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Medication Safety Issues
Sound-alike/look-alike issues:
Etidronate may be confused with etidocaine, etomidate, etretinate
Pronunciation
(e ti DROE nate dye SOW dee um)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Symptomatic treatment of Paget's disease; prevention and treatment of heterotopic ossification due to spinal cord injury or after total hip replacement
Use: Unlabeled/Investigational
Postmenopausal osteoporosis
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects have been reported in some but not all 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/use caution
Contraindications
Hypersensitivity to bisphosphonates or any component of the formulation; overt osteomalacia
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. Esophagitis, dysphagia, esophageal 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 use if new or worsening symptoms develop.
• Osteonecrosis of the jaw: Bisphosphonate therapy has been associated with osteonecrosis, primarily of the jaw; this has been observed mostly in cancer patients, but also in patients with postmenopausal osteoporosis and other diagnoses. Risk factors include a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection, or pre-existing dental disease. Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. Symptoms included nonhealing extraction socket or an exposed jawbone. There are no data addressing whether discontinuation of therapy reduces the risk of developing osteonecrosis; however, as a precautionary measure, dental exams and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. Invasive dental procedures should be avoided during treatment.
Disease-related concerns:
• Enterocolitis: Use with caution in patients with enterocolitis; diarrhea has been reported at high doses and therapy may need to be withheld.
• Renal impairment: Use with caution in patients with renal impairment.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Bone mineralization: May retard mineralization of bone; treatment may need delayed or interrupted until callus is present.
• Calcium/vitamin D intake: Ensure adequate calcium and vitamin D intake.
Adverse Reactions
Frequency not defined.
Gastrointestinal: Diarrhea, nausea
Neuromuscular & skeletal: Bone pain
Postmarketing and/or case reports: Agranulocytosis, alopecia, amnesia, angioedema, arthralgia, arthritis, asthma exacerbation, bone fracture, confusion, depression, esophageal cancer, esophagitis, follicular eruption, gastritis, glossitis, hallucination, headache, hypersensitivity reactions, leg cramps, leukopenia, macular rash, maculopapular rash, musculoskeletal pain (sometimes severe and/or incapacitating), osteomalacia, pancytopenia, paresthesia, peptic ulcer disease exacerbation, pruritus, Stevens-Johnson syndrome, urticaria
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
Food: Food decreases the absorption and bioavailability of the drug.
Storage
Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Decreases bone resorption by inhibiting osteocystic osteolysis; decreases mineral release and matrix or collagen breakdown in bone
Pharmacodynamics/Kinetics
Onset of action: 1-3 months
Duration: Can persist for 12 months without continuous therapy
Absorption: ?3%
Metabolism: None
Half-life elimination: 1-6 hours
Excretion: Primarily urine (as unchanged drug); feces (as unabsorbed drug)
Dosage
Oral: Adults:
Paget's disease:
Initial: 5-10 mg/kg/day (not to exceed 6 months) or 11-20 mg/kg/day (not to exceed 3 months). Doses >20 mg/kg/day are not recommended.
Retreatment: Initiate only after etidronate-free period ?90 days. Monitor patients every 3-6 months. Retreatment regimens are the same as for initial treatment.
Heterotopic ossification:
Caused by spinal cord injury: 20 mg/kg/day for 2 weeks, then 10 mg/kg/day for 10 weeks; total treatment period: 12 weeks
Complicating total hip replacement: 20 mg/kg/day for 1 month preoperatively then 20 mg/kg/day for 3 months postoperatively; total treatment period is 4 months
Postmenopausal osteoporosis (unlabeled use): Oral: 400 mg/day for 2 weeks, followed by 13-week period with no etidronate, then repeat cycle. Maintain adequate calcium and vitamin D intake during the entire 15-week treatment cycle
Dosing adjustment in renal impairment: Use with caution; specific guidelines are not available, however consider dose reduction.
Administration: Oral
Administer tablet on an empty stomach 2 hours before food.
Monitoring Parameters
Serum calcium and phosphorous; serum creatinine and BUN
Reference Range
Calcium (total): Adults: 9.0-11.0 mg/dL
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Tablet should be taken with water or fruit juice on an empty stomach; avoid administering foods/supplements with calcium, iron, or magnesium within 2 hours of drug; maintain adequate intake of calcium and vitamin D.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. Take with water or fruit juice on an empty stomach at least 30 minutes before any food. Do not take within 2 hours of food or dietary supplements containing calcium, iron, or magnesium. 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 muscle twitching, unusual fever, convulsions, difficulty breathing, rash, bloody stool, pain in mouth, jaws or teeth, acute or lasting bone pain, 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
Monitor serum electrolytes periodically since the elderly are often receiving diuretics which can result in decreases in serum calcium, potassium, and magnesium
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Abnormal taste.
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
There is no data on the incidence of ONJ associated with use of etidronate disodium. 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.
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
Bisphosphonates have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Use caution in patients receiving lithium.
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 results of laboratory tests, therapeutic effectiveness, 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.
Oncology: Emetic Potential
Low
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet: 200 mg [DSC]; 400 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Didronel)
200 mg (30): $114.99
400 mg (30): $226.78
References
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.
Gray RE, “Severe Reaction to Diphosphonate,” BMJ, 1988, 297(6655):1042.
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.
Storm T, Thamsborg G, Steiniche T, et al, “Effect of Intermittent Cyclical Etidronate Therapy on Bone Mass and Fracture Rate in Women With Postmenopausal Osteoporosis,” N Engl J Med, 1990, 322(18):1265-71.
Watts NB, Harris ST, Genant HK, et al, “Intermittent Cyclical Etidronate Treatment of Postmenopausal Osteoporosis,” N Engl J Med, 1990, 323(2):73-9.
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 September 2009
Content last modified September 2009
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