Bonefos (Clodronate Disodium)

BONEFOS®

Rh´ne-Poulenc Rorer

Clodronate Disodium

Bone Metabolism Regulator – Antihypercalcemic Agent

Action And Clinical Pharmacology: Clodronate belongs to the class of bisphosphonates which bind to hydroxyapatite and inhibit formation and dissolution of calcium crystals in vitro.

Bisphosphonates including clodronate act on the bony skeleton causing reduction of normal and abnormal bone resorption. Clodronate alters the activities of osteoclasts and osteoblasts and the balance of bone resorption and bone formation is changed resulting in reduction of bone turnover. In responsive patients, inhibition of abnormal bone resorption by clodronate leads to reduction of hypercalcemia of malignancy presenting with or without demonstrable skeletal metastases. During and also after i.v. administration of clodronate the elevated serum calcium decreases, in some instances to hypocalcemic levels.

Clodronate is not metabolized and absorbed drug is excreted unchanged by the kidneys. The kidneys have a prominent role in calcium homeostasis. In addition to skeletal osteolysis, renal dysfunction becomes a contributor to the pathogenesis of hypercalcemia. At the time of diagnosis most hypercalcemic patients are significantly dehydrated. The antagonistic effects of calcium on the action of antidiuretic hormone impair the renal concentration mechanisms resulting in polyuria and excessive fluid loss. Hydration status is further compromised by reduction of oral fluid intake due to nausea, vomiting and mental status. Prior to initiation of therapy with clodronate, the state of the negative fluid balance requires vigorous and adequate hydration with isotonic saline (0.9%). Normalization of blood calcium levels by clodronate in adequately hydrated patients may also normalize plasma parathyroid hormone (PTH) levels without resulting impairment of desired clodronate effects (decrease in urinary calcium, hydroxyproline and phosphate excretion).

After i.v. dose, clodronate exhibits a plasma concentration profile which fits a two-compartment model with t1/2 a approximately 0.3 hours and t1/2ã approximately 2 hours, and a terminal elimination phase with t1/2 approximately 13 hours. The latter accounts for 10 to 15% of renal excretion. Total clearance is about 110 mL/min and renal clearance is approximately 90 mL/min. Volume of distribution is approximately 20 L.

Following oral administration, absorption is estimated at 1 to 3% of the ingested dose. Unabsorbed drug is excreted unchanged in the feces.

The decrease in serum calcium concentration is rapid with significant reductions usually attained within 2 days after starting i.v. therapy and continuing for 5 to 6 days after discontinuing therapy.

Indications And Clinical Uses: For the management of hypercalcemia of malignancy.

Prior to treatment with clodronate renal excretion of excess calcium should be promoted by restoration and maintenance of adequate fluid balance and urine output.

In responsive patients i.v. infusion of clodronate decreases the flux of calcium from the bones by inhibiting the osteoclastic activity and bone resorption, thus reducing the calcium level in blood.

Treatment with oral clodronate following i.v. infusion has been found to prolong the duration of action (see Dosage).

Contra-Indications: Renal functional impairment when serum creatinine exceeds 440 µmol/L (5.0 mg/dL).

Hypersensitivity to clodronate.

Severe inflammation of the gastrointestinal tract.

Pregnancy and lactation.

Manufacturers’ Warnings In Clinical States: Clodronate should not be given as a bolus injection since severe local reactions and thrombophlebitis may occur as the result of high local concentrations. The rapid bolus injection may also precipitate acute renal failure.

The recommended daily dose of clodronate should always be diluted and administered as a slow i.v. infusion over a minimum 2 hour period (see Dosage).

Administration of clodronate may aggravate renal function in some patients. Appropriate monitoring of the renal function during and after i.v. infusion is required. Since the drug is excreted by the kidneys it is essential to establish that the excretion of the fluid load and that of the drug would not present an excessive medical risk. The effect of the drug on the renal function of patients with serum creatinine in excess of 220 µmol/L has not been studied in controlled trials. In such situations dose reduction should be considered or the drug should be withheld (see Precautions).

If during therapy there is deterioration of renal function, the i.v. infusion must be stopped.

Clodronate should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown.

Clodronate should not be mixed with calcium-containing i.v. infusions.

Precautions: Administration of I.V. Infusion: The daily dose must be diluted in 500 mL of 0.9% sodium chloride injection, USP or 5% dextrose injection, USP and administered by infusion lasting at least 2 hours. No other drugs or nutrients may be added to the diluted injection solution. Paravenous infiltration should be avoided. Local reaction may occur.

Administration of Oral Dosage Form: The drug should be taken at least 2 hours before or after food, because food may decrease the amount of clodronate absorbed by the body.

Metabolic and Fluid Balance: As many patients with hypercalcemia have other electrolyte abnormalities at presentation, appropriate attention must be given to maintaining electrolyte balance. Serum electrolytes should be monitored at least daily and supplementation provided as needed.

Patients must be adequately hydrated before and during the treatment period. Excess calcium impairs the renal concentrating mechanisms resulting in polyuria and excessive fluid loss. Nausea and lethargy caused by hypercalcemia can also reduce oral intake leading to profound negative fluid balance. Isotonic saline should be administered at a rate determined by the severity of hypercalcemia, the degree of dehydration and the cardiovascular status of the patient. Hypercalcemia may lead to impairment of renal function.

Hypocalcemia: Infusion of clodronate may present a risk of hypocalcemia. The drug tends to chelate blood calcium during therapy which may contribute to hypocalcemia. Hypocalcemia was seen in 26 of 703 patients treated with oral or i.v. clodronate but was symptomatic in only one case. Symptomatic hypocalcemia can be reversed by the administration of calcium gluconate.

Serum Phosphate: Hyperphosphatemia has not been reported during clodronate therapy. However, transient hypophosphatemia can occur following therapy with clodronate.

Hyperparathyroidism: Increased serum parathyroid levels have been observed in patients receiving clodronate and are attributed to a homeostatic response to the fall in serum calcium. The clinical importance has not been established.

Drug Interactions: The use of clodronate with other agents indicated for reduction of calcium such as corticosteroids, phosphate, calcitonin, mithramycin, loop-diuretics may result in increased hypocalcemic effect depending on tumor type and pathophysiological situation.

Concurrent use of antacids or any drug containing calcium, iron, magnesium or aluminum may prevent absorption of oral clodronate.

Although bisphosphonates are not known to affect the antineoplastic activity of various anticancer agents including carmustine, cyclophosphamide, doxorubicin or fluorouracil, no study has been reported so far of the interaction of clodronate and anticancer agents.

Compatibility with I.V. Solutions: Clodronate forms complexes with bivalent ions and must not be mixed with calcium-containing solutions such as Ringer’s solution.

It is compatible with 0.9% saline and 5% dextrose injections.

Pregnancy: The safety and efficacy of clodronate in pregnancy has not been established (see Contraindications).

Lactation: There is no clinical experience with clodronate in lactating women and it is not known whether it passes into breast milk (see Contraindications).

Children: The safety and efficacy of clodronate in children has not been established.

Laboratory Examinations: Since clodronate binds to bone, it may interfere with bone scintigraphy examinations.

Adverse Reactions: The following adverse reactions have been observed with clodronate.

Gastrointestinal: Gastrointestinal disturbances including nausea, vomiting, gastric pain and diarrhea are the most frequently reported adverse events with oral clodronate and have occurred in approximately 10% of 453 patients studied. In rare cases, treatment had to be discontinued. Difficulties in swallowing the capsule, irritation of the mouth and ulcerative pharyngitis were also rarely reported.

Renal: Occasional mild to moderate abnormalities in renal function (increase in mean serum creatinine concentrations, transient proteinuria) occurred after i.v. clodronate therapy. Three cases of fatal renal failure which may have been related to the underlying hypercalcemia and dehydration have occurred in patients receiving i.v. clodronate.

Biochemical Changes: Hypocalcemia was seen in approximately 4% (26/703) of patients treated with oral or i.v. clodronate disodium; it was symptomatic in only one case. Although not reported yet during clodronate therapy, hyperphosphatemia has been known to occur with other bisphosphonates.

Endocrine: Secondary hyperparathyroidism may develop as a result of clodronate therapy. This is a homeostatic response to the fall in serum calcium and will reverse upon discontinuation of therapy.

Hematologic: Patient surveillance encompassing about 2 700 patient-years treated with clodronate detected 5 cases of acute non-lymphocytic leukemia or myelodysplasia in patients without multiple myeloma, and 2 cases in patients with multiple myeloma (2 patients with multiple myeloma also developed non-lymphocytic leukemia while receiving placebo). The causal relationship to clodronate or to the underlying disease has not been established.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is lack of documented experience on acute overdosing with clodronate. An overdose of the i.v. preparation could provide renal damage. Renal function should be monitored. Overdosage may result in hypocalcemia. Careful monitoring for several days for signs and symptoms of hypocalcemia is recommended in cases where the dose given was too high in relation to initial serum calcium (see Precautions). Oral or parenteral calcium supplementation may be required to restore plasma calcium levels.

Gastric lavage may be used to remove unabsorbed drug following acute oral overdosage.

Dosage And Administration: I.V. Infusion: The recommended adult dose is 300 mg/day (one 5 mL ampul).

The contents of the ampul must be diluted in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection and administered by infusion lasting at least 2 hours. Treatment should be continued until plasma calcium returns to normal, this generally being achieved after 2 to 5 days of treatment. Treatment should not be prolonged beyond 7 days.

Dosage should be reduced in patients with renal impairment (see Warnings).

Capsules: The oral recommended daily maintenance dose following i.v. therapy is in the range of 1 600 mg (4 capsules) to 2 400 mg (6 capsules) given in single or 2 divided doses. Maximal recommended daily dose is 3 200 mg (8 capsules).

Dosage should be reduced in patients with severe renal impairment (see Contraindications, Warnings and Precautions).

Retreatment: Controlled studies have not been undertaken for retreatment with clodronate. Limited clinical experience has suggested that patients with re-increased serum calcium after termination of therapy with clodronate or during oral administration may be retreated either with a higher oral dosage (up to 3 200 mg/day) or with the i.v. infusion preparation (300 mg/day).

Availability And Storage: Capsules: Each yellow, hard gelatin capsule contains: anhydrous clodronate disodium (as the tetrahydrate) 400 mg. Nonmedicinal ingredients: calcium stearate, colloidal silicon dioxide, FD&C Red No. 3, gelatin, iron oxides, lactose, talc and titanium dioxide. High density polyethylene bottles of 100. Store at room temperature.

I.V. Infusion: Each mL of i.v. infusion contains: clodronate disodium tetrahydrate equivalent to anhydrous clodronate disodium 60 mg. Nonmedicinal ingredients: sodium hydroxide and water for injection. Ampuls of 5 mL, packages of 5. Store at room temperature. Diluted product may be stored for up to 24 hours at room temperature.

BONEFOS® Rh´ne-Poulenc Rorer Clodronate Disodium Bone Metabolism Regulator – Antihypercalcemic Agent

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