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Etidronate

Pronunciation

(e ti DROE nate)

Index Terms

  • Didronel
  • EHDP
  • Etidronate Disodium
  • Sodium Etidronate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as disodium:

Didronel: 400 mg [DSC]

Generic: 200 mg, 400 mg

Brand Names: U.S.

  • Didronel [DSC]

Pharmacologic Category

  • Bisphosphonate Derivative

Pharmacology

Decreases bone resorption by inhibiting osteocystic osteolysis; decreases mineral release and matrix or collagen breakdown in bone

Absorption

~3%

Metabolism

None

Excretion

Primarily urine (50% as unchanged drug); feces (as unabsorbed drug)

Onset of Action

1-3 months

Duration of Action

Can persist for 12 months without continuous therapy

Half-Life Elimination

1-6 hours

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

Contraindications

Hypersensitivity to bisphosphonates or any component of the formulation; overt osteomalacia; patients with abnormalities of the esophagus (eg, stricture, achalasia) which delay esophageal emptying

Dosing: Adult

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

Paget's disease: Oral:

Initial: 5-10 mg/kg/day (not to exceed 6 months) or 11-20 mg/kg/day (not to exceed 3 months). The recommended initial dose is 5 mg/kg/day (not to exceed 6 months). Higher doses should be used only when lower doses are ineffective or there is a need to suppress rapid bone turnover (ie, potential for irreversible neurologic damage) or reduce elevated cardiac output. Doses >20 mg/kg/day are not recommended.

Re-treatment: Initiate only after etidronate-free period ≥90 days. Monitor patients every 3-6 months. Re-treatment regimens are the same as for initial treatment.

Heterotopic ossification: Oral:

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer’s labeling recommends decreasing the dose when GFR is reduced; however, no specific dosage adjustments are provided. Use with caution and monitor closely; etidronate is eliminated intact via the kidneys.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling.

Administration

Administer tablet on an empty stomach with a full glass of plain water (6-8 oz) 2 hours before food. Patients should be instructed to stay upright (not to lie down) after taking the medication.

Dietary Considerations

Ensure adequate calcium and vitamin D intake; women and men >50 years of age should consume 1200-1500 mg/day of elemental calcium and 800-1000 units/day of vitamin D. 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. Do not take with mineral water or with other beverages.

Storage

Store at controlled room temperature of 25°C (77°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

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

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

Gastrointestinal: Diarrhea (≤30%; dose dependent), nausea (≤30%; dose dependent)

Neuromuscular & skeletal: Ostealgia (10% to 20%; dose dependent)

Postmarketing and/or case reports: Agranulocytosis, alopecia, amnesia, arthritis, bone fracture, confusion, depression, erythema multiforme, esophagitis, exacerbation of asthma, exacerbation of peptic ulcer, hallucination, headache, hypersensitivity reaction, leukemia, leukopenia, osteomalacia, osteonecrosis of the jaw, pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis

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.

• Fracture risk: Do not exceed recommended dose or use continuously for >6 months in patients with Paget's disease; risk of osteomalacia or fractures may be increased. Long bones with predominantly lytic lesions may be prone to fracture, particularly in patients unresponsive to treatment.

• 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: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates; this has been observed primarily following dental procedures such as tooth extractions and in cancer patients receiving IV bisphosphonates, but has also occurred in patients with postmenopausal osteoporosis and other diagnoses receiving oral bisphosphonates. Risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection, ill-fitting dentures, or preexisting dental disease. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), 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 manufacturer’s labeling states that discontinuing bisphosphonates in patients requiring invasive dental procedures may reduce the risk of ONJ and clinical judgment should guide the decision. However, 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]). According to the manufacturer, discontinuation of the bisphosphonate therapy should be considered (based on risk/benefit evaluation) in patients who develop ONJ.

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.

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:

• 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.

Monitoring Parameters

Paget’s disease: 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 nausea or diarrhea. Have patient report immediately to prescriber black, tarry, or bloody stools; angina; confusion; chills; pharyngitis; vomiting blood; severe abdominal pain; heartburn; difficulty swallowing; pain with swallowing; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; mood changes; depression; hallucinations; mouth sores; jaw pain; or jaw 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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