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Risedronate Sodium Delayed-Release Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Risedronate sodium is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na •2.5 H2O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:

Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Each risedronate DR tablet for oral administration contains the equivalent of 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate.

Inactive Ingredients

Edetate disodium, ferric oxide yellow, magnesium stearate, methacrylic acid copolymer, polysorbate 80, silicified microcrystalline cellulose (ProSolv SMCC90), simethicone, sodium starch glycolate, stearic acid, talc, and triethyl citrate.

2. INDICATIONS AND USAGE

2.1 Postmenopausal Osteoporosis

Risedronate DR is indicated for the treatment of osteoporosis in postmenopausal women. Bone mineral density increases achieved at one year with risedronate DR are non-inferior to increases seen with risedronate sodium 5 mg (immediate-release) daily. Daily risedronate sodium 5 mg (immediaterelease) has been shown to reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures.

2.2 Important Limitations of Use

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

3. DOSAGE AND ADMINISTRATION

Risedronate DR should be taken in the morning immediately following breakfast.

When compared with immediate-release risedronate, treatment with risedronate DR resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions. Risedronate DR should be taken immediately following breakfast and not under fasting conditions.

To facilitate delivery to the stomach, risedronate DR should be swallowed whole while the patient is in an upright position and with at least 4 ounces of plain water. Tablets should not be chewed, cut, or crushed. Patients should not lie down for 30 minutes after taking the medication [see Warnings and Precautions].

Patients should receive supplemental calcium and vitamin D [see Warnings and Precautions]. Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of risedronate DR and it is recommended they be taken at a different time of the day. Risedronate DR is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly.

3.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage]

The recommended regimen is:

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

4. CONTRAINDICATIONS

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia

• Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration, Warnings and Precautions]

• Hypocalcemia [see Warnings and Precautions]

• Known hypersensitivity to any component of this product [see Adverse Reactions].

5. MECHANISM OF ACTION

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

6. USE IN SPECIFIC POPULATIONS

6.1 Pregnancy

Pregnancy Category C

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

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

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

No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.

Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the human Paget’s disease dose of 30 mg/day resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Dosing multiples provided above are based on the recommended human Paget’s disease dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

6.2 Nursing Mothers

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

6.3 Pediatric Use

Risedronate DR 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 percent Type-I), aged 4 to < 16 years, 50 percent male and 82 percent 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 (≤30 kg body weight) or 5 mg (>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 percent of children treated with risedronate sodium immediate-release and 6 percent of patients treated with placebo. Other adverse reactions reported in ≥10 percent of patients treated with risedronate sodium immediate-release and with a higher frequency than placebo were: pain in the extremity (21 percent with risedronate sodium immediate-release versus 16 percent with placebo), headache (20 percent versus 8 percent), back pain (17 percent versus 10 percent), pain (15 percent versus 10 percent), upper abdominal pain (11 percent versus 8 percent), and bone pain (10 percent versus 4 percent).

6.4 Geriatric Use

Of the patients receiving risedronate DR in postmenopausal osteoporosis studies, 59% were 65 and over, while 13% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

6.5 Renal Impairment

Risedronate DR is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min.

6.6 Hepatic Impairment

No studies have been performed to assess risedronate sodium’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.

7. WARNINGS AND PRECAUTIONS

7.1 Drug Products with the Same Active Ingredient

Risedronate DR (Atelvia®) contains the same active ingredient found in Risedronate (Actonel®). A patient being treated with Actonel should not receive Atelvia.

7.2 Upper Gastrointestinal Adverse Reactions

Risedronate DR, 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 DR 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, Adverse Reactions, Information for Patients].

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 DR 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]. In patients who cannot comply with dosing instructions due to mental disability, therapy with risedronate DR 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.

7.3 Mineral Metabolism

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting risedronate therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [see Contraindications, Adverse Reactions].

7.4 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 (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).

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

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

7.5 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]. 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.

7.6 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.

7.7 Renal Impairment

Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

7.8 Laboratory Test Interactions

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

8. ADVERSE REACTIONS

8.1 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 DR 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate DR 35 mg once-a-week to risedronate sodium immediate-release 5 mg daily in postmenopausal women 50 years of age or older. Risedronate DR 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 H2 antagonists were included in this clinical trial. All women received daily supplementation with 1000 mg of elemental calcium plus 800-1000 IU vitamin D. As treatment with risedronate DR resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions, safety results that follow refer only to risedronate DR 35 mg once-aweek immediately following breakfast and risedronate sodium immediate-release 5 mg daily.

The incidence of all-cause mortality was 0.0% in the risedronate DR 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 DR 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 DR 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 ≥2% of patients. Adverse reactions are shown without attribution of causality.

Table 1. Adverse Reactions Occurring at a Frequency of ≥2% in Either Treatment Group

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 DR 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 DR 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 DR 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: abdominal pain (5.2% vs. 2.9%), dyspepsia (3.9% vs. 3.9%), upper abdominal pain (2.9% vs. 2.3%), gastritis (1.0% vs. 1.0%), and gastroesophageal reflux disease (1.0% vs. 1.6%). Study discontinuation due to abdominal pain occurred in 1.3% of the risedronate DR 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 DR 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 DR 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: arthralgia (6.8% vs. 7.8%), back pain (6.8% vs. 5.9%), musculoskeletal pain (2.0% vs. 1.6%), and myalgia (1.3% vs. 1.0%).

Laboratory Test Findings:

Parathyroid hormone: The effect of risedronate DR 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 DR 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 DR 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.

8.2 Postmarketing Experience

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.

The following adverse reactions have been reported with the use of risedronate sodium immediate-release.

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

Gastrointestinal Adverse Reactions: Reactions involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions].

Musculoskeletal Pain: Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions].

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

9. OVERDOSAGE

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

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

Lethality after single oral doses 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/m2).

10. DRUG INTERACTIONS

Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (e.g. Cytochrome P450).

10.1 Calcium Supplements/Antacids

When risedronate DR was administered following breakfast, the co-administration of a tablet containing 600 mg of elemental calcium and 400 IU vitamin D reduced risedronate bioavailability by approximately 38 percent [see Clinical Pharmacology (12.3)]. Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of risedronate DR and should not be taken together.

10.2 Histamine 2 (H2) Blockers and Proton Pump Inhibitors (PPIs)

Drugs that raise stomach pH (for example, PPIs or H2 blockers) may cause faster drug release from enteric coated (delayed-release) drug products such as risedronate DR. Co-administration of risedronate DR with the PPI, esomeprazole, increased risedronate bioavailability. The maximum plasma concentration (Cmax) and the area under the plasma concentration (AUC) were increased by 60 percent and 22 percent, respectively.

Concomitant administration of risedronate DR and H2 blockers or PPIs is not recommended.

10.3 Hormone Therapy

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

10.4 Aspirin/Nonsteroidal Anti-Inflammatory Drugs

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

11. PHARMACOKINETICS

Absorption

The mean absolute oral bioavailability of the 30 mg risedronate sodium immediate-release tablet taken 4 hours prior to a meal is 0.63% (90% confidence interval [CI]: 0.54% to 0.75%) and is similar to an oral solution. The time to peak concentration (Tmax) for risedronate DR tablet is ~3 hours when administered in the morning 4 hours prior to a meal.

Food Effect

In a crossover pharmacokinetic study, the bioavailability of risedronate DR 35 mg delayed-release tablets decreased by ~30% when administered immediately after a high-fat breakfast compared to administration in the morning 4 hours before a meal.

The bioavailability of the 35 mg risedronate DR tablet administered after a high-fat breakfast was similar to risedronate sodium 35 mg immediate-release tablet dosed 4 hours before a meal in one study and was approximately 2-to 4-fold greater than the immediate-release 35 mg tablet administered 30 minutes prior to a high-fat breakfast.

In a separate study, risedronate DR administered after dinner exhibited approximately 87% increase in risedronate exposure compared to administration following a breakfast. The safety and efficacy of dosing risedronate DR after dinner has not been evaluated.

Distribution

The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.

Metabolism

There is no evidence of systemic metabolism of risedronate.

Excretion

In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV=25%), and mean total clearance was 73 mL/min (CV=15%).

Specific Populations

Pediatric: Risedronate is not indicated for use in pediatric patients (see Pediatric Use).

Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Geriatric: Bioavailability and disposition are similar in elderly (>60 years of age) and younger subjects. No dosage adjustment is necessary.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min.

Hepatic Impairment: No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: ATELVIA, by WARNER CHILCOTT INC.

b) Generic drugs: None.

2) How Supplied:

Atelvia (risedronate sodium) delayed-release tablets are:

35 mg, yellow, oval-shaped, and engraved with EC 35 on one side.

NDC 0430-0979-03 Dosepak of 4 tablets

3) Storage: Store at controlled room temperature 20 - 25°C (68 - 77°F).

Rx only

Rev 07/12