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Special Alerts
Bisphosphonates (Oral) and Risk for Esophageal Cancer
July 2011
The U.S. Food and Drug Administration (FDA) is continuing to review study data to determine if oral bisphosphonate therapy is associated with an increased risk of esophageal cancer. The FDA currently believes that the benefits (on bone health) of bisphosphonate therapy outweigh potential risks. Although the review is ongoing, at this point, the FDA has not concluded that the use of oral bisphosphonates increase the risk of esophageal cancer, which is a rare cancer (especially in females).
In order to reduce esophagitis and esophageal events associated with oral bisphosphonates, patients should be advised to follow administration instructions carefully. Oral bisphosphonates should be taken first thing in the morning after awakening, with a full glass of plain water. Patients should remain in an upright position for at least 30-60 minutes after the dose. Any swallowing difficulties, chest pain, or heart burn may indicate signs of esophageal problems and should be reported.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm263320.htm
Pronunciation
(tye LOO droe nate)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Pharmacologic Category
Use: Labeled Indications
Treatment of Paget's disease of the bone (osteitis deformans) in patients who have a level of serum alkaline phosphatase (SAP) at least twice the upper limit of normal, or who are symptomatic, or who are at risk for future complications of their disease
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 bisphosphonates are administered during pregnancy.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to tiludronate, bisphosphonates, or any component of the formulation; 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. 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 (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:
• Renal impairment: Use with caution in patients with mild-to-moderate renal impairment (not recommended in patients with a Clcr <30 mL/minute).
Adverse Reactions
1% to 10%:
Cardiovascular: Chest pain (3%), edema (3%), peripheral edema (3%), flushing, hypertension, syncope
Central nervous system: Anxiety, fatigue, insomnia, nervousness, somnolence, vertigo
Dermatologic: Rash (3%), skin disorder (3%), pruritus
Endocrine & metabolic: Hyperparathyroidism (3%)
Gastrointestinal: Nausea (9%), diarrhea (9%), dyspepsia (5%), vomiting (4%), flatulence (3%), abdominal pain, anorexia, constipation, gastritis, xerostomia
Genitourinary: Urinary tract infection
Neuromuscular & skeletal: Paresthesia (4%), arthrosis (3%), fractures, muscle spasm, weakness
Ocular: Cataract (3%), conjunctivitis (3%), glaucoma (3%)
Respiratory: Rhinitis (5%), sinusitis (5%), pharyngitis (3%), bronchitis
Miscellaneous: Accidental injury (4%), infection (3%), diaphoresis
<1%, postmarketing, and/or case reports: Musculoskeletal pain (sometimes severe and/or incapacitating), osteonecrosis (primarily of the jaw), Stevens-Johnson syndrome
Metabolism/Transport Effects
None known.
Drug Interactions
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification
Aspirin: May decrease the serum concentration of Tiludronate. Risk C: Monitor therapy
Calcium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral calcium supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modification
Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Indomethacin: May increase the serum concentration of Tiludronate. Management: Separate doses of tiludronate at least two hours before or two hours after indomethacin. Risk D: Consider therapy modification
Iron Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral iron supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification
Magnesium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. 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
Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: In single-dose studies, the bioavailability of tiludronate was reduced by 90% when an oral dose was administered with, or 2 hours after, a standard breakfast compared to the same dose administered after an overnight fast and 4 hours before a standard breakfast. Management: Administer as a single oral dose with 6-8 oz of plain water. Should not be taken with beverages containing minerals (eg, mineral water), food, or with other medications. Do not take within 2 hours of food. Take calcium or mineral supplements at least 2 hours before or after tiludronate.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not remove tablets from foil strips until they are to be used.
Mechanism of Action
Inhibition of normal and abnormal bone resorption. Inhibits osteoclasts through at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to the detachment of osteoclasts from the bone surface area and the inhibition of the osteoclast proton pump.
Pharmacodynamics/Kinetics
Onset of action: Delayed, may require several weeks
Absorption: Rapid
Distribution: Widely to bone and soft tissue
Protein binding: ~90%, primarily to albumin
Metabolism: Little, if any
Bioavailability: ~6% (range: 2% to 11%); reduced by 90% when given with food
Half-life elimination: Healthy volunteers: Single dose: 50 hours; Clcr 11-18 mL/minute: 205 hours; Pagetic patients: Repeated dosing: 150 hours
Time to peak, plasma: Within 2 hours
Excretion: Urine (~60%, as tiludronic acid within 13 days)
Dosage
Oral: Adults: 400 mg (2 tablets of tiludronic acid) daily for a period of 3 months; allow an interval of 3 months to assess response
Dosing adjustment in renal impairment: Clcr <30 mL/minute: Not recommended
Dosing adjustment in hepatic impairment: Adjustment is not necessary
Administration: Oral
Administer as a single oral dose, take with 6-8 oz of plain water. Should not be taken with beverages containing minerals (eg, mineral water), food, or with other medications (may reduce absorption). Do not take within 2 hours of food. Take calcium or mineral supplements at least 2 hours before or after tiludronate. Take aluminum- or magnesium-containing antacids at least 2 hours after taking tiludronate. Patients should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation).
Monitoring Parameters
Alkaline phosphatase; pain; serum calcium and 25(OH)D
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Do not take within 2 hours of food. Ensure adequate intake of vitamin D and calcium supplements during treatment.
Patient Education
In order to be effective, this medication must be taken with a full glass of water (6-8 oz) at least 2 hours before or 2 hours after food. Do not take aspirin, antacids, or vitamin-mineral supplements containing calcium, magnesium, or aluminum within 2 hours of this medication. Consult prescriber to determine recommended lifestyle changes (eg, decreased smoking, decreased alcohol intake, dietary supplements). Certain dental procedures should be avoided if possible while you are taking this medication. Notify prescriber at once if experiencing any difficulty swallowing, pain when swallowing, or severe or persistent heartburn. You may experience mild/temporary skin rash, abdominal pain, or constipation. Report persistent muscle or bone pain or pain in the mouth, jaw, or teeth.
Geriatric Considerations
The elderly are frequently treated long-term for osteoporosis. Elderly patients should be advised to report any lower extremity, jaw (osteonecrosis), or muscle pain that cannot be explained or lasts longer than 2 weeks. Additionally, elderly often receive concomitant diuretic therapy and therefore their electrolyte status (eg, calcium, phosphate) should be periodically evaluated.
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, particularly tooth extraction, may increase the risk for 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
A review of 2408 published cases of bisphosphonate-associated osteonecrosis of the jaw bone (BP-associated ONJ) was done by Filleul, 2010. BP therapy was associated with 89% of the cases to treat malignancies and 11% of the cases to treat nonmalignant conditions. Information on the specific bisphosphonate used was available for 1694 of the patients. Intravenous therapy (primarily zoledronic acid) was received by 88% of the patients and 12% received oral treatment (primarily alendronate). Of all the cases of BP-associated ONJ, 67% were preceded by tooth extraction and for 26% of patients, there was no predisposing factor identified.
A 2010 retrospective case review reported the prevalence of BP-associated ONJ in patients using alendronate-type drugs was one out of 952 patients or ~0.1% (Lo, 2010). Of the 8572 respondents, nine cases of ONJ were identified; five had developed ONJ spontaneously and four developed ONJ after tooth extraction. When extrapolated to patient-years of bisphosphonate exposure, this prevalence rate of 0.1% equates to a frequency of 28 cases per 100,000 person-years of oral bisphosphonate treatment. An Australian group (Mavrokokki, 2007), identified the frequency of BP-associated ONJ in osteoporotic patients, mainly taking weekly oral alendronate, was 1 in 8470 to 1 in 2260 (0.01% to 0.04%) patients. If extractions were carried out, the calculated frequency was 1 in 1130 to 1 in 296 (0.09% to 0.34%) patients. The median time to onset of ONJ in alendronate patients was 24 months.
According to the 2008 report by the American Dental Association (ADA), the incidence of BP-associated ONJ remains low and the benefits of using oral bisphosphonates significantly outweighs the risk of developing BP-associated ONJ for treatment and prevention of osteoporosis and cancer treatment (Edwards, 2008). The full 26-page report can be accessed at http://www.ada.org/sections/professionalResources/pdfs/topics_osteonecrosis_bisphosphonate_report.pdf.
The ADA review stated the incidence of oral BP-associated ONJ was one case for every 140,000 person-years exposure to oral bisphosphonates (ADA, 2006).
Mental Health: Effects on Mental Status
May cause dizziness, anxiety, or nervousness
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess history for any previous adverse response to bisphosphonates. Use caution with renal impairment. Monitor blood pressure at the beginning of therapy and periodically during use. Patients at risk for osteonecrosis of the jaw (eg, chemotherapy, corticosteroids, poor oral hygiene) should have dental exams; necessary preventive dentistry should be done before beginning bisphosphonate therapy. Teach patient appropriate administration of medication (eg, timing with food, supplements, and other medications. Instruct patient in lifestyle and dietary changes that will have a beneficial impact on Paget's disease.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as tiludronic acid:
Skelid®: 200 mg [equivalent tiludronate disodium 240 mg]
References
American Dental Association Council on Scientific Affairs, “Dental Management of Patients Receiving Oral Bisphosphonate Therapy: Expert Panel Recommendations,” J Am Dent Assoc, 2006, 137(8):1144-50. Available at http://jada.ada.org/cgi/content/full/137/8/1144
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.
Edwards BJ, Hellstein JW, Jacobsen PL, et al, "Updated Recommendations for Managing the Care of Patients Receiving Oral Bisphosphonate Therapy: An Advisory Statement From the American Dental Association Council on Scientific Affairs," J Am Dent Assoc, 2008, 139(12):1674-7.
Filleul O, Crompot E, and Saussez S, "Bisphosphonate-Induced Osteonecrosis of the Jaw: A Review of 2,400 Patient Cases," J Cancer Res Clin Oncol, 2010, 136(8):1117-24.
French AE, Kaplan N, Lishner M, et al, “Taking Bisphosphonates During Pregnancy,” Can Fam Physician, 2003, 49:1281-2.
Langston AL and Ralston SH, “Management of Paget's Disease of Bone,” Rheumatology (Oxford), 2004, 43(8):955-9.
Lo JC, O'Ryan FS, Gordon NP, et al, “Prevalence of Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure,” J Oral Maxillofac Surg, 2010, 68(2):243-53.
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.
Mavrokokki T, Cheng A, Stein B, et al, “Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia,” J Oral Maxillofac Surg, 2007, 65(3):415-23.
McClung MR, Tou CK, Goldstein NH, et al, “Tiludronate Therapy for Paget's Disease of Bone,” Bone, 1995, 17(5S):493-6.
Ralston SH, “Pathogenesis of Paget's Disease of Bone,” Bone, 2008, 43(5):819-25.
Sanson LN, Necciari J, and Theircelin JF, “Human Pharmacokinetics of Tiludronate,” Bone, 1995, 17(5S):479-83.
Whyte MP, “Clinical Practice. Paget's Disease of Bone,” N Engl J Med, 2006, 355(6):593-600.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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