risedronate (Rx)

>10%

Arthralgia (7-33%)

Diarrhea (5-20%)

Headache (3-18%)

Nausea (4-13%)

Constipation (3-13%)

Rash (8-12%)

Abdominal pain (2-12%)

Hypertension (11%)

Dyspepsia (4-11%)

1-10%

Flulike syndrome (10%)

Depression (7%)

Chest pain (5-7%)

Dizziness (3-7%)

Pharyngitis (6%)

Rhinitis (6%)

Prostatic hyperplasia (5%)

Hypocalcemia (<5%)

Dyspnea (4%)

Gastritis (3%)

Nephrolithiasis (3%)

Hypophosphatemia (<3%)

Arrhythmia (2%)

<1%

Diaphyseal femur

Dysphagia

Esophageal cancer

Esophageal ulcer

Femur fracture

Gastric and duodenal ulcer

Osteonecrosis

Postmarketing Reports

Hypersensitivity reactions including angioedema, generalized rash and bullous skin reactions, some severe

Gastrointestinal: Esophagitis, flatulence, bloating, esophageal or gastric ulcers

Musculoskeletal pain: Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely

Eye inflammation: Iritis, uveitis

Jaw osteonecrosis

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Pulmonary: Asthma exacerbations

Contraindications

Hypersensitivity; angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported

Hypocalcemia

Hypercalcemia from any cause including, but not limited to, hyperparathyroidism, hypercalcemia of malignancy, or sarcoidosis

Inability to stand or sit upright for at least 30 minutes

Esophagus abnormalities (eg, stricture, achalasia) that delay esophageal emptying

Cautions

Ensure adequate intake of calcium and vitamin D; correct hypocalcemia, if present, before initiating therapy

Avoid concomitant polyvalent cation-containing medications

May cause upper GI disorders (eg, dysphagia, esophagitis, esophageal or gastric ulcer); instruct patients to follow dosing instructions; discontinue use if new or worsening symptoms occur

Severe irritation of upper GI mucosa; discontinue if new or worsening symptoms occur in patients with active upper GI disease

Osteonecrosis of the jaw, can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing; known risk factors include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders; risk of osteonecrosis of jaw may increase with duration of exposure to bisphosphonates

Food decreases bioavailability

Not recommended in severe renal impairment (CrCl <30 mL/min)

Risk of severe joint, muscle, or bone pain

Possible increased risk of atypical subtrochanteric and diaphyseal femur fractures; consider periodic reevaluation of need for continued bisphosphonate therapy, particularly if treatment lasts >5 years; patients with new thigh or groin pain should be evaluated to rule out a femoral fracture

Consider appropriate hormone replacement therapy if necessary

Administration of calcium has been associated with a slight increase in risk of kidney stones; in patients with a history of kidney stones or hypercalciuria, metabolic assessment to seek treatable causes of these conditions is warranted; if administration of calcium tablets necessary, monitor urinary calcium excretion periodically; patients with achlorhydria may have decreased absorption of calcium; taking calcium with food enhances absorption; concomitant use of calcium-containing antacids should be monitored to avoid excessive intake of calcium

Esophageal cancer risk (July 21, 2011, FDA safety communication)

• Conflicting findings exist from studies evaluating the risk of esophageal cancer with oral bisphosphonates
• Esophagitis and other esophageal events have been reported, particularly in patients who do not follow specific directions for use of oral bisphosphonates (eg, sitting up or standing after administration, taking with full glass of water)
• Ongoing review of data from published studies to evaluate whether use of oral bisphosphonates is associated with increased risk of cancer of esophagus is currently being conducted by FDA
• FDA has not concluded that taking oral bisphosphonates increases risk of esophageal cancer
• Data are insufficient to recommend endoscopic screening of asymptomatic patients
• FDA will continue to evaluate all available data supporting safety and effectiveness of bisphosphonates and will update public when more information becomes available
• Instruct patients to contact their healthcare provider if they develop symptoms of esophagitis (eg, swallowing difficulties, chest pain, new or worsening heartburn, trouble or pain when swallowing)

Pregnancy

Available data on use in pregnant women are insufficient to inform a drug- associated risk of adverse maternal or fetal outcomes; discontinue therapy when pregnancy recognized

Animal data

In animal reproduction studies, daily oral administration to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately 5-26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m2)

A low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to 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

• Effects of bisphosphonates on bones

  • Bisphosphonates are incorporated into bone matrix, from which they are gradually released over a period of years; the amount of bisphosphonate incorporated into adult bone and available for release into systemic circulation is directly related to dose and duration of bisphosphonate use
  • Based on mechanism of action of bisphosphonates, there is 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

Females and males of reproductive potential

• There are no data available in humans; female and male fertility may be impaired based on animal studies demonstrating adverse effects on fertility parameters

Lactation

There are no data on presence in human milk, effects on breastfed infant, or on milk production; a small degree of lacteal transfer occurred in nursing rats

Concentration of the drug in animal milk does not necessarily predict the concentration of drug in human milk; however, when a drug is present in animal milk, it is likely that the drug will be present in human milk

Developmental and health benefits of breast-feeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breast-fed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Bisphosphonate; binds to hydroxyapatite crystals in bone and inhibits osteoclast-mediated bone resorption

Absorption

Bioavailability: 0.54-0.75%

Peak plasma time: 1-3 hr

Distribution

Protein bound: 24%

Vd: 13.8 L/kg

Metabolism

Not metabolized

Elimination

Half-life: Initial, 1.5 hr; terminal, 480 hr

Renal clearance: 105 mL/min

Total body clearance: 122 mL/min

Excretion: Urine (up to 85%), feces (unabsorbed drug)

Instructions

Immediate release

• Take at least 30 minutes with 6-8 oz water before first food or drink of day
• Swallow with plain water only, not coffee or juice
• Stand or sit upright; do not lie down for 30 minutes after taking to avoid esophageal irritation

Delayed release

• Administer in morning immediately after breakfast; compared with immediate-release risedronate, Atelvia resulted in significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions
• To facilitate delivery to stomach, swallow whole while in upright position and with ≥4 oz plain water
• Tablets should not be chewed, cut, or crushed
• Do not lie down for 30 minutes after taking medication