"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Upper Gastrointestinal Adverse Reactions
Didronel, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Didronel is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Didronel and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with dosing instructions due to mental disability, therapy with Didronel should be used under appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
In Paget's patients the response to therapy may be of slow onset and continue for months after Didronel therapy is discontinued. Dosage should not be increased prematurely. A 90-day drug-free interval should be provided between courses of therapy.
No specific warnings.
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). 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.
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.
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.
Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of Didronel in those patients unresponsive to treatment.
Long-term studies in rats have indicated that Didronel is not carcinogenic.
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.
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.
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.
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.
Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Didronel Information
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