ACTONEL^®
(risedronate sodium tablets)

ACTONEL (risedronate sodium tablets) is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, 35, or 75 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 C₇H₁₀NO₇P₂Na •2.5 H₂O. 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.

Crospovidone, ferric oxide red (35 mg and 75 mg tablets only), ferric oxide yellow (5 mg and 35 mg tablets only), hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate (5 mg, 30 mg and 35 mg tablets only), magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

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

The fracture efficacy of ACTONEL 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 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (ACTONEL 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 bone mineral density (BMD) levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.

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 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% vs. 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.

ACTONEL 5 mg daily prevented bone loss in a majority of postmenopausal women (age range 42 to 63 years) within 3 years of menopause in a 2-year, double-blind, placebo-controlled study in 383 patients (ACTONEL 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 treatment. ACTONEL 5 mg 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). ACTONEL 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 and placebo-treated women following 1 year of treatment.

ACTONEL 35 mg once a week prevented bone loss in postmenopausal women (age range 44 to 64 years) without osteoporosis in a 1-year, double-blind, placebo-controlled study in 278 patients (ACTONEL 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 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 risedronate +1.83%; placebo -1.05%). ACTONEL 35 mg once a week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of +1.5% (risedronate +1.01%; placebo -0.53%), femoral neck of +1.2% (risedronate +0.22%; placebo -1.00%), and trochanter of +1.8% (risedronate +1.07%; placebo -0.74%).

The effects of ACTONEL 35 mg once a week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (ACTONEL, n = 192). The patients had a mean age of 60.6 years (range 36-84 years) and 95% were Caucasian. At baseline, mean lumbar spine T-score was -3.2 and mean femoral neck T-score was -2.4. All patients in the study had either, 1) a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, or 2) a BMD T-score ≤-1 at the femoral neck and ≤-2.5 at the lumbar spine. All patients were supplemented with calcium 1000 mg/day and vitamin D 400-500 IU/day. ACTONEL 35 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter, and total hip compared to placebo after 2 years of treatment (treatment difference: lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total proximal femur, 1.5%).

Two 1-year, double-blind, placebo-controlled trials in patients who were taking ≥7.5 mg/day of prednisone or equivalent demonstrated that ACTONEL 5 mg once 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 prevention study enrolled 228 patients (ACTONEL 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 5 mg group. At each skeletal site there were statistically significant differences between the ACTONEL 5 mg group and the placebo 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 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and ACTONEL 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. ACTONEL was effective at the lumbar spine, femoral neck, and trochanter regardless of age (<65 vs. ≥65), gender, prior and concomitant glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

The treatment study of similar design enrolled 290 patients (ACTONEL 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 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between ACTONEL and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. ACTONEL was similarly effective on lumbar spine BMD regardless of age (<65 vs. ≥65), gender, or pre-study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

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 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 group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures).

The efficacy of ACTONEL 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 30 mg daily for 2 months or Didronel^® (etidronate disodium) 400 mg daily for 6 months. At Day 180, 77% (43/56) of ACTONEL-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel (p<0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of ACTONEL-treated patients and 14% (4/29) of Didronel-treated patients with available data remained in biochemical remission.

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

Response to ACTONEL therapy was similar in patients with mild to very severe Paget's disease. Table 4 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 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 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 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 based on surface area (mg/m²) 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 0.35 to 1.4 times the human daily dose of 5 mg based on surface area (mg/m²).

In dogs treated with an oral dose of 1 mg/kg/day (approximately 5 times the human daily dose of 5 mg based on surface area, mg/m²), 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 of 0.1 mg/kg/day (approximately 0.5 times the human daily dose of 5 mg based on surface area, mg/m²).

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested (5 mg/kg/day, subcutaneously), which was 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 based on surface area (mg/m²). This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia.

ACTONEL is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

ACTONEL is indicated for treatment to increase bone mass in men with osteoporosis.

ACTONEL is indicated for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage equivalent to 7.5 mg or greater of prednisone) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

ACTONEL is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone (1) who have a level of serum alkaline phosphatase at least 2 times the upper limit of normal, or (2) who are symptomatic, or (3) who are at risk for future complications from their disease, to induce remission (normalization of serum alkaline phosphatase).

• Hypocalcemia (see PRECAUTIONS, Mineral Metabolism)
• Known hypersensitivity to any component of this product
• Inability to stand or sit upright for at least 30 minutes

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer (see PRECAUTIONS).

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget's disease in whom bone turnover is significantly elevated. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Bisphosphonates have been associated with gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. This association has been reported for bisphosphonates in postmarketing experience, but has not been found in most pre-approval clinical trials, including those conducted with ACTONEL. Patients should be advised that taking the medication according to the instructions is important to minimize the risk of these events. They should take ACTONEL with sufficient plain water (6 to 8 oz) to facilitate delivery to the stomach, and should not lie down for 30 minutes after taking the drug.

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures such as tooth extraction, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment, prior to the procedure, reduces the risk of osteonecrosis of the jaw. Clinical judgment should guide the management plan of each patient based on individual benefit/risk assessment.

In postmarketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates (see ADVERSE REACTIONS). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

The risk versus benefit of ACTONEL for the prevention and treatment of glucocorticoid-induced osteoporosis at daily doses of glucocorticoids <7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered.

The efficacy of ACTONEL for this indication has been established in studies of 1-year duration. The efficacy of ACTONEL beyond 1 year has not been studied.

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 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 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 (see PRECAUTIONS, Upper Gastrointestinal Effects). 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.

Patients should be instructed that if they miss a dose of ACTONEL 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 75 mg on two consecutive days/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 ACTONEL 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 ACTONEL 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 ACTONEL 75 mg on two consecutive days/month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days.

If one or both tablets of ACTONEL 75 mg on two consecutive days/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 75 mg on two consecutive days/month as originally scheduled.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see PRECAUTIONS, Mineral Metabolism). Calcium supplements or calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL 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 5 mg, 35 mg, or 75 mg and to re-read it each time the prescription is renewed.

Patients should be reminded to give all of their health care providers an accurate medication history. Instruct patients to tell all of their health care providers that they are taking ACTONEL. Patients should be instructed that any time they have a medical problem they think may be from ACTONEL, they should talk to their doctor.

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).

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

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

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

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

There are no adequate and well-controlled studies of ACTONEL in pregnant women. ACTONEL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether risedronate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

Of the patients receiving ACTONEL in postmenopausal osteoporosis studies (see CLINICAL STUDIES), 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget's disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving ACTONEL were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for ACTONEL compared to placebo was 5.6% for subjects <65 years and 2.9% for subjects ≥65 years. No overall differences in safety between geriatric and younger patients were observed in the ACTONEL trials, but greater sensitivity of some older individuals cannot be ruled out.

In a 1-year, double-blind, multicenter study comparing ACTONEL 5 mg daily and ACTONEL 35 mg once a week in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar. Table 6 uls the adverse events in ≥2% of patients from this trial. Events are shown without attribution of causality.

One year of treatment with ACTONEL 5 mg daily was compared to ACTONEL 75 mg two consecutive days/month in a double-blind, multicenter study in postmenopausal women with osteoporosis. The overall safety and tolerability profiles of the 2 oral dosing regimens were similar. The incidence of serious adverse events was 4.7% in the ACTONEL 5 mg daily group and 7.5% in the ACTONEL 75 mg two consecutive days/month group. The percentage of patients who withdrew from treatment due to adverse events was 9.0% in the ACTONEL 5 mg daily group and 9.1% in the ACTONEL 75 mg two consecutive days/month group. Table 7 uls the adverse events in ≥2% of patients from this trial. Events are shown without attribution of causality.

There were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once a week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on risedronate experienced arthralgia (risedronate 13.9%; placebo 7.8%), myalgia (risedronate 5.1%; placebo 2.1%), and nausea (risedronate 7.3%; placebo 4.3%) than subjects on placebo.

In a 2-year, double-blind, multi-center study, 284 men with osteoporosis were treated with ACTONEL 35 mg once a week (n = 191) or placebo (n = 93). The overall safety and tolerability profile of ACTONEL in men with osteoporosis was similar to the adverse events reported in the ACTONEL postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (ACTONEL 35 mg 5%; placebo 3%), nephrolithiasis (ACTONEL 35 mg 3%; placebo 0%), and arrhythmia (ACTONEL 35 mg 2%; placebo 0%).

ACTONEL has been studied in 392 patients with Paget's disease of bone. As in trials of ACTONEL for other indications, the adverse experiences reported in the Paget's disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.

In a double-blind, active-controlled study, the adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months.

Very rare hypersensitivity and skin reactions have been reported, including angioedema, generalized rash and bullous skin reactions, some severe.

Musculoskeletal: bone, joint, or muscle pain, rarely described as severe or incapacitating (see PRECAUTIONS, Musculoskeletal Pain).

Very rare reactions of eye inflammation including iritis and uveitis have been reported.

Osteonecrosis of the jaw has been reported very rarely (see PRECAUTIONS, Jaw Osteonecrosis).

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 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. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m²).

ACTONEL 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 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 (see PRECAUTIONS, Upper Gastrointestinal Effects).

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see PRECAUTIONS, Mineral Metabolism). Calcium supplements and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL and should be taken at a different time of the day. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly.

ACTONEL is available as follows:

5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.
NDC 0149-0471-01 bottle of 30
NDC 0149-0471-03 bottle of 2000

30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other.
NDC 0149-0470-01 bottle of 30

35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other.
NDC 0149-0472-01 dose pack of 4
NDC 0149-0472-04 dose pack of 12

75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other.
NDC 0149-0477-01 dose pack of 2

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

Sold under U.S. patent No. 5,583,122; 6,096,342 and 6,165,513

Mfg. by: Procter & Gamble Pharmaceuticals, Inc.
Cincinnati, OH 45202, or
OSG Norwich Pharmaceuticals, Inc.
North Norwich, NY 13814

Dist. by: Procter & Gamble Pharmaceuticals, Inc., TM Owner
Cincinnati, OH 45202

Marketed with:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

May 2007

ACTONEL^®(AK-toh-nel) Tablets

ACTONEL (risedronate sodium tablets) 5 mg,
ACTONEL (risedronate sodium tablets) 35 mg, and
ACTONEL (risedronate sodium tablets) 75 mg
for Osteoporosis

Read this information carefully before you start to use your medicine. Read the information you get every time you get more medicine. There may be new information. This information does not take the place of talking with your health care provider about your medical condition or your treatment. If you have any questions or are not sure about something, ask your health care provider or pharmacist.

What is the most important information I should know about ACTONEL?

ACTONEL may cause problems in your stomach and esophagus (the tube that connects the mouth and the stomach), such as trouble swallowing (dysphagia), heartburn (esophagitis), and ulcers. You might feel pain in your bones, joints, or muscles (See “What are the Possible Side Effects of ACTONEL?”).

You must follow the instructions exactly for ACTONEL to work and to lower the chance of serious side effects. (See “How should I take ACTONEL?”).

What is ACTONEL?

ACTONEL is a prescription medicine used:

• to prevent and treat osteoporosis in postmenopausal women (See “What is Osteoporosis?”).
• to increase bone mass in men with osteoporosis
• to prevent and treat osteoporosis in men and women that is caused by treatment with steroid medicines such as prednisone.
• to treat Paget's disease of bone in men and women. The treatment for Paget's disease is very different than for osteoporosis and uses a different type of ACTONEL. This leaflet does not cover using ACTONEL for Paget's disease. If you have Paget's disease, ask your health care provider how to use ACTONEL.

ACTONEL may reverse bone loss by stopping more loss of bone and increasing bone strength in most people who take it, even though they won't be able to see or feel a difference. ACTONEL helps lower the risk of breaking bones (fractures). Your health care provider may measure the thickness (density) of your bones or do other tests to check your progress.

See the end of this leaflet for information about osteoporosis.

Who should not take ACTONEL?

Do not take ACTONEL if you:

• have low blood calcium (hypocalcemia)
• cannot sit or stand up for 30 minutes
• have kidneys that work poorly
• have an allergy to ACTONEL. The active ingredient in ACTONEL is risedronate sodium. (See the end of this leaflet for a ul of all the ingredients in ACTONEL.)

Tell your doctor before using ACTONEL if:

• you are pregnant or may become pregnant. We do not know if ACTONEL can harm your unborn child.
• you are breast-feeding or plan to breast-feed. We do not know if ACTONEL can pass through your milk and if it can harm your baby.
• you have kidney problems. ACTONEL may not be right for you.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. ACTONEL can interact with other medicines. Keep a ul of all the medicines you take. Show it to all your health care providers, including your dentist and pharmacist, each time you get a new medicine.

How should I take ACTONEL?

The following instructions are for ACTONEL 5 mg (daily), ACTONEL 35 mg (Once-a-Week), and ACTONEL 75 mg (Two Consecutive Days each Month):

• Take ACTONEL first thing in the morning before you eat or drink anything except plain water.
• Take ACTONEL while you are sitting up or standing.
• Take ACTONEL with 6 to 8 ounces (about 1 cup) of plain water. Do not take it with any other drink besides plain water. Do not take it with coffee, tea, juice, milk, or other dairy drinks.
• Swallow ACTONEL whole. Do not chew the tablet or keep it in your mouth to melt or dissolve.
• After taking ACTONEL you must wait at least 30 minutes BEFORE:
  • lying down. You may sit, stand, or do normal activities like read the newspaper or take a walk.
  • eating or drinking anything except plain water.
  • taking vitamins, calcium, or antacids. Take vitamins, calcium, and antacids at a different time of the day from when you take ACTONEL.
• Keep taking ACTONEL for as long as your health care provider tells you.
• For ACTONEL to treat your osteoporosis or keep you from getting osteoporosis, you have to take it exactly as prescribed.
• Your health care provider may tell you to take calcium and vitamin D supplements and to exercise.

What is my ACTONEL schedule?

If your doctor has prescribedACTONEL 5 mg daily (a yellow tablet):

• Take 1 ACTONEL 5 mg tablet every day in the morning.
• If you miss a dose of your ACTONEL 5 mg in the morning, do not take it later in the day. Take only 1 ACTONEL 5 mg tablet the next morning and continue your usual schedule of 1 tablet a day. Do not take 2 tablets on the same day.

If your doctor has prescribedACTONEL 35 mg Once-a-Week (an orange tablet):

• Choose 1 day of the week that you will remember and that best fits your schedule to take your ACTONEL 35 mg. Every week, take 1 ACTONEL 35 mg tablet in the morning on your chosen day.
• If you miss a dose of your ACTONEL 35 mg in the morning, do not take it later in the day. Take only 1 ACTONEL 35 mg tablet the next morning and continue your usual schedule of 1 tablet on your chosen day of the week. Do not take 2 tablets on the same day.

If your doctor has prescribedACTONEL 75 mg Two Consecutive Days each Month (a pink tablet):

• Choose 2 days in a row during the month that best fits your schedule and that you will remember to take your ACTONEL 75 mg. Take 1 ACTONEL 75 mg tablet in the morning of your first chosen day. Take the second tablet in the morning of the following day. ACTONEL 75 mg tablets should be taken on the same two consecutive days each month.
• If you miss one or both tablets of your dose of ACTONEL 75 mg in the morning, do not take it later in the day.
  
  
  •  If the next month's scheduled doses are more than 7 days away do the following:
    
  •  If both tablets were missed, take the first ACTONEL 75 mg tablet on the morning after the day it is remembered and the second tablet on the next consecutive morning.
    
    
  •  If only one tablet is missed, take the missed tablet on the morning after the day it is remembered.
    
    
  •  You should then continue your usual schedule of ACTONEL 75 mg on two consecutive days each month.
    
    
  •  Do not take more than two 75 mg tablets within 7 days.
    
    
  •  If the next month's scheduled doses are 1 to 7 days away, you should wait until next month's scheduled doses and then resume taking ACTONEL 75 mg on two consecutive days each month as originally scheduled.
    
    
• If you are not sure what to do if you miss a dose, contact your health care provider who will be able to advise you.

What should I avoid while taking ACTONEL?

• Do not eat or drink anything except water before you take ACTONEL and for at least 30 minutes after you take it.
• Do not lie down for at least 30 minutes after you take ACTONEL.
• Foods and some vitamin supplements and medicines can stop your body from absorbing (using) ACTONEL. Therefore, do not take anything other than plain water at or near the time you take ACTONEL. (See "How should I take ACTONEL?").

What are the possible side effects of ACTONEL?

Stop taking ACTONEL and tell your health care provider right away if:

• swallowing is difficult or painful
• you have chest pain
• you have very bad heartburn or it doesn't get better

ACTONEL may cause:

• pain or trouble swallowing (dysphagia)
• heartburn (esophagitis)
• ulcers in your stomach and esophagus (the tube that connects the mouth and the stomach)
• pain in bones, joints or muscles, sometimes severe. Pain may start as soon as one day or up to several months after starting ACTONEL.

The most common side effects with ACTONEL include back pain, joint pain, upset stomach, abdominal (stomach area) pain, constipation, diarrhea, gas, and headache. Tell your health care provider if you have pain or discomfort in your stomach or esophagus. Rarely, severe skin reactions may occur. Patients may get allergic reactions such as rash, hives, or in rare cases, swelling that can be of the face, lips, tongue, or throat, which may cause trouble breathing or swallowing.

In rare cases, patients taking ACTONEL may get eye inflammation, usually with pain, redness and sensitivity to light.

Rarely, patients had jaw problems associated with delayed healing and infection, often following tooth extraction.

These are not all the possible side effects of ACTONEL. You can ask your health care provider or pharmacist about other side effects. Any time you have a medical problem you think may be from ACTONEL, talk to your doctor.

What is osteoporosis?

Osteoporosis is a disease that causes bones to become thinner. Thin bones can break easily. Most people think of their bones as being solid like a rock. Actually, bone is living tissue, just like other parts of the body—your heart, brain, or skin, for example. Bone just happens to be a harder type of tissue. Bone is always changing. Your body keeps your bones strong and healthy by replacing old bone with new bone.

Osteoporosis causes the body to remove more bone than it replaces. This means that bones get weaker. Weak bones are more likely to break. Osteoporosis is a bone disease that is quite common, especially in older women. However, young people and men can develop osteoporosis, too. Osteoporosis can be prevented, and with proper therapy it can be treated.

How can osteoporosis affect me?

• You may not have any pain or other symptoms when osteoporosis begins.
• You are more likely to break (fracture) a bone especially if you fall because osteoporosis makes your bones weaker. You are most likely to break a bone in your back (spine), wrist, or hip.
• You may “shrink” (get shorter).
• You may get a “hump” (curve) in your back.
• You may have bad back pain that makes you stop some activities.

Who is at risk for osteoporosis?

Many things put people at risk for osteoporosis. The following people have a higher chance of getting osteoporosis:

Women who

• are going through or who are past menopause ("the change")
• are white (Caucasian) or Asian

People who

• are thin
• have a family member with osteoporosis
• do not get enough calcium or vitamin D
• do not exercise
• smoke
• drink alcohol often
• take bone thinning medicines (like prednisone or other corticosteroids) for a long time

General information about ACTONEL:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ACTONEL for a condition for which it was not prescribed. Do not give ACTONEL to other people, even if they have the same symptoms you have. It may harm them.

What if I have other questions about ACTONEL?

This leaflet summarizes the most important information about ACTONEL for osteoporosis. If you have more questions about ACTONEL, ask your health care provider or pharmacist. They can give you information written for health care professionals. For more information, call 1-877-ACTONEL (toll-free) or visit our web site at www.actonel.com.

What are the ingredients of ACTONEL?

ACTONEL (active ingredient): risedronate sodium.

ACTONEL (inactive ingredients): crospovidone, ferric oxide red (35 mg and 75 mg tablets only), ferric oxide yellow (5 mg and 35 mg tablets only), hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate (5 mg, 30 mg and 35 mg tablets only), magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, and titanium dioxide.

ACTONEL^® is marketed by:
Procter & Gamble Pharmaceuticals, Inc.
Cincinnati, OH 45202
and
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

May 2007

© 2007 Procter & Gamble Pharmaceuticals, Inc.