) 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to Actonel (Risedronate sodium) 5 mg daily (N = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.6% (3.3, 3.9; 95% CI) in the 5 mg daily group (N = 527) and 3.4% (3.1, 3.7; 95% CI) in the 75 mg two days per month group (N = 524) with a mean difference between groups being 0.2% (-0.2, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

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

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

Effect on Height
In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both Actonel (Risedronate sodium) and placebo-treated groups lost height during the studies. Patients who received Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) 5 mg daily group.

The safety and effectiveness of Actonel (Risedronate sodium) 5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a 2-year, double-blind, placebo-controlled study of 383 postmenopausal women (age range 42 to 63 years) within three years of menopause (Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) treatment. Actonel (Risedronate sodium) 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 (). Actonel (Risedronate sodium) 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both Actonel (Risedronate sodium) and placebo-treated women following 1 year of treatment.

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

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

Histology/Histomorphometry
Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Actonel (Risedronate sodium) 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (N = 47) demonstrated that the bone of patients treated with Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: Actonel (Risedronate sodium) plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover.

Bone Mineral Density
Two 1-year, double-blind, placebo-controlled trials in patients who were taking ≥7.5 mg/day of prednisone or equivalent demonstrated that Actonel (Risedronate sodium) 5 mg daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing glucocorticoid therapy. The efficacy of Actonel (Risedronate sodium) therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.

The prevention study enrolled 228 patients (Actonel (Risedronate sodium) 5 mg, N = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T-score -0.7). All patients in this study received supplemental calcium 500 mg/day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the Actonel (Risedronate sodium) 5 mg group. At each skeletal site there were statistically significant differences between the placebo group and the Actonel (Risedronate sodium) 5 mg group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the Actonel (Risedronate sodium) 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and Actonel (Risedronate sodium) 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in . The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. Actonel (Risedronate sodium) was effective at the lumbar spine, femoral neck, and trochanter regardless of age (
The treatment study of similar design enrolled 290 patients (Actonel (Risedronate sodium) 5 mg, N = 100) (19 to 85 years of age) with continuing, long-term (≥6 months) use of glucocorticoids (mean duration of use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.63 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400 IU/day.

After 1 year of treatment, the BMD of the placebo group was within ±1% of baseline levels at the lumbar spine, femoral neck, and trochanter. Actonel (Risedronate sodium) 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between Actonel (Risedronate sodium) and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in . The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. Actonel (Risedronate sodium) was similarly effective on lumbar spine BMD regardless of age (
Vertebral Fractures
In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at 1 year was reduced from 17% in the placebo group to 6% in the Actonel (Risedronate sodium) group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the Actonel (Risedronate sodium) group (). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures).

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

The efficacy of Actonel (Risedronate sodium) was demonstrated in 2 clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget’s disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with Actonel (Risedronate sodium) 30 mg daily for 2 months or Didronel (etidronate disodium) 400 mg daily for 6 months. At Day 180, 77% (43/56) of Actonel (Risedronate sodium) -treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel (p
During the first 180 days of the active-controlled study, 85% (51/60) of Actonel (Risedronate sodium) -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
Response to Actonel (Risedronate sodium) therapy was similar in patients with mild to very severe Paget’s disease. shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.

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

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

Actonel (Risedronate sodium) is available as follows:

5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.

NDC 0430-0471-15 bottle of 30

30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other.

NDC 0430-0470-15 bottle of 30

35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other.

NDC 0430-0472-03 dose pack of 4NDC 0430-0472-07 dose pack of 12

75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other.

NDC 0430-0477-02 dose pack of 2

150 mg film-coated, oval, blue tablets with RSN on 1 face and 150 mg on the other.

NDC 0430-0478-01 dose pack of 1NDC 0430-0478-02 dose pack of 3

Store at controlled room temperature 20° to 25° C (68° to 77° F) [ USP].

[See FDA-Approved Patient Labeling ()]

The patient should be informed to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, Actonel (Risedronate sodium) should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation, patients should take Actonel (Risedronate sodium) while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication [ ]. Patients should not chew or suck on the tablet because of a potential for oropharyngeal irritation.

Patients should be instructed 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 Actonel (Risedronate sodium) .

Patients should be instructed that if they miss a dose of Actonel (Risedronate sodium) 35 mg once a week, they should take 1 tablet on the morning after they remember and return to taking 1 tablet once a week, as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.

If one or both tablets of Actonel (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:

Patients should then return to taking their Actonel (Risedronate sodium) 75 mg on two consecutive days per month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days.

If one or both tablets of Actonel (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 Actonel (Risedronate sodium) 75 mg on two consecutive days per month as originally scheduled.

If the dose of Actonel (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 Actonel (Risedronate sodium) 150 mg once-a-month as originally scheduled. Patients should not take more than one 150 mg tablet within 7 days.

If the dose of Actonel (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 Actonel (Risedronate sodium) 150 mg once-a-month as originally scheduled.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate [ ]. Calcium supplements or calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of Actonel (Risedronate sodium) and should be taken at a different time of the day, as with food.

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.

Physicians should instruct their patients to read the Patient Information before starting therapy with Actonel (Risedronate sodium) 5 mg, 35 mg, 75 mg, or 150 mg and to re-read it each time the prescription is renewed.

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

Read the Medication Guide that comes with Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) .

What is the most important information I should know about Actonel (Risedronate sodium) ?

Actonel (Risedronate sodium) may lower the calcium levels in your blood. If you have low blood calcium before you start taking Actonel (Risedronate sodium) , it may get worse during treatment. Your low blood calcium must be treated before you take Actonel (Risedronate sodium) . 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:

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Actonel (Risedronate sodium) . Take calcium and vitamin D as your doctor tells you to.

Severe jaw bone problems may happen when you take Actonel (Risedronate sodium) . Your doctor should examine your mouth before you start Actonel (Risedronate sodium) . Your doctor may tell you to see your dentist before you start Actonel (Risedronate sodium) . It is important for you to practice good mouth care during treatment with Actonel (Risedronate sodium) .

Some people who take Actonel (Risedronate sodium) develop severe bone, joint, or muscle pain.

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.

Actonel (Risedronate sodium) is a prescription medicine used to:

It is not known how long Actonel (Risedronate sodium) works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if Actonel (Risedronate sodium) is still right for you.

Actonel (Risedronate sodium) is not for use in children.

Especially tell your doctor if you take:

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.

After swallowing Actonel (Risedronate sodium) tablet, wait at least 30 minutes:

If you miss a dose of Actonel (Risedronate sodium) , take it later in the day. Take your missed dose the next morning and then return to your normal schedule. Do not take 2 doses at the same time.

If you miss more than 2 doses of Actonel (Risedronate sodium) in a month, call your doctor for instructions.

If you take too much Actonel (Risedronate sodium) , call your doctor. Do not try to vomit. Do not lie down.

Actonel (Risedronate sodium) may cause serious side effects

You may get allergic reactions, such as hives or, in rare cases, 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 Actonel (Risedronate sodium) . 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.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Actonel (Risedronate sodium) for a condition for which it was not prescribed. Do not give Actonel (Risedronate sodium) 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 Actonel (Risedronate sodium) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Actonel (Risedronate sodium) that is written for health professionals.

For more information, go to or call 1-800-521-8813.

Active ingredient: risedronate sodium

Inactive ingredients in all dose strengths: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

Inactive ingredients specific to a dose strength: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake.

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

Covered under one or more of U.S. Patent Nos. 5,583,122; 5,994,329; 6,015,801; 6,096,342; 6,165,513; 6,410,520; 6,432,932; 6,465,443; and 6,562,974.

Manufactured by:Warner Chilcott Puerto Rico LLC,Manati, Puerto Rico 00674

or

Norwich Pharmaceuticals, Inc.,North Norwich, NY 13814

or

Chinoin Pharmaceutical and Chemical Works Private Co. LtdVeresegyhaz, Hungary

Marketed by:Warner Chilcott (US), LLCRockaway, NJ 078661-800-521-8813

0472G125

Dispense the enclosed Medication Guide to each patient

Actonel (Risedronate sodium)

(risedronate sodium) tablets

5 mg

30 Tablets

0471G051

Rx Only

NDC 0430-0470-15

Dispense the enclosed Medication Guide to each patient

Actonel (Risedronate sodium)

(risedronate sodium) tablets

30 mg

30 Tablets

0470G052

4 Week Supply

(4 tablets)

Actonel (Risedronate sodium)

(risedronate sodium) tablets

35 mg

NDC 0430-0472-03

Dispense the enclosed Medication Guide to each patient

Once-a-Week

4 tablets

One Month Pack

(1 tablet)

Actonel (Risedronate sodium)

(risedronate sodium) tablets

150 mg

NDC 0430-0478-01

Dispense the enclosed Medication Guide to each patient

Once-a-Month

1 tablet