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Tiludronate

Pronunciation

(tye LOO droe nate)

Index Terms

  • Tiludronate Disodium

Pharmacologic Category

  • Bisphosphonate Derivative

Pharmacology

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.

Absorption

Rapid

Distribution

Widely to bone and soft tissue

Metabolism

Little, if any

Excretion

Urine (~60%, as tiludronic acid within 13 days)

Onset of Action

Delayed, may require several weeks

Time to Peak

Plasma: Within 2 hours

Half-Life Elimination

Healthy volunteers: Single dose: 50 hours; CrCl 11-18 mL/minute: 205 hours; Pagetic patients: Repeated dosing: 150 hours

Protein Binding

~90%, primarily to albumin

Special Populations: Elderly

Plasma concentrations of tiludronic acid were higher in elderly pagetic patients; however, this difference was not clinically significant.

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

Contraindications

Hypersensitivity to tiludronate, bisphosphonates, or any component of the formulation; inability to stand or sit upright for at least 30 minutes

Dosing: Adult

Note: Skelid has been discontinued in the US for more than 1 year.

Paget's disease: Oral: 400 mg (2 tablets of tiludronic acid) daily for a period of 3 months

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling. However, tiludronate is excreted renally. It is not recommended for use in patients with severe renal impairment (CrCl <30 mL/minute) and is not removed by dialysis.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Administration

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).

Dietary Considerations

Do not take within 2 hours of food. Ensure adequate intake of vitamin D and calcium supplements during treatment.

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.

Drug Interactions

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. 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. Consider therapy modification

Aspirin: May decrease the serum concentration of Tiludronate. 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. 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. Monitor therapy

Indomethacin: May increase the serum concentration of Tiludronate. 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 Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. 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. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. 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. Monitor therapy

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Test Interactions

Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.

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% (Limited to important or life-threatening): Musculoskeletal pain (sometimes severe and/or incapacitating), osteonecrosis (primarily of the jaw), Stevens-Johnson syndrome

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): According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) has been associated with bisphosphonate and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. The AAOMS suggests there is currently no evidence that interrupting oral bisphosphonate therapy alters the risk of ONJ following tooth extraction, and that in patients receiving oral bisphosphonates for <4 years who have no clinical risk factors, no alternations or delay in any procedure common to oral/maxillofacial surgeons, periodontists, and other dental providers is necessary (special considerations apply to patients receiving dental implants). Conversely, in patients receiving oral bisphosphonates for >4 years or in patients receiving oral bisphosphonates for <4 years who have also taken corticosteroids or antiangiogenic medications concomitantly, the AAOMS recommends considering a 2-month drug free period prior to invasive dental procedures (recommendation based on a theoretical benefit). Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]).

Disease-related concerns:

• Renal impairment: Use with caution in patients with mild-to-moderate renal impairment (not recommended in patients with a CrCl <30 mL/minute).

Monitoring Parameters

Alkaline phosphatase; pain; serum calcium and 25(OH)D

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. It is not known if bisphosphonates cross the placenta, but fetal exposure is expected (Djokanovic, 2008; Stathopoulos, 2011). Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by dose and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy; however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic, 2008; Levy, 2009; Stathopoulos, 2011). Until additional data is available, most sources recommend discontinuing bisphosphonate therapy in women of reproductive potential as early as possible prior to a planned pregnancy; use in premenopausal women should be reserved for special circumstances when rapid bone loss is occurring (Bhalla, 2010; Pereira, 2012; Stathopoulos, 2011). Because hypocalcemia has been described following in utero bisphosphonate exposure, exposed infants should be monitored for hypocalcemia after birth (Djokanovic, 2008; Stathopoulos, 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber black, tarry, or bloody stools; angina; dysphagia; painful swallowing; pharyngitis; heartburn; vomiting blood; severe abdominal pain; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; burning or numbness feeling; swelling of hands or feet; vision changes; or jaw pain or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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