Didronel (Etidronate Disodium)

DIDRONEL®

Procter & Gamble Pharmaceuticals

Etidronate Disodium

Bone Metabolism Regulator – Antipagetic Agent – Antihypercalcemic Agent

Action And Clinical Pharmacology: Etidronate 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.

General: The gastrointestinal absorption of etidronate is approximately 3.5%. The plasma half life (t1/2) is between 1 to 6 hours. The drug is not metabolized. It is either rapidly excreted unchanged in the urine or is taken up by bone. About half the dose is deposited in the skeleton, with the subsequent elimination controlled by bone turnover rate, which in turn is influenced by the metabolic conditions and specific bone type.

Paget’s Disease: Etidronate acts on bones by slowing the rate of turnover (resorption and accretion) both in Pagetic lesions and to a lesser extent in the normal bone remodeling process. During treatment with etidronate histologic examination of bone from Pagetic lesions shows a decrease in the excessive cellular activity accompanied by a suppression of bone turnover, an improved histologic pattern including lamellar bone formation, a decrease in fibrotic marrow pattern, a decrease in vascularity, and an increase in normal hematopoietic marrow elements.

Etidronate therapy, in patients with Paget’s disease, results in lowering of urinary hydroxyproline as well as serum alkaline phosphatase, and radionuclide uptake by Pagetic bone is reduced in many patients. The associated pathophysiological manifestations of increased bone vascularity, increased skin temperature, and increased cardiac output are also improved. These actions are generally accompanied by symptomatic improvement, including reduction of bone pain.

At a dose of 20 mg/kg/day in excess of 3 months and after 6 or more months of therapy at doses of 10 mg/kg/day, unmineralized osteoid can accumulate (see Precautions).

Hypercalcemia of Malignancy: Hypercalcemia of malignancy is usually related to increased bone resorption associated with the presence of neoplastic tissue. It occurs in 8 to 20% of patients with malignant disease. Whereas hypercalcemia is more often seen in patients with demonstrable osteolytic, osteoblastic, or mixed metastatic tumors in bone, discrete skeletal lesions cannot be demonstrated in at least 30% of patients. Etidronate’s reduction of abnormal bone resorption is responsible for its therapeutic benefit in hypercalcemia. Following successful treatment with etidronate i.v. infusion, which effectively reduces total and ionized serum calcium, etidronate tablets help maintain clinically acceptable serum calcium levels.

Indications And Clinical Uses: For the treatment of symptomatic Paget’s disease of the bone (osteitis deformans).

For the short-term (30 to 90 days) maintenance of clinically acceptable serum calcium levels following treatment with etidronate i.v. infusion (for patients with hypercalcemia of malignancy). The relapse rate without oral etidronate follow-up after about 1 month is high (90%); with such follow-up it is lower (50%). A second course of etidronate i.v. may be effective if hypercalcemia recurs.

Contra-Indications: Patients with known hypersensitivity to the drug. Also contraindicated for patients with clinically overt osteomalacia; appropriate treatment to resolve their osteomalacia should be initiated before prescribing etidronate.

Manufacturers’ Warnings In Clinical States: General: Since absorbed etidronate is excreted through the kidneys, periodic renal function assessment should be carried out in patients whose renal function may be deteriorating. While there is no experience to specifically guide treatment in patients with impaired renal function, in such cases renal function should be monitored carefully.

Paget’s Disease: The physician should adhere to the recommended dose regimen in order to avoid unnecessary overtreatment with etidronate (see Precautions and Adverse Effects). The response to therapy may be slow onset and may continue even for months after treatment when the drug has been discontinued. Dosage should neither be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process.

Retreatment should not be initiated until the patient has had at least a 3-month drug-free interval to determine whether remission has occurred and to promote mineralization of any unmineralized osteoid which may have developed.

The incidence of osteogenic sarcoma is known to be increased in Paget’s disease. Pagetic lesions, with or without therapy, may appear by x-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma.

Although there is no evidence of impaired fracture healing with etidronate, in case of spontaneous or pathological fractures occurring during etidronate therapy, the drug should be discontinued until complete healing of the fracture takes place (see Adverse Effects).

Precautions: General: To assure optimal absorption of etidronate, the drug should be taken on an empty stomach as a single oral daily dose, at least two hours before or after meals with a full glass of water. It should not be taken with milk.

Etidronate therapy should be approached with caution in patients with gastrointestinal disease, because etidronate may cause diarrhea in some patients at doses above 5 mg/kg/day.

Paget’s Disease: Patient Monitoring: During therapy, periodic monitoring of urinary hydroxyproline excretion and/or serum alkaline phosphatase levels to assess disease activity is desirable. Additionally, monitoring of serum phosphate levels may provide indications of patient compliance. A failure of serum phosphate levels to increase at etidronate dose levels of 10 mg/kg/day or above may be suggestive of non-compliance.

Osteoid Mineralization (see Contraindications – osteomalacia): Etidronate may retard mineralization of osteoid laid down during the bone accretion process. This effect is dose and time dependent. There may be an overlap of beneficial and mineralization inhibition effects in some patients at higher doses. Extended periods of continuous medication should be approached cautiously.

When administered at doses of 20 mg/kg/day, etidronate suppresses bone turnover and essentially stops mineralization of new bone in Pagetic lesions and, to a lesser extent, in the uninvolved skeleton. Mineralization of Pagetic lesions has been demonstrated to occur normally after discontinuation of the drug.

Nutrition: Patients with Paget’s disease of bone should maintain an adequate nutritional status, and particularly, an adequate intake of calcium and vitamin D. Patients with restricted vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely followed while under etidronate treatment.

Hyperphosphatemia: Etidronate therapy at daily doses of 10 mg/kg/day and above, and occasionally at doses of 5 mg/kg/day, is associated with serum phosphate elevations, probably due to increased renal tubular reabsorption of phosphate. Serum values of up to 2.26 mmol/L (7 mg%) are seen at the highest doses. The usual increments are approximately 0.32 mmol/L (1 mg%) over the pretreatment levels. Serum phosphate returns to normal within 2 to 4 weeks after the drug is discontinued.

Therapy with etidronate disodium alone is not accompanied by clinically significant changes in serum parathyroid hormone or serum calcium levels.

Bone Pain: Bone pain at the Pagetic site may increase or recur during etidronate therapy even in patients who are experiencing relief of their original symptoms. Continuance of therapy will usually result in resolution of pain. However, on occasion, therapy may have to be discontinued (see Adverse Effects).

Hypercalcemia of Malignancy: Patient Monitoring: Serum calcium levels should be monitored in patients receiving etidronate i.v. infusion therapy and/or oral etidronate maintenance therapy for hypercalcemia of malignancy. The physiologically important component of serum calcium is the ionized portion. In most institutions, this cannot be measured directly. It is important to recognize that factors influencing the ratio of free and bound calcium such as serum proteins, particularly albumin, may complicate the interpretation of total serum calcium measurements. If indicated, a corrected (adjusted) serum calcium value should be calculated using an established algorithm, such as:

Caadj = CaT-0.71 (A-Am) where, Caadj = adjusted calcium concentration (mg/100 mL) CaT = total calcium concentration (mg/100 mL) A = albumin concentration (g/100 mL) Am = mean normal albumin concentration for given laboratory. (g/100 mL)

Serum creatinine and blood urea nitrogen should be monitored in patients with known or suspected renal insufficiency.

Drug Interactions: The concurrent use of etidronate with corticosteroid, phosphate, calcitonin, furosemide or mithramycin therapies may result in additive effects.

The concurrent use of etidronate with warfarin has been associated with isolated reports of patients experiencing increases in their prothrombin time. 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 more closely monitored.

Laboratory Tests: Depending on the time elapsed since the last dose of etidronate, the etidronate therapy may prevent bone-imaging diagnostic agents (e.g., technetium-9mmethylene diphosphonate) used in bone scans, from adhering to bone and thus affect the interpretation of imaging results.

Children: The safety and effectiveness of Didronel in children has not been established.

Geriatrics: Special precautions related to the use of etidronate in geriatric patients have not been identified. However, serum creatinine levels should be closely monitored in patients with renal impairment.

Pregnancy: Studies performed in rats and rabbits using orally administered etidronate at doses up to 5 times the maximum human dose have revealed no evidence of impaired fertility or harm to the fetus. At doses of 22 times the maximum human dose, a decrease in live fetuses was observed in rats. Malformations occurred only in rats at exaggerated doses following parenteral administration and were skeletal in nature. These malformations were deemed to be the result of the pharmacologic action of the drug. The relationship of oral and i.v. routes of administration in reproduction/teratology studies is unknown. There are no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: Etidronate is not intended for administration during lactation. It is not known whether etidronate is excreted in human milk; it is excreted in the milk of rats. Because many drugs are excreted in human milk and because of the potential for adverse effects on the skeletons of infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Osteoporosis: An etidronate 400 mg tablet (see Supplied) is available as part of an intermittent cyclical therapy (ICT) indicated for the treatment of established post menopausal osteoporosis (see Didrocal Product Monograph). The efficacy of solely using etidronate 200 or 400 mg tablets without the ICT regimen has not been established for this indication.

Adverse Reactions: General: Diarrhea and loose bowel movement may occur in some patients when etidronate is administered at doses greater than 5 mg/kg/day. The incidence is approximately 20% in patients treated with 20 mg/kg/day of the drug.

Postmarketing Experience: Other adverse events that have been reported in postmarketing studies of a number of indications, and were thought to be possibly related to etidronate include the following: nausea; alopecia; arthropathies, including arthralgia and arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including angioedema, skin rashes (such as follicular eruption, macular rash, maculopapular rash), pruritus, Stevens-Johnson syndrome, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression, and hallucination; paresthesias; burning tongue; erythema multiforme; and exacerbation of asthma.

In patients receiving etidronate, there have been rare reports of leukopenia, agranulocytosis and pancytopenia. Also, there have been very rare cases of leukemia reported with etidronate use (1/100 000) in ongoing safety surveillance since 1978 encompassing approximately 1.5 million patient-years of treatment. Any causal relationship to either the treatment or to the patients’ underlying disease has not been established.

Exacerbation of existing peptic ulcer disease with resulting complications has been reported in a few patients.

Paget’s Disease: Increased or recurrent bone pain at existing Pagetic sites and/or the appearance of pain at sites previously asymptomatic may occur even when the patient’s overall clinical status is improved. The incidence was about 7% in placebo-treated patients and not substantially higher at the 5 mg/kg/day dose level. At higher doses the figure rose to approximately 20%. In etidronate-treated patients, the pain resolved while therapy was continued in some patients, but persisted for several months in others.

Fractures are recognized as a common feature in patients with Paget’s disease. The risk of fracture may be increased when etidronate is taken at a dose level of 20 mg/kg/day in excess of 3 months. This risk may be greater in patients with extensive and severe disease, a history of multiple fractures, and/or rapidly advancing osteolytic lesions. It is recommended that the drug be discontinued when fractures occur and that therapy should not be reinstated until fracture healing is complete.

Hypercalcemia of Malignancy: Continuous oral medication at doses of 20 mg/kg/day for longer than 3 months, or 10 mg/kg/day for longer than 6 months, may result in the accumulation of unmineralized osteoid. Adverse reactions associated with such changes have not been reported in patients treated for hypercalcemia of malignancy.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Clinical experience with etidronate 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. In one event, an 18-year old female who ingested an estimated single dose of 4 000 to 6 000 mg (67 to 100 mg/kg) of etidronate was reported to be mildly hypocalcemic (1.88 mmol/L or 7.52 mg/dL) and experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with i.v. calcium gluconate. A 92-year-old female who accidentally received 1 600 mg of etidronate per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Some patients may develop vomiting and expel the drug.

Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the i.v. administration of ionizable calcium salts, would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia. Such treatment has been effective.

Dosage And Administration: General: Etidronate should be taken on an empty stomach as a single oral daily dose, at least 2 hours before or after meals with a full glass of water. However, should gastrointestinal discomfort occur, the dose may be divided. To maximize absorption, patients should avoid taking the following items within 2 hours of dosing: food, especially those high in calcium, such as milk or milk products; vitamins with mineral supplements or antacids which are high in metals such as calcium, iron, magnesium or aluminum.

Paget’s Disease: Initial Treatment Guidelines: The recommended initial dose of etidronate for most patients is 5 mg/kg body weight/day, not to exceed a period of 6 months. Doses above 10 mg/kg/day should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget’s disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10 mg/kg/day should be approached cautiously and should not exceed 3 months’ duration. Doses in excess of 20 mg/kg/day are not recommended.

Urinary hydroxyproline excretion and/or serum alkaline phosphatase levels should be monitored periodically during the course of etidronate therapy.

Retreatment Guidelines: Retreatment should be initiated only after 1) an etidronate-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.

Hypercalcemia of Malignancy: Etidronate tablets may be started on the day following the last dose of etidronate i.v. infusion. The recommended oral dose of etidronate for patients who have hypercalcemia is 20 mg/kg body weight/day for 30 days. If serum calcium levels remain normal or at clinically acceptable levels, treatment may be extended. Treatment for more than 90 days has not been adequately studied and is not recommended.

Availability And Storage: 200 mg: Each white, rectangular tablet, with “P & G” on one face and “402” on the other face, contains: etidronate disodium USP 200 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose and pregelatinized starch. Lactose-free. Bottles of 60. Store at controlled room temperature (15 to 30°C).

400 mg: Each white, unscored capsule shaped tablet, with “NE1” engraved on one face and sculptured on the opposite side in an engraved box, contains: etidronate disodium USP 400 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose and pregelatinized starch. Lactose-free. Store at controlled room temperature (15 to 30°C).

Note: 400 mg tablet is only available as part of the Didrocal Intermittent Cyclical Therapy (see Precautions, Osteoporosis).

DIDRONEL® Procter & Gamble Pharmaceuticals Etidronate Disodium Bone Metabolism Regulator – Antipagetic Agent – Antihypercalcemic Agent

Connected Diseases :

Paget’s Disease

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