|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Medication Safety Issues
Sound-alike/look-alike issues:
Actonel® may be confused with Actos®
Risedronate may be confused with alendronate
Pronunciation
(ris ED roe nate)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of Paget's disease of the bone; treatment and prevention of glucocorticoid-induced osteoporosis; treatment and prevention of osteoporosis in postmenopausal women; treatment of osteoporosis in men
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic and nonteratogenic embryo/fetal effects have been reported in animal studies. There are no adequate and well-controlled studies in pregnant women. Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. Based on limited case reports with pamidronate, serum calcium levels in the newborn may be altered if administered during pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
The manufacturer recommends discontinuing nursing or discontinuing risedronate.
Contraindications
Hypersensitivity to risedronate, bisphosphonates, or any component of the formulation; hypocalcemia; inability to stand or sit upright for at least 30 minutes
Warnings/Precautions
Concerns related to adverse effects:
• Bone/joint/muscle pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Dysphagia, esophagitis, esophageal or gastric ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue if new or worsening symptoms occur.
• Osteonecrosis of the jaw (ONJ): ONJ has been reported in patients receiving bisphosphonates. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery); a diagnosis of cancer, with concomitant chemotherapy or corticosteroids; poor oral hygiene, ill-fitting dentures; and comorbid disorders (anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. A dental exam and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. The manufacturer's labeling states that discontinuing bisphosphonates in patients requiring invasive dental procedures may reduce the risk of ONJ. However, other experts suggest that there is no evidence that discontinuing therapy reduces the risk of developing ONJ (Assael, 2009). The benefit/risk must be assessed by the treating physician and/or dentist/surgeon prior to any invasive dental procedure. Patients developing ONJ while on bisphosphonates should receive care by an oral surgeon.
Disease-related concerns:
• Glucocorticoid-induced osteoporosis: Evaluate sex steroid hormonal status prior to treatment initiation; consider appropriate hormone replacement if necessary.
• Hypocalcemia: Before initiation of therapy hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake, especially for patients with Paget's disease in whom the pretreatment rate of bone turnover may be greatly elevated.
• Renal impairment: Use with caution in patients with renal impairment (not recommended in patients with a Clcr <30 mL/minute).
Special populations:
• Pediatrics: Not approved for use in pediatric patients with osteogenesis imperfecta due to lack of efficacy in reducing the risk of fracture.
Adverse Reactions
Frequency may vary with dose and indication.
>10%:
Cardiovascular: Hypertension (11%)
Central nervous system: Headache (10% to 18%)
Dermatologic: Rash (8% to 12%)
Endocrine & metabolic: Serum PTH levels decreased (<30%)
Gastrointestinal: Diarrhea (5% to 20%), constipation (7% to 13%), nausea (7% to 13%), abdominal pain (7% to 12%), dyspepsia (7% to 11%)
Genitourinary: Urinary tract infection (11%)
Neuromuscular & skeletal: Arthralgia (12% to 33%), back pain (18% to 28%)
Miscellaneous: Infection (?31%)
1% to 10%:
Cardiovascular: Peripheral edema (8%), chest pain (5% to 7%), arrhythmia (2%)
Central nervous system: Depression (7%), dizziness (7%), insomnia (5%)
Endocrine & metabolic: Hypocalcemia (?5%), hypophosphatemia (<3%)
Gastrointestinal: Gastritis (3%), duodenitis (?1%), glossitis (?1%)
Genitourinary: Prostatic hyperplasia (5%; benign), nephrolithiasis (3%)
Neuromuscular & skeletal: Joint disorder (7%), myalgia (5% to 7%), neck pain (5%), weakness (5%), neuralgia (4%)
Ocular: Cataract (7%), dry eyes (3%)
Respiratory: Bronchitis (3% to 10%), pharyngitis (6%), rhinitis (6%), dyspnea (4%)
Miscellaneous: Flu-like syndrome (10%), acute phase reaction (?8%; includes fever, influenza-like illness)
<1%, postmarketing, and/or case reports: Allergic reaction, angioedema, arthritis, bullous skin reaction, cough, dysphagia, esophageal cancer, esophageal ulcer, esophagitis, gastric ulcer, hypersensitivity reaction, iritis, joint pain, liver function test abnormality, musculoskeletal pain (rarely severe or incapacitating), osteonecrosis (primarily of the jaw), sinusitis, uveitis
Drug Interactions
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Antacids: May decrease the absorption of Bisphosphonate Derivatives. Antacids containing aluminum, calcium, or magnesium are of specific concern. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification
Calcium Salts: May decrease the absorption of Bisphosphonate Derivatives. Risk D: Consider therapy modification
Iron Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral iron salts are of concern. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification
Magnesium Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral magnesium salts are of concern. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase risk of osteoporosis).
Food: Food reduces absorption (similar to other bisphosphonates); mean oral bioavailability is decreased when given with food.
Storage
Store at room temperature of 20°C to 25°C (68°F to 77°F).
Mechanism of Action
A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget's disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.
Pharmacodynamics/Kinetics
Onset of action: May require weeks
Absorption: Rapid
Distribution: Vd: 13.8 L/kg
Protein binding: ~24%
Metabolism: None
Bioavailability: Poor, ~0.54% to 0.75%
Half-life elimination: Initial: 1.5 hours; Terminal: 480-561 hours
Time to peak, serum: 1 hour
Excretion: Urine (up to 85%); feces (as unabsorbed drug)
Dosage
Oral: Adults:
Paget's disease of bone: 30 mg 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 one course of retreatment.
Osteoporosis (postmenopausal) prevention and treatment: 5 mg once daily or 35 mg once weekly or 150 mg once a month
Osteoporosis (male) treatment: 35 mg once weekly
Osteoporosis (glucocorticoid-induced) prevention and treatment: 5 mg once daily
Dosage adjustment in renal impairment:
Clcr ?30 mL/minute: No adjustment required
Clcr <30 mL/minute: Not recommended for use
Dosage adjustment in hepatic impairment: No studies performed in hepatic impairment; no hepatic metabolism suggests no dosage adjustment necessary
Administration: Oral
Risedronate should be administered at least 30 or more minutes before the first food or drink of the day other than water. Risedronate should be taken in an upright position with a full glass (6-8 oz) of plain water and the patient should avoid lying down for 30 minutes to minimize the possibility of GI side effects. Tablet should be swallowed whole; do not crush or chew.
Monitoring Parameters
Alkaline phosphatase should be periodically measured; serum calcium, phosphorus; monitor pain and fracture rate; bone mineral density
Evaluate sex steroid hormonal status prior to treatment initiation (when treating glucocorticoid-induced osteoporosis).
Reference Range
Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging; phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Take ?30 minutes before the first food or drink of the day other than water. Supplemental calcium and/or vitamin D may be required if dietary intake is not adequate.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. Take with a full glass of water on an empty stomach at least 30 minutes before eating or taking anything else. Stay in sitting or standing position for 30 minutes following administration and until after the first food of the day to reduce potential for esophageal irritation. Consult prescriber to determine necessity of dietary supplements of calcium or increased dietary vitamin D. Certain dental procedures should be avoided if possible while you are taking this medication; consult prescriber. You may experience temporary nausea or vomiting (small frequent meals may help); diarrhea; or bone pain (consult prescriber for analgesic). Report persistent muscle or bone pain; leg cramps; muscle twitching; unusual fever; convulsions; difficulty breathing; rash; bloody stool; pain in mouth, jaws, or teeth; or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant or if you are breast-feeding.
Geriatric Considerations
No dosage adjustment required if Clcr ?30 mL/minute. Since elderly often receive diuretics, evaluate electrolyte status periodically due to the drug class (bisphosphonates). Should assure that immobile patients are sitting up for at least 30 minutes after swallowing tablets.
Dental Health: Effects on Dental Treatment
Osteonecrosis of the jaw (ONJ), generally associated with local infection and/or tooth extraction and often with delayed healing, has been reported in patients taking bisphosphonates. Symptoms included nonhealing extraction socket or an exposed jawbone. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates. However, some have occurred in patients with postmenopausal osteoporosis taking oral bisphosphonates. Dental surgery may exacerbate ONJ. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. See Dental Health Professional Considerations.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
Cases of oral bisphosphonate-associated ONJ have been reported. A report by the Council of Scientific Affairs of the American Dental Association (accessed at: http://www.ada.org/prof/resources/topics/osteonecrosis.asp) as of July 2006 gave an estimated incidence of 0.7 cases for every 100,000 person-years of exposure to alendronate (Fosamax®). This translates to one case for every 142,857 person-years exposure. This figure from the ADA report was based on information received from Merck & Co citing 170 worldwide cases for alendronate (Fosamax®). In addition, Procter & Gamble Pharmaceuticals has cited 20 cases for risedronate (Actonel®) and Roche Laboratories has cited one case for ibandronate (Boniva®).
Consumer Reports On Health stated that the risk of jaw bone osteoporosis due to alendronate (Fosamax®), risedronate (Actonel®), or ibandronate (Boniva®) taken to prevent osteoporosis is very low and is estimated to be one out of every 20,000 users. That report mentioned that tooth extraction or implants increase the risk of developing osteonecrosis in patients taking any of these drugs for osteoporosis. The report also recommended that patients should stop taking any of these oral drugs 1-2 months before and after such dental treatment. No evidence was presented to support this statement.
In terms of length of exposure to oral bisphosphonates prior to onset of ONJ, data from large population studies or controlled studies is lacking. A report by Marx et al, observed that of three cases of ONJ associated with Fosamax® exposure, one patient had been taking 10 mg/day by mouth for 6 years and the other two patients 10 mg/day by mouth for 3 and 2 years respectively. In contrast, they observed that in cancer patients receiving intravenous bisphosphonates, the time period between the first doses of the bisphosphonate to first recognition of exposed bone either by the patients or by the clinician, was 9.4 months for zoledronate (Zometa®), 14.3 months for pamidronate (Aredia®), and 12.1 months for pamidronate then to zoledronate.
The prescribing information for Actonel® states that discontinuing bisphosphonates in patients requiring invasive dental procedures may reduce the risk of ONJ. However, other experts suggest that there is no evidence that discontinuing therapy reduces the risk of developing ONJ (Assael, 2009).
Mental Health: Effects on Mental Status
May cause depression, insomnia, anxiety, and dizziness
Mental Health: Effects on Psychiatric Treatment
Nausea and diarrhea are common; concomitant use with SSRIs, lithium, valproic acid, or carbamazepine may produce additive effects
Nursing: Physical Assessment/Monitoring
Assess history for any previous adverse response to bisphosphonates and ability to comply with administration instructions. Use caution with renal impairment. Correct any hypocalcemia prior to beginning treatment. Monitor blood pressure at the beginning of therapy and periodically during use. Patients at risk for osteonecrosis (eg, chemotherapy, corticosteroids, poor oral hygiene) should have dental exams and necessary preventive dentistry should be done before beginning bisphosphonate therapy. Assess other pharmacological or herbal products patient may be taking for potential interactions or toxicity. Assess results of periodic laboratory tests, therapeutic effectiveness (eg, pain, fracture rate, bone density), and adverse reactions (eg, immediate or long-term musculoskeletal pain). Teach appropriate use and specific administration directions, lifestyle and dietary changes according to purpose for use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, as sodium:
Actonel®: 5 mg, 30 mg, 35 mg, 75 mg [DSC], 150 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Actonel)
5 mg (30): $118.61
30 mg (10): $260.85
35 mg (4): $113.84
150 mg (1): $119.75
References
Assael LA, “Oral Bisphosphonates as a Cause of Bisphosphonate-Related Osteonecrosis of the Jaws: Clinical Findings, Assessment of Risks, and Preventive Strategies,” J Oral Maxillofac Surg, 2009, 67(5 Suppl):35-43.
Author Unknown, “Safety Update: Bone-Building Drugs: Risks Explained,,” Consum Rep Health, 2006, 18(5):3.
French AE, Kaplan N, Lishner M, et al, “Taking Bisphosphonates During Pregnancy,” Can Fam Physician, 2003, 49:1281-2.
Marx RE, Sawatari Y, Fortin M, et al, “Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment,” J Oral Maxillofac Surg, 2005, 63(11):1567-75.
National Osteoporosis Foundation, “Clinician's Guide to Prevention and Treatment of Osteoporosis,” Washington, DC, 2008. Available at http://www.nof.org
Wysowski DK, “Reports of Esophageal Cancer With Oral Bisphosphonate Use,” N Engl J Med, 2009, 360(1):89-90.
International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
| 
