Didronel

Yes

FOR DIDRONEL

• The recommended dose for treating adults with Paget's disease is 5-10 mg/kg daily for up to 6 months or 11 to 20/mg/kg daily for up to 3 months. The maximum dose is 20 mg/kg daily.
• The dose for preventing heterotopic ossification after hip replacement is 20 mg/kg daily one month before and for 3 months after surgery.
• For prevention of heterotopic ossification after spinal cord injury the dose is 20 mg/kg daily for 2 weeks then 10 mg/kg daily for 10 weeks.

Food (especially, calcium rich foods such as dairy products), antacids, vitamins with mineral supplements, and certain medications can interfere with the absorption of Didronel. Therefore, Didronel should be taken on an empty stomach 2 hours before or after eating or taking other medications.

Contraindications

Osteomalacia

Hypersensitivity

Esophagus abnormalities (eg, stricture, achalasia) that delay esophageal emptying

Cautions

Enterocolitis, renal impairment

May cause local irritation of upper GI mucosa

Potentially causes severe esophagitis, esophageal ulcers and erosions

Ensure adequate intake of calcium, vitamin D

Osteonecrosis of the jaw, can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing; known risk factors 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; risk of osteonecrosis of the jaw may increase with duration of exposure to bisphosphonates

Risk of severe bone, joint and/or muscle pain

At higher doses both resorption inhibition and bone growth inhibition increases

Esophageal cancer risk (July 21, 2011 FDA safety communication)

• Conflicting findings exist from studies evaluating the risk of esophageal cancer with oral bisphosphonates
• Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates (eg, sit up or stand after administration, take with full glass of water)
• An 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 is currently being conducted by the FDA
• The 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
• Instruct patients to contact their healthcare provider if they develop symptoms of esophagitis (eg, swallowing difficulties, chest pain, new or worsening heartburn, trouble or pain when swallowing)

Mechanism of Action

Bisphosphonate binds to hydroxyapatite crystals in bone and inhibits osteoclast-mediated bone resorption. Decreases mineral release and collagen or matrix breakdown in bone.

Pharmacokinetics

Half-Life elimination: 1-6 hr (PO)

Onset: Within 1-3 months of treatment

Duration: Effect can persist up to 12 months without continuous treatment

Bioavailability: 3%

Vd: 1.37 L/kg

Metabolism: None

Excretion: Primarily unchanged in urine, unabsorbed drug excreted in feces

• Adsorbs to hydroxyapatite crystals and their amorphous precursors in bone matrix and inhibits their aggregation, growth, mineralization, and dissolution.125 c

• Heterotopic ossification: Prevents or slows the formation of heterotopic bone during the active stage.125 c

• Paget’s disease of bone: Reduces the number of osteoclasts and osteoblasts.125

• 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.125 c

• Paget’s disease of bone: Reduces vascularity of pagetic bone, skin temperature over superficially located pagetic lesions, and cardiac output.125 c

• Can increase serum phosphate concentration by increasing renal tubular reabsorption of phosphate.125 c

• No immunosuppressive activity in animal studies.104

Didronel is indicated for the treatment of symptomatic Paget's disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel is not approved for the treatment of osteoporosis.

Paget's Disease: Didronel is indicated for the treatment of symptomatic Paget's disease of bone. Didronel therapy usually arrests or significantly impedes the disease process as evidenced by:

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

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

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

--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 1 year following cessation of therapy. The upper limit of this period has not been determined.

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

Heterotopic Ossification: Didronel is indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury.

Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, Didronel retards the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months posttherapy) suggest these benefits persist.

In total hip replacement patients, Didronel does not promote loosening of the prosthesis or impede trochanteric reattachment.

In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of the spine.

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.

Didronel 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. Didronel dosage should be reduced when reductions in glomerular filtration rates are present. Patients with renal impairment should be closely monitored. In approximately 10 percent of patients in clinical trials of Didronel® I. V. Infusion (etidronate disodium) 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.

Didronel 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 Didronel. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).

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 postmarketing 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.

Paget's Disease: In Paget's patients, treatment regimens exceeding the recommended (see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous administration of medication for periods greater than 6 months may be associated with osteomalacia and an increased risk of fracture.

Long bones predominantly affected by lytic lesions, particularly in those patients unresponsive to Didronel therapy, may be especially prone to fracture.

Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of Didronel in those patients unresponsive to treatment.

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 Didronel is not carcinogenic.

Pregnancy:

Teratogenic Effects:

Pregnancy Category C. In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

There are no adequate and well-controlled studies in pregnant women. Didronel (etidronate disodium) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 Didronel is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with Didronel, 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 Didronel 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, Didronel dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored.

The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for Didronel at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20 mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often alleviated by dividing the total daily dose.

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 (versus 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 Postmarketing Experience: The worldwide postmarketing 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, 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.

Didronel® (etidronate disodium) is available as 400 mg, white, scored, capsule-shaped tablets with "N‌|E" on one face and "406" on the other.

NDC 0430-0406-20         Bottles of 60 tablets

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F)
[see USP Controlled Room Temperature]

Manufactured by:
Norwich Pharmaceuticals, Inc.
North Norwich, NY 13814

Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
1-800-521-8813

0406G041                 Revised November 2011

To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

NDC 0430-0406-20

Rx Only

400 mg

Didronel®
(etidronate disodium)

60 Tablets

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Avoid drinking milk or eating dairy products within 2 hours after taking Didronel. Also avoid taking supplements that contain calcium, magnesium, iron, or aluminum (such as in multivitamins with iron, and in many types of antacids).

Summary of Use during Lactation

Because no information is available on the use of etidronate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of etidronate by a breastfed infant is unlikely.

Drug Levels

Etidronate is poorly absorbed orally (average in adults 3% on an empty stomach, less with food), so absorption of etidronate by a breastfed infant is unlikely.

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Pamidronate

References