Risedronate Sodium: Package Insert and Label Information

RISEDRONATE SODIUM — risedronate sodium tablet, film coated
Macleods Pharmaceuticals Limited

1 INDICATIONS & USAGE

1.1 Postmenopausal Osteoporosis

Risedronate sodium tablets, USP are indicated for the treatment and prevention of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, risedronate sodium tablets, USP reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see Clinical Studies (14.1, 14.2)].

1.2 Osteoporosis in Men

Risedronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis.

1.3 Glucocorticoid-Induced Osteoporosis

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

1.4 Paget’s Disease

Risedronate sodium tablets, USP are indicated for treatment of Pagets’s disease of bone in men and women.

1.5 Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium tablets, USP for the treatment of osteoporosis are based on clinical data of three years 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.

2 DOSAGE & ADMINISTRATION

2.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]

Indications and Usage (1.1)]

The recommended regimen is:

•one 5 mg tablet orally, taken daily
or
•one 35 mg tablet orally, taken once-a-week
or
•one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month

2.2 Prevention of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]

[see Indications and Usage (1.1) ]

  • The recommended regimen is:
    one 5 mg tablet orally, taken daily
    or
  • one 35 mg tablet orally, taken once-a-week
  • or
    alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be considered

2.3 Treatment to Increase Bone Mass in Men with Osteoporosis [see Indications and Usage (1.2)]

[see Indications and Usage (1.2)]

  • one 35 mg tablet orally, taken once-a-week

2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis [see Indications and Usage (1.3)]

[see Indications and Usage (1.3) ]

The recommended regimen is:

· one 5 mg tablet orally, taken daily

2.5 Treatment of Paget’s Disease [see Indications and Usage (1.4)]

[see Indications and Usage (1.4) ]

The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.

2.6 Important Administration Instructions

Instruct patients to do the following:

· Take risedronate sodium tablets at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [see Drug Interactions (7.1) ]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium.

· Swallow risedronate sodium tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [see Warnings and Precautions (5.1) ]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.

· Do not eat or drink anything except plain water, or take other medications for at least30 minutes after taking risedronate sodium tablets

2.7 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; 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 tablets.

2.8 Administration Instructions for Missed Doses

Instruct patients about missing risedronate sodium tablets doses as follows:

• If a dose of risedronate sodium tablet 35 mg once-a-week is missed:

○ 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.

○ Do not take 2 tablets on the same day.

• If one or both tablets of risedronate sodium 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away:

○ If both tablets are missed, take one risedronate sodium 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning.

○ If only one risedronate sodium 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered

○ Return to taking their risedronate sodium 75 mg on two consecutive days per month as originally scheduled.

• If one or both tablets of risedronate sodium 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are within 7 days:

○ Wait until their next month’s scheduled doses and then continue taking risedronate sodium 75 mg on two consecutive days per month as originally scheduled.

3 DOSAGE FORMS & STRENGTHS

• 5 mg yellow coloured, circular, biconvex, film coated tablet debossed with “CL 90” on one side and plain on other side.

• 30 mg white to off white, circular, biconvex, film coated tablet debossed with “CL 91” on one side and plain on other side

4 CONTRAINDICATIONS

Risedronate sodium is contraindicated in patients with the following conditions:

· Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1) ]

· Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2), Warnings and Precautions (5.1)]

· Hypocalcemia [see Warnings and Precautions (5.2) ]

· Known hypersensitivity to risedronate sodium or any of its excipients.Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Drug Products with the Same Active Ingredient

Risedronate sodium tablet contains the same active ingredient found in Atelvia®. A patient being treated with Atelvia should not receive risedronate sodium 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 (17.1)].

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 full glass (6 to 8 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. Treat hypocalcemia and other disturbances of bone and mineral metabolism 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, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].

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 sodium. 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 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 [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).

5.8 Glucocorticoid-Induced Osteoporosis

Before initiating risedronate sodium treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.

5.9 Laboratory Test Interactions

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

6 ADVERSE REACTIONS

6.1 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

Daily Dosing

The safety of risedronate sodium 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate sodium 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 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 D3 level was below normal at baseline.

The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the risedronate sodium 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the risedronate sodium 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the risedronate sodium 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality.

Table 1 Adverse Events Occurring at a Frequency greater than or equal to 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials
Body System Placebo N = 1619 % 5 mg Risedronate Sodium N = 1613 %
Body as a Whole
Infection 29.9 31.1
Back Pain 26.1 28.0
Accidental Injury 16.8 16.9
Pain 14.0 14.1
Abdominal Pain 9.9 12.2
Flu Syndrome 11.6 10.5
Headache 10.8 9.9
Asthenia 4.5 5.4
Neck Pain 4.7 5.4
Chest Pain 5.1 5.0
Allergic Reaction 5.9 3.8
Cardiovascular System
Hypertension 9.8 10.5
Digestive System
Constipation 12.6 12.9
Diarrhea 10.0 10.8
Dyspepsia 10.6 10.8
Nausea 11.2 10.5
Metabolic & Nutritional Disorders
Peripheral Edema 8.8 7.7
Musculoskeletal System
Arthralgia 22.1 23.7
Arthritis 10.1 9.6
Traumatic Bone Fracture 12.3 9.3
Joint Disorder 5.3 7.0
Myalgia 6.2 6.7
Bone Pain 4.8 5.3
Nervous System
Dizziness 5.7 7.1
Depression 6.1 6.8
Insomnia 4.6 5.0
Respiratory System
Bronchitis 10.4 10.0
Sinusitis 9.1 8.7
Rhinitis 5.1 6.2
Pharyngitis 5.0 6.0
Increased Cough 6.3 5.9
Skin and Appendages
Rash 7.1 7.9
Special Senses
Cataract 5.7 6.5
Urogenital System
Urinary Tract Infection 10.4 11.1

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

Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and risedronate sodium 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%).

Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with risedronate sodium 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium 5 mg once 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 5 mg once 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 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.

Endoscopic Findings: In the risedronate sodium 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 [75 (14.5%) placebo; 75 (11.9%) risedronate sodium]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate sodium).

Once-a-Week Dosing
The safety of risedronate sodium 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium 5 mg daily and risedronate sodium 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to risedronate sodium 5 mg daily and 485 exposed to risedronate sodium 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 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 D3 level was below normal at baseline.

The incidence of all-cause mortality was 0.4% in the risedronate sodium 5 mg daily group and 1.0% in the risedronate sodium 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the risedronate sodium 5 mg daily group and 8.2% in the risedronate sodium 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the risedronate sodium 5 mg daily group and 11.5% in the risedronate sodium 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the risedronate sodium 5 mg daily group and the risedronate sodium 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%).

Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the risedronate sodium 5 mg daily group and 14.2% of patients in the risedronate sodium 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the risedronate sodium 5 mg daily group and 6.2% of patients in the risedronate sodium 35 mg once-a-week group.

Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the risedronate sodium 5 mg daily and risedronate sodium 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).

Monthly Dosing

Two Consecutive Days per Month

The safety of risedronate sodium 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to risedronate sodium 5 mg daily and 616 were exposed to risedronate sodium 75 mg two consecutive days per month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was 1.0% for the risedronate sodium 5 mg daily group and 0.5% for the risedronate sodium 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the risedronate sodium 5 mg daily group and 14.4% in the risedronate sodium 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the risedronate sodium 5 mg daily group and 13.0% in the risedronate sodium 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on risedronate sodium 5 mg daily and 7.6% of patients on risedronate sodium 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on risedronate sodium 5 mg daily and 0.6% of patients on risedronate sodium 75 mg two consecutive days per month.

Gastrointestinal Adverse Events: The risedronate sodium 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% versus 0.2%) and diarrhea (1.0% versus 0.3%) compared to the risedronate sodium 5 mg daily group. Most of these events occurred within a few days of dosing.

Ocular Adverse Events: None of the patients treated with risedronate sodium 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with risedronate sodium 5 mg daily reported uveitis.

Laboratory Test Findings: When risedronate sodium 5 mg daily and risedronate sodium 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the risedronate sodium 5 mg daily group, risedronate sodium 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3.0%).

Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Prevention of Postmenopausal Osteoporosis

Daily Dosing

The safety of risedronate sodium 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and risedronate sodium-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to risedronate sodium 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to risedronate sodium 5 mg. All women received 1000 mg of elemental calcium per day.

In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the risedronate sodium 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the risedronate sodium 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the risedronate sodium 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of risedronate sodium 5 mg group.

In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the risedronate sodium 5 mg group.

The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the risedronate sodium 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the risedronate sodium 5 mg group.

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

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

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

The safety of risedronate sodium 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to risedronate sodium 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.

The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the risedronate sodium 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the risedronate sodium 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the risedronate sodium 5 mg daily group.Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the risedronate sodium 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the risedronate sodium 5 mg daily group.

Treatment of Paget’s Disease

Risedronate sodium has been studied in 392 patients with Paget’s disease of bone. As in trials of risedronate sodium 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.

The safety of risedronate sodium was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to risedronate sodium and 61 patients exposed to Didronel®. The adverse event profile was similar for risedronate sodium and Didronel: 6.6% (4/61) of patients treated with risedronate sodium 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. Table 2 lists adverse events reported in greater than or equal to 5% of risedronate sodium-treated patients in Phase 3 Paget’s disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient.

Table 2 Adverse Events Reported in greater than or equal to 5% of Risedronate Sodium -Treated Patients* in Phase 3 Paget’s Disease Trials
Body System 30 mg/day x 2 months Risedronate Sodium %(N = 61) 400 mg/day x 6 months Didronel%(N = 61)
Body as a Whole
Flu Syndrome 9.8 1.6
Chest Pain 6.6 3.3
Gastrointestinal
Diarrhea 19.7 14.8
Abdominal Pain 11.5 8.2
Nausea 9.8 9.8
Constipation 6.6 8.2
Metabolic and Nutritional Disorders
Peripheral Edema 8.2 6.6
Musculoskeletal
Arthralgia 32.8 29.5
Nervous
Headache 18.0 16.4
Dizziness 6.6 4.9
Skin and Appendages
Rash 11.5 8.2
*Considered to be possibly or probably causally related in at least one patient.

Gastrointestinal Adverse Events: During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the risedronate sodium group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.

Ocular Adverse Events: Three patients who received risedronate sodium 30 mg daily experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during risedronate sodium treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

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