Risedronate Sodium (risedronate sodium monohydrate 35 mg) Dailymed

Recent Major Changes Section

Contraindications (4) 03/2015

Warnings and Precautions (5.4) 04/2015

1 Indications And Usage

Risedronate sodium delayed-release tablets are a bisphosphonate in a delayed-release formulation and is indicated for treatment of postmenopausal osteoporosis (1.1)

Limitations of Use

Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (1.2)

1.1 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 [see Clinical Studies (14.1)].

1.2 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.

2 Dosage And Administration

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 []

The recommended regimen is:

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

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.

• 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 delayed-release tablets, 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 delayed-release tablets are 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 delayed-release tablets 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 delayed-release tablets should be used under appropriate supervision.

There have been postmarketing 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 delayed-release tablets 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 preexisting 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 delayed-release tablets are 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 delayed-release tablets have not been performed.

6 Adverse Reactions

Most common adverse reactions (greater than 5%) include: diarrhea, influenza, arthralgia, back pain, and abdominal pain (6.1)

Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and eye inflammation (iritis, uveitis) have been reported rarely (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

Once-a-Week Dosing with risedronate sodium delayed-release tablets

The safety of risedronate sodium delayed-release tablet, 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 tablet, 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 tablets were 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 preexisting 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 daily supplementation with 1000 mg of elemental calcium plus 800 to 1000 international units vitamin D. As treatment with risedronate sodium delayed-release tablets 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 uls 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 Tablets	5 mg Risedronate sodium Immediate-release
	Weekly N = 307	Daily N = 307
	%	%
Gastrointestinal disorders
Diarrhea	8.8	4.9
Abdominal pain	5.2	2.9
Constipation	4.9	2.9
Vomiting	4.9	1.6
Dyspepsia	3.9	3.9
Nausea	3.6	3.9
Abdominal pain upper	2.9	2.3
Infections and infestations
Influenza	7.2	6.2
Bronchitis	3.9	4.2
Upper respiratory tract infection	3.6	2.6
Musculoskeletal and connective tissue disorders
Arthralgia	6.8	7.8
Back pain	6.8	5.9
Pain in extremity	3.9	2.3
Musculoskeletal pain	2.0	1.6
Muscle spasms	1.0	2.3
Nervous system disorders
Dizziness	2.6	3.3
Headache	2.6	4.9

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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 tablet, 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 preexisting gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), 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 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 [75 (14.5%) placebo; 75 (11.9%) risedronate sodium immediate-release 5 mg daily]. 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).

6.2 Postmarketing Experience

The following adverse reactions have been reported with the use of risedronate sodium delayed-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 [see Warnings and Precautions (5.2)].

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.5)].

Eye Inflammation

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

Jaw Osteonecrosis

Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions (5.4)].

Pulmonary

Asthma exacerbations