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Pronunciation
(tye LOO droe nate)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
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%), tooth disorder (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
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 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 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 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 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.
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
No dose adjustment necessary.
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
According to the 2008 report by the American Dental Association (ADA), the incidence of osteonecrosis of the jawbone associated with oral bisphosphonate therapy remains low. It was also stated that the benefits of using oral bisphosphonates to prevent osteoporosis significantly outweighs the small risk of developing bisphosphonate-associated osteonecrosis (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 bisphosphonate-associated osteonecrosis of the jaw was one case for every 140,000 person-years exposure to oral bisphosphonates (ADA, 2006). This figure 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, Inc has cited one case for ibandronate (Boniva®).
In addition, the ADA 2008 report reiterates that the risk of osteonecrosis of the jawbone with oral bisphosphonates is minute compared to the risks with intravenous bisphosphonates therapy in cancer patients. The ADA cites an ~20% incidence in patients receiving bisphosphonates intravenously for cancer therapy. Fewer than 10% of all cases of bisphosphonate-associated osteonecrosis of the jaw occurs in patients taking the oral drugs.
Information on alendronate (Fosamax®) use in Australia and the incidence of ONJ has been reported (Mavrokokki, 2007). A survey form was sent to all of the Australian members of the Australian and New Zealand Association of Oral and Maxillofacial Surgeons requesting cases that they had identified as ONJ in 2004 and 2005. The definition of ONJ for the survey was an area of exposed bone in the jawbone that failed to heal within 6 weeks in patients taking bisphosphonates for bone disease. The frequency of 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 minimum values in these cases were determined from the survey, whereas, the maximum values were extrapolated from survey data. The median time to onset of ONJ in alendronate patients was 24 months.
A 2010 study reported the prevalence of osteonecrosis of the jaw in patients using alendronate-type drugs was 1 out of 952 patients or ~0.1% (Lo, 2010). The study's protocol involved a survey mailed out to 13,946 members of Kaiser Permanente of Northern California healthcare delivery system; 8572 patients responded to the survey. Investigators identified respondents reporting oral problems and dental symptoms. These respondents were then interviewed by telephone for presence of dental problems including exposed bone, gingival sores, moderate periodontal disease, and persistent symptoms or complications after dental procedures. Those selected were then invited for an examination or to have their dental records reviewed. The diagnosis of ONJ was made according to the 2006 American Association of Oral and Maxillofacial Surgeons criteria which required treatment with a bisphosphonate, exposed bone in the maxillofacial region lasting >8 weeks, and no radiotherapy involving the jaw. Of the 8572 respondents, 9 cases of ONJ were identified; 5 had developed ONJ spontaneously and 4 developed ONJ after tooth extraction. Specific oral bisphosphonates were not identified. 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.
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.
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 May 2011
Content last modified May 2011
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