risedronate (Actonel, Atelvia, Actonel with Calcium)

Dosing and uses of Actonel (risedronate)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 5mg
• 30mg
• 35mg
• 150mg

tablet, delayed release

• 35mg

 

Postmenopausal Osteoporosis

Treatment and prevention

5 mg PO once daily or 35 mg PO once weekly or 150 mg PO once monthly

35 mg once-weekly dosing copackaged with calcium carbonate 1250 mg for remaining 6 days of week

 

Glucocorticoid-Induced Osteoporosis

5 mg/day PO

 

Paget Disease

30 mg/day PO for 2 months

Monitor serum alkaline phosphatase

 

Osteoporosis in Men

35 mg PO once weekly

 

Osteogenesis Imperfecta (Orphan)

Orphan indication sponsor

• Warner Chilcott Pharmaceuticals; 100 Enterprise Drive; Rockaway, NJ 07866

 

Dosing Modifications

Renal impairment

• CrCl >30 mL/min: No dose adjustment necessary
• CrCl <30 mL/min: Not recommended

Hepatic impairment

• Safety and efficacy not established
• No dose adjustment suggested; drug does not undergo hepatic metabolism

 

Administration

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

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Actonel (risedronate) adverse (side) effects

>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

 

Warnings

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 and lactation

Pregnancy category: C

Lactation: Unknown whether drug crosses into breast milk; avoid using

 

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.

 

Pharmacology of Actonel (risedronate)

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)

 

Administration

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