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Tiludronate

Index Terms

  • Tiludronate Disodium

Pharmacologic Category

  • Bisphosphonate Derivative

Pharmacology

A bisphosphonate which inhibits bone resorption via actions on osteoclasts. In Paget’s disease, maintains a normal bone formation rate while inhibiting resorptive process, leading to an increase in bone mass.

Use: Labeled Indications

Note: Not approved in the US and/or Canada

Paget disease: For the treatment of Paget disease of the bone

Contraindications

Hypersensitivity to tiludronate, bisphosphonates, or any component of the formulation; treatment of juvenile Paget’s disease

Dosing: Adult

Paget disease: Oral: 400 mg daily for 3 months

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment (CrCl 30 to 90 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling; use caution.

Severe impairment (CrCl <30 mL/minute): Use not recommended.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Oral: Administer as single dose with a glass of water, at least 2 hours before or after a meal. Tablets should be swallowed whole to reduce risk of developing stomatitis and/or oropharyngeal ulceration; do not chew or suck. Patients should be instructed to stay upright (not lie down) for 30 minutes after taking the tablet.

Dietary Considerations

Ensure adequate intake of vitamin D and calcium supplements during treatment.

If dietary intake is inadequate, dietary supplementation is recommended. Women and men should consume:

Calcium: 1,000 mg daily (men: 50 to 70 years) or 1,200 mg daily (women ≥51 years and men ≥71 years) (IOM 2011; NOF [Cosman 2014])

Vitamin D: 800 to 1,000 units daily (men and women ≥50 years) (NOF [Cosman 2014]). Recommended Dietary Allowance (RDA): 600 units daily (men and women ≤70 years) or 800 units daily (men and women ≥71 years) (IOM 2011).

Storage

Store below 30°C (86°F).

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.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures have been reported in patients receiving bisphosphonate therapy, primarily for long-term treatment of osteoporosis. Fractures may occur with no or minimal trauma. Some patients experience prodromal pain weeks or months before the fracture occurs. Patients with thigh or groin pain should be assessed for atypical fracture. Discontinue bisphosphonate therapy in patients suspected to have or who develop an atypical femoral fracture.

• 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).

• 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]).

• Osteonecrosis of the external auditory canal: Cases of osteonecrosis of the external auditory canal have been reported with bisphosphonate use.

Disease-related concerns:

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Calcium/vitamin D intake: Ensure adequate calcium and vitamin D intake. Calcium and vitamin D deficiencies should be corrected prior to initiating treatment.

Monitoring Parameters

Alkaline phosphatase; pain; serum calcium and 25(OH)D; dental exam prior to initiating therapy and periodically in patient’s with risk factors for development of osteonecrosis of the jaw.

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).

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