Didronel tablets contain either 200 mg or 400 mg of etidronate disodium, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP, regulates bone metabolism. It is a white powder, highly soluble in water, with a molecular weight of 250 and the following structural formula:
Inactive Ingredients: Each tablet contains magnesium stearate, microcrystalline cellulose, and starch.
Didronel acts primarily on bone. It can inhibit the formation, growth, and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases.
Didronel is not metabolized. The amount of drug absorbed after an oral dose is approximately 3%. In normal subjects, plasma half-life (t 1/2 ) of etidronate, based on non-compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half the absorbed dose is excreted in urine; the remainder is distributed to bone compartments from which it is slowly eliminated. Animal studies have yielded bone clearance estimates up to 165 days. In humans, the residence time on bone may vary due to such factors as specific metabolic condition and bone type. Unabsorbed drug is excreted intact in the feces. Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier.
Didronel therapy does not adversely affect serum levels of parathyroid hormone or calcium.
Paget' 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' disease.
Didronel 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 Didronel 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' disease, as well as in association with a variety of benign and malignant neoplasms).
Clinical trials have demonstrated the efficacy of Didronel in heterotopic ossification following total hip replacement, or due to spinal cord injury.
Didronel 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 Didronel prevents or retards heterotopic ossification. There is no evidence Didronel affects mature heterotopic bone.
Didronel is indicated for the treatment of symptomatic Paget' 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' Disease: Didronel is indicated for the treatment of symptomatic Paget' disease of bone. Didronel therapy usually arrests or significantly impedes the disease process as evidenced by:
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' 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.
Didronel tablets are contraindicated in patients with known hypersensitivity to etidronate disodium or in patients with clinically overt osteomalacia.
Paget' Disease: In Paget' 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.
Heterotopic Ossification: No specific .
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% 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 posttherapy. In patients with fractures, especially of long bones, it may be advisable to delay or interrupt treatment until callus is evident.
Paget' 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.
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.
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' Disease: In Paget' 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' 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, a single case of 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 has been reported in a few patients. In one patient, perforation also occurred.
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.
Clinical experience with acute Didronel overdosage is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients. Some patients may develop vomiting. In one event, an 18-year-old female who ingested an estimated single dose of 4000 to 6000 mg (67 to 100 mg/kg) of Didronel was reported to be mildly hypocalcemic (7.52 mg/dl) and experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92-year-old female who accidentally received 1600 mg of etidronate disodium per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Orally administered etidronate disodium may cause hematologic abnormalities in some patients (see ADVERSE REACTIONS ).
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 of chronic, continuous dosing mineralizes normally posttherapy.
Prolonged continuous treatment (chronic overdosage) has been reported to cause nephrotic syndrome and fracture.
Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the administration of Ca++ intravenously, would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia. Such treatment has been effective.
Didronel should be taken as a single, oral dose. However, should gastrointestinal discomfort occur, the dose may be divided. To maximize absorption, patients should avoid taking the following items within two hours of dosing:
Paget' Disease: Initial Treatment Regimens: 5 to 10 mg/kg/day, not to exceed 6 months, or 11 to 20 mg/kg/day, not to exceed 3 months.
The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there is an overriding need to suppress rapid bone turnover (especially when irreversible neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20 mg/kg/day are not recommended.
Retreatment Guidelines: Retreatment should be initiated only after 1) a Didronel -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:
Retreatment has not been studied.
Didronel is available as 200-mg, white, rectangular tablets with "P & G" on one face and "402" on the other.
NDC 0149-0405-60 bottle of 60
400-mg, white, scored, capsule-shaped tablets with "N E" on one face and "406" on the other.
NDC 0149-0406-60 bottle of 60
Avoid excessive heat (over 104°F or 40°C).
Procter & Gamble Pharmaceuticals
Cincinnati, Ohio 45202
REVISED AUGUST 1998