Didronel

Generic Name: Etidronate Disodium
Class: Bone Resorption Inhibitors
VA Class: HS900
CAS Number: 7414-83-7

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals and patients about its ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer. There are insufficient data to recommend endoscopic screening of asymptomatic patients. FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.

BACKGROUND: Oral bisphosphonates are commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget’s disease. There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates. See the Data Summary in the Drug Safety Communication for additional details at: .

RECOMMENDATION: Patients should talk with their healthcare professional about the benefits and risks of taking oral bisphosphonates and how long they should expect to take them. Patients should talk with their healthcare professional if they develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when swallowing. Patients should be instructed to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed. For more information visit the FDA website at: and .

[Posted 10/13/2010] ISSUE: FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including alendronate (Fosamax), alendronate with cholecalciferol (Fosamax Plus D), risedronate (Actonel and Atelvia), risedronate with calcium carbonate (Actonel with Calcium), ibandronate (Boniva), tiludronate (Skelid), and zoledronic acid (Reclast) and their generic products. A Medication Guide will also be required to be given to patients when they pick up their bisphosphonate prescription.

BACKGROUND: Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in patients taking bisphosphonates.

RECOMMENDATIONS: Patients should continue to take their medication unless told to stop by their healthcare professional. FDA recommends that healthcare professionals should discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. For more information visit the FDA website at: and .

[Posted 03/11/2010] FDA notified healthcare professionals and patients that at this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.

FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing oral bisphosphonates.

Patients should continue taking oral bisphosphonates unless told by their healthcare professional to stop. Patients should talk to their healthcare professional if they develop new hip or thigh pain or have any concerns with their medications. For more information visit the FDA website at: and .

[Posted 11/12/2008] FDA issued an update to the Agency’s review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. For more information visit the FDA website at: , and .

[Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.

Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: and .

[Posted 10/01/2007] FDA issued an early communication about the ongoing review of new safety data regarding the association of atrial fibrillation with the use of bisphosphonates. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, treat bone metastases, and lower elevated levels of blood calcium in patients with cancer.

FDA reviewed spontaneous postmarketing reports of atrial fibrillation reported in association with oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of once-yearly Reclast for the treatment of postmenopausal osteoporosis, FDA evaluated the possible association between atrial fibrillation and the use of Reclast (zoledronic acid). Most cases of atrial fibrillation occurred more than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the 11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation between patients who received Reclast and patients who received placebo.

Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time. For more information visit the FDA website at: and .

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.^c

Uses for Didronel

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Paget’s Disease of Bone

Used in the treatment of moderate to severe symptomatic Paget’s disease of bone (osteitis deformans). ^{131 132 141 142 143 144 145 146 b}

Efficacy not established in asymptomatic patients.^b May consider prophylactic treatment in patients with extensive involvement of the skull or spinal column and the possibility of irreversible neurologic damage or in those with extensive involvement threatening major joints or weight-bearing bones.^{b c}

Less effective than risedronate or alendronate in the treatment of moderate to severe Paget’s disease of bone.^{128 129 d}

Relapse generally tends to occur within about 3–24 months in patients most likely to relapse (e.g., higher pretreatment markers of bone turnover).^c

Resistance is most likely to develop in patients receiving >1 course of therapy per year or those with higher pretreatment indices of bone turnover.¹⁰⁷

Heterotopic Ossification

Used in the prevention and treatment of heterotopic ossification (myositis ossificans, ectopic calcification, periarticular ossification, or paraosteoarthropathy) following total hip arthroplasty or resulting from spinal cord injury.^b

Efficacy not established for treatment of idiopathic heterotopic ossification† or heterotopic ossification associated with conditions other than total hip arthroplasty or spinal cord injury†.^c

Corticosteroid-induced Osteoporosis

Bisphosphonates, including etidronate, have been used effectively for the prevention and treatment of corticosteroid-induced osteoporosis†.^{131 132 133 134 135 136 137 139 141 142 143 144 145 146} American College of Rheumatology (ACR) recommends alendronate or risedronate therapy in men, premenopausal women (with caution), and postmenopausal women receiving long-term corticosteroid therapy (≥5 mg of prednisone or equivalent dosage daily for ≥3 months).¹³⁹

Postmenopausal Osteoporosis

Bisphosphonates, including etidronate, have been used for the treatment of postmenopausal osteoporosis† and are recommended by the North American Menopause Society for this use.^a However, the American College of Obstetricians and Gynecologists (ACOG) recommends alendronate and risedronate as first-line agents for the treatment of osteoporosis.^f

Didronel Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Paget’s Disease of Bone

• 
  

  Monitor patients for recurrence of disease every 3–6 months.^b Consider retreatment only after a drug-free interval of ≥90 days following the previous course of therapy if biochemical, symptomatic, or other evidence of recurrence is present.^b

  
  

Heterotopic Ossification

• 
  

  Initiate therapy as soon as it is feasible following spinal cord injury and preferably before any radiographic evidence of heterotopic ossification.^b Efficacy of retreatment has not been established in these patients nor in patients undergoing total hip arthroplasty.^b

  
  

Administration

Oral Administration

Administer as a single daily dose; may divide dosage if adverse GI effects occur.^b May be given with water or fruit juice.^c

Avoid food, especially food rich in calcium, vitamins with mineral supplements, or antacids that contain metals such as calcium, iron, magnesium, or aluminum for 2 hours before and after administration.^{b c} (See Food under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as etidronate disodium; dosage expressed in terms of the salt.^b

Adults

Paget’s Disease of Bone

Oral

Initially, 5–10 mg/kg daily for ≤6 months, or 11–20 mg/kg daily for ≤3 months, have been used.^b Recommended initial dosage is 5 mg/kg daily for ≤6 months.^b

Onset of therapeutic response may be delayed,^b and therapeutic effects may persist for months following a course of therapy.^b (See Onset under Pharmacokinetics.) Avoid premature increases in dosage^b since increased dosage may cause mineralization defects.^{b c}

Patients who require immediate suppression of Paget’s disease or in whom lower dosages are ineffective: >10 mg/kg daily for ≤3 months.^b Use with caution.^c

Dosages >20 mg/kg daily not recommended.^b

Retreatment: Dosage usually the same as initial treatment.^b Consider increasing dosage within the recommended range if inadequate response with original dosage.^b (See General: Paget’s Disease of Bone under Dosage and Administration.)

Heterotopic Ossification

Prevention and Treatment

Oral

Spinal cord injury: Initially, 20 mg/kg daily for 2 weeks followed by 10 mg/kg daily for an additional 10 weeks (12 weeks total).^b

Total hip arthroplasty: Initially, 20 mg/kg daily administered preoperatively for 1 month and postoperatively for an additional 3 months (4 months total).^b

Corticosteroid-Induced Osteoporosis†

Prevention and Treatment

Oral

400 mg daily for 2 weeks every 3 months has been used, usually in conjunction with calcium (e.g., 500 mg daily) and vitamin D supplementation during the remaining 10–11 weeks of each cycle or continuously.^{141 142 143 144 145 146 147}

Administer for as long as corticosteroid therapy continues.¹³⁹

Postmenopausal Osteoporosis†

Treatment

Oral

400 mg daily for 14 days every 3 months has been used, in conjunction with calcium supplementation during the last 10 weeks of each cycle.^a

Prescribing Limits

Adults

Paget’s Disease of Bone

Oral

Maximum 20 mg/kg daily.^b

Treatment duration: ≤6 months; continuous therapy for >6 months may increase the risk of fracture and osteomalacia.^b

Special Populations

Renal Impairment

Reduce dosage in patients with reduced glomerular filtration; monitor such patients closely.¹²⁵

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^b

Cautions for Didronel

Contraindications

• 
  

  Known hypersensitivity to etidronate disodium.¹²⁵

  
  


• 
  

  Clinically overt osteomalacia.¹²⁵

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and stillbirths demonstrated in animals.^b

Theoretical risk to fetus exists if pregnancy occurs after completing a course of bisphosphonate therapy.¹²⁵ Impact of variables such as time between cessation of bisphosphonate therapy to conception, particular bisphosphonate used, and route of administration (IV versus oral) on this risk not established.^{125 b}

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Metabolic Effects

Maintain an adequate intake of calcium and vitamin D during therapy.^b

Hyperphosphatemia may occur, especially with dosages of 10–20 mg/kg daily.¹²⁵ (See Actions.) Usually returns to pretreatment values 2–4 weeks after treatment discontinuance.¹²⁵

GI Effects

Therapy has been withheld in some patients with enterocolitis, since diarrhea may occur, especially with high dosages.¹²⁵

Musculoskeletal Effects

Impairs mineralization of new osteoid, principally in pagetic lesions and to a lesser extent in normal bone at dosages of 10–20 mg/kg daily.^{b c} Also may delay mineralization of ectopic bone.^c Mineralization occurs normally following completion of therapy.^b

Long bones affected mainly by lytic pagetic lesions, particularly in patients whose disease is unresponsive to therapy, may be especially prone to fractures.^b Monitor patients with predominantly lytic lesions closely, both radiographically and biochemically, to permit timely discontinuance of therapy in those whose disease is unresponsive.^b If fractures occur, may be advisable to delay or withhold therapy until callus is evident.^b

Osteonecrosis and osteomyelitis of the jaws have been reported principally in cancer patients receiving bisphosphonates.^{147 148 149 150 151 b} Most cases were associated with dental procedures (e.g., tooth extraction), but some cases occurred in patients with postmenopausal osteoporosis† or other diagnoses.^b Most instances of osteonecrosis of the jaw occurred with IV bisphosphonate therapy, but can occur with oral therapy.^b

Dental examination with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene).ⁱ Avoid invasive dental procedures if possible during therapy in such patients.ⁱ In patients requiring dental procedures, no data are available to suggest whether discontinuance of therapy prior to procedure reduces the risk of osteonecrosis of the jaw.^{b d} Base management of patients requiring dental treatment on an individual assessment of risks and benefits.^{b d}

Severe, occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.^{b d} The time to the onset of symptoms varied from 1 day to several months after treatment initiation.^{b d} Such pain improves following discontinuance and may recur upon subsequent rechallenge with the same drug or another bisphosphonate.^{b d}

Specific Populations

Pregnancy

Category C.^b (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether etidronate is distributed into milk.^b Use with caution.^b

Pediatric Use

Safety and efficacy in children not established.^b Has been used in children for the prevention of heterotopic ossification or soft tissue calcification at weight-adjusted dosages recommended for adults.^b

Rachitic syndrome reported infrequently in children receiving dosages of ≥10 mg/kg daily for approximately 1 year or longer.^b Epiphyseal radiographic changes associated with retarded mineralization of new osteoid and cartilage and associated occasional symptoms were reversible following discontinuance of the drug.^b

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.¹²⁵ (See Geriatric Patients under Dosage and Administration.)

Possible age-related impaired renal function and risk of toxic reactions; use with care.¹²⁵ (See Renal Impairment under Cautions and under Dosage and Administration.)

Renal Impairment

Monitor patients with impaired renal function carefully.^{100 125} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Paget’s disease of bone: Bone pain, diarrhea, nausea.^b

Heterotopic ossification: Diarrhea, nausea.^b

Interactions for Didronel

Specific Drugs

Drug	Interaction	Comments
Warfarin	Increases in PT, mostly without clinically important sequelae125	Monitor PT when etidronate added to therapy125

Didronel Pharmacokinetics

Absorption

Bioavailability

Approximately 3% of a dose is absorbed.¹²⁵

Onset

Paget’s disease of bone: Reduced urinary excretion of hydroxyproline occurs after 1–3 months of therapy.^c Reductions in markers of bone turnover reach a plateau in about 6 months.^c

Duration

Paget’s disease of bone: May persist for ≥1 year following discontinuance of therapy.^b In patients whose disease is most likely to relapse, relapse generally tends to occur within about 3–24 months.^c

Heterotropic ossification: Persists for ≥9 months following drug discontinuance.^b

Food

Food decreases extent of absorption.^c

Distribution

Extent

Following oral administration, about 50% of absorbed drug distributed almost exclusively into bone.^{b c} Eliminated slowly (weeks to years) via bone turnover.^{100 101 106 b}

Drug does not cross blood-brain barrier in animals.¹²⁵

Not known whether etidronate is distributed into milk.^b

Elimination

Metabolism

No evidence of metabolism.¹²⁵

Elimination Route

Excreted unchanged in urine (approximately half of an absorbed dose)¹⁰¹ within 24 hours.¹²⁵ Unabsorbed drug is excreted intact in feces.^b

Half-life

Plasma elimination half-life is 1–6 hours.¹²⁵ Terminal half-life estimated to be 394 days.^h

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).^b

Actions

• 
  

  Adsorbs to hydroxyapatite crystals and their amorphous precursors in bone matrix and inhibits their aggregation, growth, mineralization, and dissolution.^{b c}

  
  


• 
  

  Heterotopic ossification: Prevents or slows the formation of heterotopic bone during the active stage.^{b c}

  
  


• 
  

  Paget’s disease of bone: Reduces the number of osteoclasts and osteoblasts.^b

  
  


• 
  

  Paget’s disease of bone: Reduces rate of bone turnover as evidenced by decreases in markers of bone turnover and reduced radionuclide uptake at pagetic lesions.^{b c}

  
  


• 
  

  Paget’s disease of bone: Reduces vascularity of pagetic bone, skin temperature over superficially located pagetic lesions, and cardiac output.^{b c}

  
  


• 
  

  Can increase serum phosphate concentration by increasing renal tubular reabsorption of phosphate.^{b c}

  
  


• 
  

  No immunosuppressive activity in animal studies.¹⁰⁴

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of proper administration (e.g., avoiding food, vitamins with mineral supplements, or antacids that contain metals for 2 hours before and after administration).^b

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^b

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^b

  
  


• 
  

  Importance of informing patients of other important precautionary information.^b (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Etidronate Disodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	200 mg	Didronel	Procter & Gamble
		400 mg	Didronel (scored)	Procter & Gamble

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 08/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Didronel 400MG Tablets (WARNER CHILCOTT PHARMA): 30/$226.78 or 90/$643.61

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 22, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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124. Boyce BF, Fogelman I, Ralston S et al. Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet. 1984; 1:821-4. [IDIS 184178] [PubMed 6143140]

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129. Miller PD, Brown JP, Siris ES et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Am J Med. 1999; 106:513-20. [IDIS 428270] [PubMed 10335722]

130. Plotkin LI, Weinstein RS, Parfitt AM et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999; 104:1363-74. [PubMed 10562298]

131. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997; 337:382-7. [IDIS 389180] [PubMed 9241127]

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133. Adachi JD, Saag KG, Delmas PD et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 2001; 44:202-11. [PubMed 11212161]

134. Reid DM, Hughes RA, Laan RF et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res. 2000; 15:1006-20. [PubMed 10841169]

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136. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 1999; 42:2309-18. [IDIS 438381] [PubMed 10555025]

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