Ostac (Clodronate Disodium)

OSTAC®

Roche

Clodronate Disodium

Bone Metabolism Regulator

Action And Clinical Pharmacology: Clodronate belongs to the class of bisphosphonates which act primarily on bone. This tissue specificity is due to the high affinity of bisphosphonates for calcium phosphate crystals. Clodronate forms complexes with the hydroxyapatite of bone, altering the crystalline structure in such a way that dissolution of the crystals is inhibited.

The major effect of clodronate is to inhibit osteoclast-mediated bone resorption without an inhibitory effect on mineralization. In responsive patients, inhibition of abnormal bone resorption by clodronate leads to the management of osteolytic bone metastases and, if present, reduction of hypercalcemia.

In patients with bone metastases, clodronate prevents the progression of bone destruction. Prevention of the progression and dissemination of existing metastases, as well as the formation of new skeletal metastases has been demonstrated both by scintigraphy and by radiography. In normocalcemic patients, the anti-osteolytic action of clodronate is also clearly shown in reduced urinary calcium and hydroxyproline excretion. During and also after i.v. administration of clodronate, the elevated serum calcium decreases, in some rare instances to hypocalcemic levels.

Several variables interfere with a precise assessment of the duration of the effect. Variations in the tumor load, in the amount and type of osteolytic mediators produced by the tumor cells, concomitant anticancer therapy and the renal handling of calcium can influence the duration of action.

In hypercalcemic patients, after successful treatment patients remain normocalcemic for some days up to several weeks. In general they become hypercalcemic again within 2 to 3 weeks after termination of therapy with clodronate.

Clodronate is not metabolized and is excreted unchanged by the kidneys. In calcium homeostasis the kidneys have a prominent role. Skeletal osteolysis may be accompanied by the pathogenesis of hypercalcemia and renal dysfunction may occur. 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 negative fluid balance requires vigorous and adequate hydration with isotonic saline (0.9% w/v).

Normalization of blood calcium levels by clodronate in adequately hydrated patients may also normalize suppressed plasma parathyroid hormone (PTH) levels and decrease urinary calcium, hydroxyproline and phosphate excretion.

Pharmacokinetics: Clodronate is rapidly cleared from the blood. The mean value for plasma half-life after oral administration of clodronate is 5.6 hours. About 20% of the quantity absorbed is bound to bone. Since no biotransformation occurs, the drug is exclusively cleared by the kidneys at a rate of about 80 mL/min., when kidney function is normal. As with all bisphosphonates, the intestinal absorption and bioavailability of clodronate after oral administration is low (1 to 3%).

After i.v. dose, clodronate exhibits a plasma concentration profile which fits a two-compartment model with a t1/2â approximately 0.3 hours and a t1/2ã approximately 2 hours, and 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.

The clinical effect of clodronate is based on its concentration at the site of action, i.e., in bone tissue. Its half-life is dependent on the rate of skeletal turnover. When the bound substance is released from bone tissue during bone resorption, high local concentrations develop at the site of osteolysis, which has a direct action on the bone-resorbing osteoclasts.

Indications And Clinical Uses: As an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.

Clodronate is also indicated 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 inhibits osteoclastic activity and bone resorption by decreasing the flux of calcium from the bones and thus reducing the calcium level in the blood.

Clodronate may be administered as a higher single infusion dose or a lower dose for multiple infusion use. Both methods have been shown to be effective.

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

Contra-Indications: Renal functional impairment (serum creatinine exceeding 440 mol/L [5 mg/dL]). Hypersensitivity to clodronate or to other bisphosphonates. 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 i.v. concentrate for i.v. infusion should always be diluted and administered as a slow i.v. infusion over a minimum 2-hour period (during multiple infusion use) or a minimum 4-hour period (during single infusion use) (see Dosage).

Administration of clodronate may aggravate renal function in some patients. Therefore, appropriate monitoring of renal function during and after i.v. infusion is required. The effect of the drug on the renal function of patients with serum creatinine in excess of 220 mol/L (2.5 mg/dL) has not been studied in controlled trials. In such situations dose reduction should be considered or the drug should be withheld (see Precautions).

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

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

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

Precautions: Administration of I.V. Infusion: Clodronate i.v. may be administered either as a single infusion or as multiple infusions.

Clodronate for infusion is available as a concentrated preparation which must be diluted before use. The only recommended diluents are 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP.

For Single Infusion: Five 10 mL ampuls of clodronate i.v. (concentrate for i.v. infusion) should be added aseptically to 500 mL 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP. No other drugs or nutrients may be added. The diluted solution should be administered by slow i.v. infusion over a period of not less than 4 hours. As with any other highly concentrated i.v. solution there exists a potential for injection site symptoms if extravenous infiltration occurs. The infusion should be monitored closely to avoid infiltration. Prior to infusion of a single 1 500 mg dose, it is important to establish and maintain full hydration with oral or i.v. fluids.

For Multiple Infusions: A single 10 mL ampul of clodronate i.v. should be added aseptically to 500 mL of 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP. No other drugs or nutrients may be added. The diluted injection solution should be administered by slow i.v. infusion over a period of 2 to 6 hours. Slow infusion is important for safety. In patients with hypercalcemia it is recommended that oral or i.v. fluids be administered to establish or maintain full hydration.

Paravenous infiltration should be avoided. Local reactions may occur.

Metabolic and Fluid Balance: Hypercalcemia causes a reversible tubular defect in the kidney that results in the loss of urinary concentrating ability and polyuria, both of which promote dehydration. Hypovolemia in patients with hypercalcemia can diminish glomerular filtration and lead to progressive renal insufficiency.

Most hypercalcemic patients are significantly dehydrated at initial presentation and restoration of intravascular volume is an important initial measure.

The cornerstone of initial treatment is vigorous hydration with isotonic saline (0.9%). It is essential to institute hydration to replenish extracellular fluid volume and restore normal glomerular filtration, as well as sodium diuresis to promote calcium excretion even after hydration status has been corrected.

The rate of administration of isotonic saline should be determined primarily by the severity of the hypercalcemia, the degree of dehydration, and the cardiovascular status of the patient. In general, at least 3 L/day should be administered initially and hydration continued until normocalcemia has been achieved. Urine output must be maintained to avoid possible fluid overload. As many patients with hypercalcemia have other electrolyte abnormalities at presentation, appropriate attention must be given to maintaining electrolyte balance. For example, for hypokalemia, which may be further aggravated by aggressive diuresis, supplementation may be required. The development of hypernatremia during rehydration has been reported, especially in obtunded patients, and may complicate management.

Patient Monitoring: Serum calcium levels should be monitored throughout treatment with clodronate.

Corrected (adjusted) serum calcium values should be calculated using established algorithms, such as:

Caadj=Cat-0.71 (A-Am)

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 the given laboratory (g/100 mL)

Alternative: corrected calcium (mg/dL)=measured calcium+[4.0-albumin (g/dL)]´0.8

Appropriate monitoring of hepatic function and hematological parameters, including white cell count is advised.

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

Hypocalcemia: Infusion of clodronate may present a risk of hypocalcemia. The drug may chelate blood calcium during therapy, this may contribute to hypocalcemia.

In most cases, plasma calcium concentrations remain within the normal range during the administration of recommended doses of clodronate. When plasma calcium falls into the hypocalcemic range, the patient may remain asymptomatic.

In these cases i.v. administration should be stopped or the oral dose should be decreased. In severe or symptomatic cases of hypocalcemia, oral or parenteral calcium supplementation may be required.

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

Hyperparathyroidism: Clodronate has not been shown to affect the renal handling of calcium and/or the action of plasma parathyroid hormone (PTH) on this process. A transitory increase in PTH has been reported in certain subjects.

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.

Concomitant use of clodronate with mithramycin and thiazides is not recommended.

Concomitant use of i.v. clodronate and aminoglycosides can result in an increased incidence of hypocalcemia.

Concomitant use of clodronate and NSAIDs may promote renal dysfunction. However, a synergistic action has not been established.

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

Lactation: There is no clinical experience in lactating women and it is not known whether clodronate 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.

Retreatment: No formalized studies have been carried out with respect to retreatment. Clinical experience shows 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 as a single infusion (1 500 mg/day) or multiple infusions (300 mg/day). Oral or i.v. treatment should be chosen dependent on the severity of hypercalcemia.

It is recommended that appropriate monitoring of renal function with serum creatinine and/or blood urea nitrogen be carried out during treatment. Serum calcium and phosphate should be monitored periodically. Appropriate monitoring of hepatic function and hematological parameters, including white cell count is advised.

Compatibility with I.V. Solutions: Ostac i.v. is a concentrate for i.v. infusion which must be diluted before use. The only recommended diluents are 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP. A single 10 mL ampul (for multiple infusion use) or five 10 mL ampuls (for single infusion use) of Ostac i.v. (300 mg/10 mL) should be added aseptically to 500 mL of 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP. No other drugs or nutrients may be added (see Dosage).

Adverse Reactions: Listed in Table I are the crude incidence rates for most common adverse events reported during therapy with the 400 mg capsules and i.v. (concentrate for i.v. infusion).

Gastrointestinal symptoms such as nausea, vomiting, anorexia and diarrhea are the most frequent adverse events reported during clodronate therapy, particularly with the oral form. A reduction in dosage, a change to i.v. clodronate or a temporary interruption of therapy may assist in the management of patients where these symptoms are relevant.

Adverse events affecting the calcium homeostasis leading to hypocalcemia were all assessed as possible or probable and reflect the calcium lowering properties of clodronate.

Hypercalcemia of malignancy is frequently associated with abnormal elevation in serum creatinine and BUN. Transient increases in serum creatinine were observed during clodronate therapy. Although in some cases a causal relationship could not be excluded with certainty, the assessment of causality is difficult since in longstanding hypercalcemia, an impairment in renal function, possibly due to the nephrocalcinosis, can reasonably be expected. Careful monitoring of renal function is advised. Transient proteinuria and oliguria have also been reported in few cases immediately following single infusion use of i.v. clodronate.

A causal relationship between clodronate and liver function abnormalities, i.e., increased liver enzymes (ALT, AP, LDH) is also difficult to assess. Pre-existing liver metastases and abnormal liver function values often exist prior to therapy with clodronate. Causal relationship, however, cannot be excluded with certainty in some patients. Careful monitoring of liver function values is advised.

Adverse events affecting the cardiovascular and respiratory systems or reported as spontaneous fractures were all assessed as unrelated to clodronate therapy since alternative causalities were evident (e.g., heart failure prior to clodronate therapy; pneumonia; deficient immune state in patients suffering from advanced malignant diseases).

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. Appropriate monitoring of hematological parameters, including white cell count is still advised.

A case of bronchospastic reaction in a female patient suffering from an ASA-sensitive asthma bronchiole has been reported after administration of i.v. clodronate.

Hypersensitivity reactions, including angioedema, urticaria, rash and/or pruritus, in association with oral or parenteral clodronate, have been reported in 2 patients.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is a lack of documented experience on acute overdosing with clodronate. An overdose of the i.v. preparation could provoke 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.: Single Infusion: Recommended Dosage: The contents of five 10 mL ampuls is administered by slow i.v. infusion over a period of not less than 4 hours.

Administration: Five 10 mL ampuls is diluted with 500 mL of 0.9 % w/v sodium chloride injections, USP or 5% w/v dextrose, USP and administered by slow i.v. infusion over a period of not less than 4 hours.

Note: Other diluents should not be used. No other drugs or nutrients may be added.

Multiple Infusions: Recommended Dosage: The contents of 1 ampul is administered as a single daily dose over a period of 2 to 6 hours.

Administration: 1 ampul is diluted with 500 mL of 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP and administered by slow i.v. infusion over a period of 2 to 6 hours.

Note: Other diluents should not be used. No other drugs or nutrients may be added.

Since the duration of treatment is adjusted in accordance with patient response, daily determination of serum calcium levels must be carried out. Duration of treatment by multiple i.v. infusion should not exceed 10 days.

Response: In most cases, elevated serum calcium levels can be reduced to normal within 2 to 5 days, whichever method of infusion is used. Following normalization, treatment should be continued with clodronate 400 mg capsules in order to maintain normocalcemia. Should the serum calcium level rise again during oral treatment, the i.v. infusion can be reintroduced.

Prior to using clodronate (single or multiple infusions) it is important to establish and maintain full hydration with oral or i.v. fluids.

Oral: Recommended Dosage: 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).

Oral doses higher than 3 200 mg daily have not been evaluated but would be likely to increase the frequency of adverse intestinal effects.

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

Administration: Capsules should be administered whole with copious fluids, but not with milk. The patient should not eat 1 hour before or after clodronate intake.

The total daily amount can be given as 1 single dose or, if necessary, in 2 divided doses in order to improve gastrointestinal tolerance. The standard daily dosage generally consists of 4´400 mg capsules (1 600 mg/day). However, in some individual cases, a higher daily dose of up to 8´400 mg capsules (3 200 mg/day) may be necessary.

The duration of treatment is normally 6 months. Treatment, however, can be extended beyond 6 months depending on the course of the disease. Similarly it may be necessary to restart treatment after an interruption.

Reconstitution: The recommended daily dose must be added aseptically to 500 mL of 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP. Note: No other diluent should be used and no other drugs or nutrients may be added.

Storage of Diluted Solution: Protect the diluted solution from temperatures below 15°C and above 30°C. The reconstituted solution should be administered within 12 hours of preparation by slow i.v. infusion over a period of 2 to 6 hours.

Availability And Storage: Ampuls: Each mL of concentrate for i.v. infusion contains: clodronate disodium 30 mg. Nonmedicinal ingredients: disodium hydrogen carbonate. Ampuls of 10 mL, boxes of 5.

Capsules: Each white, gelatin capsule contains: clodronate disodium 400 mg. Nonmedicinal ingredients: gelatin, iron oxide, magnesium stearate, maize starch, polydimethyl siloxane, shellac, sodium starch glycolate, soya lecithin, talc and titanium oxide. Blister packs of 120.

Store at room temperature (15 to 30°C). Protect from high humidity.

OSTAC® Roche Clodronate Disodium Bone Metabolism Regulator

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