Risedronate Drug Information

    Generic name: RISEDRONATE SODIUM

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    Uses of Risedronate

    Postmenopausal Osteoporosis Risedronate sodium delayed-release tablets are indicated for the treatment of

    osteoporosis in postmenopausal women. In postmenopausal women, risedronate sodium has been shown to reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures.

    Important Limitations of Use

    The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium delayed-release tablets for the treatment of osteoporosis are based on clinical data of one year duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

    Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

    Dosage & Administration of Risedronate

    • One 35 mg delayed-release tablet once-a-week (2.1) Instruct patients to:
    • Take risedronate sodium delayed-release tablets in the morning immediately following breakfast with at least 4 ounces of plain water (2.2)
    • Avoid lying down for 30 minutes after taking risedronate sodium delayed-release tablets (2.2)
    • Take supplemental calcium and vitamin D if dietary intake is inadequate (2.3) 2.1 Treatment of Postmenopausal Osteoporosis [ see Indications and Usage (1.1) ] The recommended regimen is:
    • one 35 mg delayed-release tablet orally, taken once-a-week [see Indications and Usage (1.1)] 2.2 Important Administration Instructions Instruct patients to do the following:
    • Take risedronate sodium delayed-release tablets in the morning immediately following breakfast. Risedronate sodium delayed-release tablets should be taken immediately following breakfast and not under fasting conditions because of a higher risk of abdominal pain if taken before breakfast when fasting.
    • Swallow risedronate sodium delayed-release tablets whole while in an upright position and with at least 4 ounces of plain water to facilitate delivery to the stomach. Avoid lying down for 30 minutes after taking the medication [ see Warnings and Precautions (5.2) ].
    • Do not chew, cut, or crush risedronate sodium delayed-release tablets. 2.3 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [ see Warnings and Precautions (5.3) ] and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium delayed-release tablets. 2.4 Administration Instructions for Missed Doses If the once-weekly dose is missed, instruct patients to take one tablet on the morning after they remember and return to taking one tablet once-a-week, as originally scheduled on their chosen day. Patients should not take two tablets on the same day.

    Side Effects of Risedronate

    Clinical Studies Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Postmenopausal Osteoporosis Once-a-Week Dosing with Risedronate Sodium Delayed-Release tablets The safety of risedronate sodium delayed-release 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium delayed-release 35 mg once-a-week to risedronate sodium immediate-release 5 mg daily in postmenopausal women 50 years of age or older. Risedronate sodium delayed-release was administered either at least 30 minutes before (N = 308) or immediately following (N = 307) breakfast, and risedronate sodium immediate-release 5 mg daily (N = 307) was administered at least 30 minutes before breakfast.

    Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H 2 antagonists were included in this clinical trial. All women received daily supplementation with 1000 mg of elemental calcium plus 800 to 1000 international units vitamin D. As treatment with risedronate sodium resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions, safety results that follow refer only to risedronate sodium delayed-release 35 mg once-a-week immediately following breakfast and risedronate sodium immediate-release 5 mg daily. The incidence of all-cause mortality was 0.0% in the risedronate sodium delayed-release 35 mg once-a-week group and 0.3% in the risedronate sodium immediate-release 5 mg daily group.

    The incidence of serious adverse reactions was 6.5% in the risedronate sodium delayed-release 35 mg once-a-week group and 7.2% in the risedronate sodium immediate-release 5 mg daily group. The percentage of patients who withdrew from the study due to adverse reactions was 9.1% in the risedronate sodium delayed-release 35 mg once-a-week group and 8.1% in the risedronate sodium immediate-release 5 mg daily group. The overall safety and tolerability profiles of the two dosing regimens were similar.

    Table 1 lists adverse reactions reported in greater than or equal to 2% of patients. Adverse reactions are shown without attribution of causality. Table 1 Adverse Reactions Occurring at a Frequency of greater than or equal to 2% in Either Treatment Group System Organ Class Preferred Term 35 mg Risedronate sodium Delayed-release Weekly N = 307% 5 mg Risedronate sodium Immediate-release Daily N = 307% Gastrointestinal disorders Diarrhea 8.8

    Nausea 3.6 3.9 Abdominal pain upper 2.9 2.3 Infections and infestations Influenza

    7.2

    Bronchitis 3.9 4.2 Upper respiratory tract infection 3.6 2.6 Musculoskeletal and connective

    tissue disorders Arthralgia 6.8

    Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported

    with bisphosphonate use. The overall incidence of acute phase reaction was 2.3% in the risedronate sodium delayed-release 35 mg once-a-week group and 1.3% in the risedronate sodium immediate-release 5 mg daily group. These incidence rates are based on reporting of one or more pre-specified acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less.

    Gastrointestinal Adverse Reactions : Adverse reactions related to the upper gastrointestinal tract occurred in 16% of subjects treated with risedronate sodium delayed-release 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily. The incidence of upper gastrointestinal tract adverse reactions in the risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: abdominal pain (5.2% versus 2.9%), dyspepsia (3.9% versus 3.9%), upper abdominal pain (2.9% versus 2.3%), gastritis (1.0% versus 1.0%), and gastroesophageal reflux disease (1.0% versus 1.6%). Study discontinuation due to abdominal pain occurred in 1.3% of the risedronate sodium delayed-release 35 mg once-a-week group and 0.7% of the risedronate sodium immediate-release 5 mg daily group. Musculoskeletal Adverse Reactions: Selected musculoskeletal adverse reactions were reported in 16% of subjects treated with risedronate sodium delayed-release 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily.

    The incidence of musculoskeletal adverse reactions in the risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: arthralgia (6.8% versus 7.8%), back pain (6.8% versus 5.9%), musculoskeletal pain (2.0% versus 1.6%), and myalgia (1.3% versus 1.0%). Laboratory Test Findings : Parathyroid hormone: The effect of risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily on parathyroid hormone was evaluated in postmenopausal women with osteoporosis. At week 52, in subjects with normal levels at baseline, PTH levels greater than 65 pg/mL (upper limit of normal) were noted in 9% of subjects receiving risedronate sodium delayed-release 35 mg once-a-week and 8% of subjects receiving risedronate sodium immediate-release 5 mg daily. In subjects with normal levels at baseline, PTH levels greater than 97 pg/mL (1.5 times the upper limit of normal) were seen in 2% of subjects receiving risedronate sodium delayed-release 35 mg once-a-week and no subjects receiving risedronate sodium immediate-release 5 mg daily.

    There were no clinically significant differences between treatment groups for levels of calcium, phosphorus and magnesium. Daily Dosing with Risedronate Sodium Immediate-Release 5 mg tablets The safety of risedronate sodium immediate-release 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate sodium immediate-release 5 mg daily.

    Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), and H 2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D 3 level was below normal at baseline. The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the risedronate sodium immediate-release 5 mg daily group.

    The incidence of serious adverse reactions was 24.6% in the placebo group and 27.2% in the risedronate sodium immediate-release 5 mg daily group. The percentage of patients who withdrew from the study due to adverse reactions was 15.6% in the placebo group and 14.8% in the risedronate sodium immediate-release 5 mg daily group. The most common adverse reactions reported in greater than 10% of subjects were: back pain, arthralgia, abdominal pain and dyspepsia.

    Gastrointestinal Adverse Reactions: The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10.0% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the risedronate sodium immediate-release 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse reactions was similar between the placebo and risedronate sodium immediate-release 5 mg daily groups. Musculoskeletal Adverse Reactions: The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%). Laboratory Test Findings : Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with risedronate sodium immediate-release 5 mg daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium immediate-release 5 mg daily at 3 years.

    Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and risedronate sodium immediate-release 5 mg daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with risedronate sodium immediate-release 5 mg daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings : In the risedronate sodium immediate-release 5 mg daily clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind.

    Endoscopies were performed on equal numbers of patients between the placebo and treated groups. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate sodium immediate-release 5 mg daily).

    Postmarketing Experience

    The following adverse reactions have been reported with the use of risedronate sodium immediate-release. 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, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.

    Gastrointestinal Adverse Reactions Reactions 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. Pulmonary Asthma exacerbations

    Warnings & Cautions for Risedronate

    • Products Containing Same Active Ingredient : Patients receiving Actonel should not be treated with risedronate sodium delayed-release tablets (5.1)
    • Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue use if new or worsening symptoms occur (5.2)
    • Hypocalcemia may worsen and must be corrected prior to use (5.3)
    • Osteonecrosis of the Jaw has been reported (5.4)
    • Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop (5.5, 6.2)
    • Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture (5.6) 5.1 Drug Products with the Same Active Ingredient Risedronate sodium delayed-release tablets contain the same active ingredient found in Actonel ® . A patient being treated with Actonel should not receive risedronate sodium delayed-release tablets. 5.2 Upper Gastrointestinal Adverse Reactions 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 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) [ see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17) ]. 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 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 4 ounces 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 [ see Dosage and Administration (2) ]. In patients who cannot comply with dosing instructions due to mental disability, therapy with 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. 5.3 Mineral Metabolism Hypocalcemia has been reported in patients taking risedronate sodium delayed-release tablets. Treat hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting risedronate sodium therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients [ see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17) ]. 5.4 Jaw Osteonecrosis 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 risedronate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. 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 ONJ 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 [ see Adverse Reactions (6.2) ]. 5.5 Musculoskeletal Pain In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [ see Adverse Reactions (6.2) ]. 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. Consider discontinuing use if severe symptoms develop. 5.6 Atypical Subtrochanteric and Diaphyseal Femoral Fractures 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 (for example, 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. 5.7 Renal Impairment Risedronate sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. 5.8 Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate sodium have not been performed.

    Drug Interactions with Risedronate

    Calcium Supplements/Antacids

    When risedronate sodium was administered following breakfast, the co-administration of a tablet containing 600 mg of elemental calcium and 400 international units vitamin D reduced risedronate bioavailability by approximately 38%. Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of risedronate sodium and should not be taken together.

    Histamine 2 (H 2 ) Blockers and Proton Pump Inhibitors (PPIs) Drugs

    that raise stomach pH (for example, PPIs or H 2 blockers) may cause faster drug release from enteric coated (delayed-release) drug products such as risedronate sodium. Co-administration of risedronate sodium with the PPI, esomeprazole, increased risedronate bioavailability. The maximum plasma concentration (C max ) and the area under the plasma concentration (AUC) were increased by 60 percent and 22 percent, respectively.

    Concomitant administration of risedronate sodium and H 2 blockers or PPIs is not recommended.

    Hormone Therapy

    Concomitant use of risedronate sodium with estrogens and estrogen agonist/antagonists has not been studied.

    Aspirin/Nonsteroidal Anti-Inflammatory Drugs

    In the Phase 3 study comparing risedronate sodium 35 mg once-a-week immediately following breakfast and risedronate sodium 5 mg daily, 18% of NSAID users (any use) in both groups developed upper gastrointestinal adverse reactions. Among non-users, 13% of patients taking risedronate sodium 35 mg once-a-week immediately following breakfast developed upper gastrointestinal adverse reactions, compared to 12% taking risedronate sodium 5 mg daily.

    Pregnancy Safety for Risedronate

    Pregnancy Risk Summary Available data on use of risedronate sodium in pregnant women are insufficient to inform drug-associated risk of adverse maternal or fetal outcomes. Discontinue risedronate sodium when pregnancy is recognized. In animal reproduction studies, daily oral administration of risedronate to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately 5 and 26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m 2 ), the dose indicated for treatment of Paget’s disease.

    A low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to the 30 mg human daily dose. Delayed skeletal ossification was observed in fetuses of dams treated at approximately 2.5 to 5 times the 30 mg human daily dose. Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates upon daily oral administration of risedronate to pregnant rats during mating and/or gestation starting at doses equivalent to the 30 mg daily human dose.

    Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of weeks to years. The amount of bisphosphonate incorporated into adult bone available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on mechanism of action of bisphosphonates, there is a potential 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. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

    In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal data In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human Paget’s disease dose of 30 mg/day (based on body surface area, mg/m 2 ). 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. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose.

    The number of fetuses exhibiting incomplete ossification of sternebrae or skull of 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 fetuses of dams treated with oral doses approximately 5 times the human dose. No significant ossification effects were seen in fetuses of 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.

    Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates when pregnant rats were treated daily during mating and/or gestation with oral doses equivalent to the human dose or higher.

    Pediatric Use of Risedronate

    Pediatric Use Risedronate sodium is not indicated for use in pediatric patients. The safety and effectiveness of risedronate sodium immediate-release 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 OI (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate sodium immediate-release group compared to the placebo group was observed.

    However, treatment with risedronate sodium immediate-release did not result in a reduction in the risk of fracture in pediatric patients with OI. In risedronate sodium immediate-release 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 sodium immediate-release and 6% of patients treated with placebo.

    Other adverse reactions reported in greater than or equal to 10% of patients treated with risedronate sodium immediate-release and with a higher frequency than placebo were: pain in the extremity (21% with risedronate sodium immediate-release 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%).

    Contraindications for Risedronate

    • Risedronate sodium delayed-release tablets contraindicated in patients with the following conditions: 1. Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [ see Warnings and Precautions (5.2) ] 2. Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration (2), Warnings and Precautions (5.2) ] 3. Hypocalcemia [ see Warnings and Precautions (5.3) ] 4. Known hypersensitivity to any component of this product. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported [ see Adverse Reactions (6.2) ]
    • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (4, 5.2)
    • Inability to stand or sit upright for at least 30 minutes (4, 5.2)
    • Hypocalcemia (4, 5.3)
    • Known hypersensitivity to any component of this product (4, 6.2)

    Overdosage Information for Risedronate

    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. While milk or antacids containing calcium may be given to bind risedronate sodium immediate-release and reduce absorption of the drug, the impact of this intervention for risedronate sodium delayed-release tablets has not been evaluated.

    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 of risedronate 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 human Paget’s disease dose of 30 mg/day based on surface area (mg/m 2 ).

    Clinical Studies of Risedronate

    Treatment of Osteoporosis in Postmenopausal Women

    The efficacy of risedronate sodium delayed-release 35 mg once-a-week in the treatment of postmenopausal osteoporosis was demonstrated in a randomized, double-blind, active-control trial of approximately 900 subjects. All patients in this study received supplemental calcium (1000 mg/day) and vitamin D (800 to 1000 international units/day). The primary efficacy endpoint was percent change in lumbar spine bone mineral density at 1 year. Risedronate sodium delayed-release 35 mg once-a-week administered after breakfast was shown to be non-inferior to risedronate sodium immediate-release 5 mg daily.

    Table 2 presents the primary efficacy analysis, percent change in lumbar spine BMD, in the intent-to-treat population with last observation carried forward (LOCF). Table 2 Lumbar Spine BMD-Percent Change from Baseline at Endpoint Risedronate sodium immediate-release 5 mg Daily N = 307 Risedronate sodium delayed-release 35 mg Once-a-Week Following Breakfast N = 307 Primary Efficacy (LOCF) n 270 261 LS Mean (95% CI) 3.1 * 3.3 * LS Mean Difference (95% CI) -0.2 (-0.8, 0.3) N = number of intent-to-treat patients within specified treatment; n = number of patients with values at the visit. * Indicates a statistically significant difference from baseline determined from 95% CI unadjusted for multiple comparisons. LS = Least Squares at 1 year LOCF LS Mean Difference is 5 mg daily minus 35 mg weekly treatment. Fracture efficacy with Risedronate Sodium Immediate-Release 5 mg daily The fracture efficacy of risedronate sodium immediate-release 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) (risedronate sodium immediate-release 5 mg daily, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (risedronate sodium immediate-release 5 mg daily, 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 3 levels (approximately 40 nmol/L or less) also received 500 international units/day supplemental vitamin D. 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 (that is, clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient’s first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Risedronate sodium immediate-release 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 3). 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.

    Table 3 The Effect of Risedronate sodium 5 mg Immediate-Release Daily on the Risk of Vertebral Fractures VERT NA Proportion of Patients with Fracture (%) a Placebo N = 678 Risedronate sodium 5 mg N = 696 Absolute Risk Reduction (%) Relative Risk Reduction (%) New and Worsening 0 to 1 Year 7.2 3.9 3.3 49 0 to 2 Years 12.8 8.0 4.8 42 0 to 3 Years 18.5 13.9 4.6 33 New 0 to 1 Year 6.4 2.4 4.0 65 0 to 2 Years 11.7 5.8 5.9 55 0 to 3 Years 16.3 11.3 5.0 41 VERT MN Placebo N = 346 Risedronate sodium 5 mg N = 344 Absolute Risk Reduction (%) Relative Risk Reduction (%) New and Worsening 0 to 1 Year 15.3 8.2 7.1 50 0 to 2 Years 28.3 13.9 14.4 56 0 to 3 Years 34.0 21.8 12.2 46 New 0 to 1 Year 13.3 5.6 7.7 61 0 to 2 Years 24.7 11.6 13.1 59 0 to 3 Years 29.0 18.1 10.9 49 a Calculated by Kaplan-Meier methodology. 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.

    Risedronate sodium immediate-release 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies. Figure 1 Nonvertebral Osteoporosis-Related Fractures Cumulative Incidence Over 3 years Combined VER MN and VERT NA Histology/Histomorphometry Bone biopsies from 110 postmenopausal women were obtained at endpoint in the VERT NA study.

    Patients had received placebo or daily risedronate sodium immediate-release (2.5 mg or 5 mg) for 2 to 3 years. Histologic evaluation (N = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in risedronate sodium immediate-release treated women. These findings demonstrate that bone formed during risedronate sodium immediate-release administration is of normal quality.

    The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 21 treated with placebo and 23 patients treated with risedronate sodium immediate-release 5 mg daily. Mineralizing surface decreased moderately in risedronate sodium immediate-release treated patients (median percent change: placebo, -21%; risedronate sodium immediate-release 5 mg daily, -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 risedronate sodium immediate-release 5 mg daily and placebo-treated groups lost height during the studies. Patients who received risedronate sodium immediate-release 5 mg daily had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -2.4 mm/yr in the placebo group compared to -1.3 mm/yr in the risedronate sodium immediate-release 5 mg daily group.

    In VERT NA, the median annual height change was -1.1 mm/yr in the placebo group compared to -0.7 mm/yr in the risedronate sodium immediate-release 5 mg daily group. 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 risedronate sodium immediate-release 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo.

    In both VERT studies (VERT MN and VERT NA), risedronate sodium immediate-release 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points. Table 4 Mean Percent Increase in BMD from Baseline in Patients Taking Risedronate sodium Immediate-Release 5 mg or Placebo at Endpoint a VERT MN b VERT NA b BMD MN c BMD NA c Placebo N = 323 5 mg N = 323 Placebo N = 599 5 mg N = 606 Placebo N = 161 5 mg N = 148 Placebo N = 191 5 mg N = 193 Lumbar Spine 1.0 6.6 0.8 5.0 0.0 4.0 0.2

    Femoral Neck -1.4 1.6 -1.0 1.4 -1.1 1.3 0.1 2.4 Femoral Trochanter

    -1.9 3.9 -0.5 3.0 -0.6 2.5 1.3

    Midshaft Radius -1.5 * 0.2 * -1.2 * 0.1 * ND ND

    a The endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last post-baseline BMD value prior to the study's last time point is used. b The duration of the studies was 3 years. c The duration of the studies was 1.5 to 2 years. * BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, N = 222; 5 mg, N = 214) and VERT NA (placebo, N = 310; 5 mg, N = 306). ND = analysis not done figure1

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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