Etidronate: Package Insert / Prescribing Info

Paget’s Disease

Paget’s disease of bone (osteitis deformans) is an idiopathic, progressive disease characterized by abnormal and accelerated bone metabolism in one or more bones. Signs and symptoms may include bone pain and/or deformity, neurologic disorders, elevated cardiac output and other vascular disorders, and increased serum alkaline phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in patients with Paget’s disease.

Etidronate disodium slows accelerated bone turnover (resorption and accretion) in pagetic lesions and, to a lesser extent, in normal bone. This has been demonstrated histologically, scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced bone turnover is often accompanied by symptomatic improvement, including reduced bone pain. Also, the incidence of pagetic fractures may be reduced and elevated cardiac output and other vascular disorders may be improved by etidronate disodium therapy.

Heterotopic Ossification

Heterotopic ossification, also referred to as myositis ossificans (circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents with signs of localized inflammation or pain, elevated skin temperature, and redness. When tissues near joints are involved, functional loss may also be present.

Heterotopic ossification may occur for no known reason as in myositis ossificans progressiva or may follow a wide variety of surgical, occupational, and sports trauma (e.g., hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises). Heterotopic ossification has also been observed in non-traumatic conditions (e.g., infections of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis, Peyronie’s disease, as well as in association with a variety of benign and malignant neoplasms).

Clinical trials have demonstrated the efficacy of etidronate disodium in heterotopic ossification following total hip replacement or due to spinal cord injury.

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Heterotopic ossification complicating total hip replacement typically develops radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected hip joint. The overall incidence is about 50%; about one-third of these cases are clinically significant.

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Heterotopic ossification due to spinal cord injury typically develops radiographically 1 to 4 months after injury. It occurs below the level of injury, usually at major joints. The overall incidence is about 40%; about one-half of these cases are clinically significant.

Etidronate disodium chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors, blocking the aggregation, growth, and mineralization of these crystals. This is thought to be the mechanism by which etidronate disodium prevents or retards heterotopic ossification. There is no evidence etidronate disodium affects mature heterotopic bone.

Paget’s Disease

Etidronate disodium tablets are indicated for the treatment of symptomatic Paget’s disease of bone. Etidronate disodium therapy usually arrests or significantly impedes the disease process as evidenced by:

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Symptomatic relief, including decreased pain and/or increased mobility (experienced by 3 out of 5 patients).

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Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30% or more in 4 out of 5 patients).

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Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and more lamellar bone formation.

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Bone scans showing reduced radionuclide uptake at pagetic lesions.

In addition, reductions in pagetically elevated cardiac output and skin temperature have been observed in some patients.

In many patients, the disease process will be suppressed for a period of at least one year following cessation of therapy. The upper limit of this period has not been determined.

The effects of the etidronate disodium treatment in patients with asymptomatic Paget’s disease have not been studied. However, etidronate disodium treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones.

Heterotopic Ossification

Etidronate disodium tablets are indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury.

Etidronate disodium tablets reduce the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, etidronate disodium tablets retard the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months post-therapy) suggests these benefits persist.

In total hip replacement patients, etidronate disodium tablets do not promote loosening of the prosthesis or impede trochanteric reattachment.

In spinal cord injury patients, etidronate disodium tablets do not inhibit fracture healing or stabilization of the spine.

General

Paget’s Disease

In Paget’s patients the response to therapy may be of slow onset and continue for months after etidronate disodium therapy is discontinued. Dosage should not be increased prematurely. A 90-day drug-free interval should be provided between courses of therapy.

Heterotopic Ossification

No specific warnings.

General

Patients should maintain an adequate nutritional status, particularly an adequate intake of calcium and vitamin D.

Therapy has been withheld from some patients with enterocolitis since diarrhea may be experienced, particularly at higher doses.

Etidronate disodium is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to 4 weeks post therapy. There is no experience to specifically guide treatment in patients with impaired renal function. Etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. Patients with renal impairment should be closely monitored. In approximately 10% of patients in clinical trials of etidronate disodium I.V. infusion, for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in renal function (increases of > 0.5 mg/dL serum creatinine) were observed during or immediately after treatment.

Etidronate disodium suppresses bone turnover, and may retard mineralization of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally post therapy. In patients with fractures, especially of long bones, it may be advisable to delay or interrupt treatment until callus is evident.

Osteonecrosis of the Jaw (ONJ)

ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including etidronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

Musculoskeletal Pain

In post-marketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates (see ADVERSE REACTIONS). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Drug Interactions

There have been isolated reports of patients experiencing increases in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored.

Carcinogenesis

Long-term studies in rats have indicated that etidronate disodium is not carcinogenic.

Pregnancy

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etidronate disodium is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with etidronate disodium, at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued.

Geriatric Use

Clinical studies of etidronate disodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. As stated in PRECAUTIONS, etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored.

Paget’s Disease

In Paget’s patients, increased or recurrent bone pain at pagetic sites, and/or the onset of pain at previously asymptomatic sites has been reported. At 5 mg/kg/day about 1 patient in 10 (vs. 1 in 15 in the placebo group) report these phenomena. At higher doses the incidence rises to about 2 in 10. When therapy continues, pain resolves in some patients but persists in others.

Heterotopic Ossification

No specific adverse reactions.

Worldwide Post-Marketing Experience

The worldwide post-marketing experience for etidronate disodium reflects its use in the following approved indications: Paget’s disease, heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of etidronate disodium for osteoporosis where approved in countries outside the US. Other adverse events that have been reported and were thought to be possibly related to etidronate disodium include the following: alopecia; arthropathies, including arthralgia and arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression, and hallucination; and paresthesias.

In patients receiving etidronate disodium, there have been rare reports of agranulocytosis, pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition, there have been rare reports of exacerbation of asthma. Exacerbation of existing peptic ulcer disease including perforation has been reported rarely.

In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a significantly greater incidence in patients who received etidronate as compared with those who received placebo.

Paget’s Disease

Retreatment Guidelines

Retreatment should be initiated only after 1) an etidronate disodium-free period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of active disease process. It is advisable to monitor patients every 3 to 6 months although some patients may go drug free for extended periods. Retreatment regimens are the same as for initial treatment. For most patients the original dose will be adequate for retreatment. If not, consideration should be given to increasing the dose within the recommended guidelines.

Heterotopic Ossification

The following treatment regimens have been shown to be effective:

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Total Hip Replacement Patients: 20 mg/kg/day for 1 month before and 3 months after surgery (4 months total).

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Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10 weeks (12 weeks total). Etidronate disodium therapy should begin as soon as medically feasible following the injury, preferably prior to evidence of heterotopic ossification.

Retreatment has not been studied.