Clasteon: Indications, Dosage, Precautions, Adverse Effects
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Clasteon - Product Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Hypercalcemia, Osteolytic Bone Lesions of Multiple Myeloma
Class: Bisphosphonates, Bone resorption inhibitors
Form: Liquid solution, Intravenous (IV), Capsules
Ingredients: clodronate disodium, gelatin, indigotin, magnesium stearate, maize starch, sodium starch glycolate, talc, titanium oxide

clodronate disodium

Summary Product Information

Route of Administration Dosage Form/Strength Clinically Relevant Nonmedicinal Ingredients
Oral Capsule/400mg gelatin
For a complete listing see Dosage Forms, Composition and Packaging section.
Intravenous (i.v.) Concentrate for i.v. infusion disodium hydrogen carbonate
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

CLASTEON (clodronate disodium) is indicated:

  • as an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.
  • for the management of hypercalcemia of malignancy.

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

In responsive patients, intravenous infusion of clodronate disodium 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 disodium 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 disodium following intravenous infusion has been found to prolong the duration of action (see DOSAGE AND ADMINISTRATION).

Contraindications

  • Renal functional impairment (serum creatinine exceeding 440 μmol/L (5.0 mg/dL).
  • Patients who are hypersensitive to clodronate disodium or other bisphosphonates, or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
  • Severe inflammation of the gastrointestinal tract.
  • Pregnancy and lactation.

Warnings And Precautions

Serious Warnings and Precautions


  • CLASTEON (clodronate disodium) 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.

General

The recommended daily dose of CLASTEON i.v. concentrate for intravenous infusion should always be diluted and administered as a slow intravenous infusion over a minimum 2-hour period (during multiple infusion use) or a minimum 4-hour period (during single infusion use) (see DOAGE AND ADMINISTRATION).

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

CLASTEON should not be mixed with calcium-containing intravenous infusions.

Endocrine, Metabolism 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 normocalcaemia 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.

Hypocalcemia

Infusion of clodronate disodium 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 disodium. When plasma calcium falls into the hypocalcemic range, the patient may remain asymptomatic.

In these cases intravenous 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 disodium therapy in hypercalcemic patients. However, transient hypophosphatemia can occur following therapy with clodronate disodium.

Hyperparathyroidism

Clodronate disodium 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.

Ophthalmologic

Ocular disturbances including conjunctivitis, uveitis, episcleritis, and scleritis have been reported with bisphosphonate therapy. Patients with ocular events other than uncomplicated conjunctivitis should be referred to an ophthalmologist for evaluation. Treatment may need to be discontinued.

Skeletal/Muscle

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Low-energy fractures of the subtrochanteric and proximal femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. Poor healing of these fractures was also reported. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered pending a risk/benefit assessment.

Renal

Administration of clodronate disodium may aggravate renal function in some patients. Therefore, appropriate monitoring of renal function during and after intravenous infusion is required. The effect of the drug on the renal function of patients with serum creatinine in excess of 220 μmol/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 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

If during therapy there is deterioration of renal function, the intravenous solution should be stopped.

Special Populations

Pregnant Women: The safety and efficacy of CLASTEON in pregnancy has not been established (see CONTRAINDICATIONS).

Nursing Women: There is no clinical experience with CLASTEON in lactating women and it is not known whether CLASTEON passes into breast milk (see CONTRAINDICATIONS).

Pediatrics: The safety and efficacy of CLASTEON in children has not been established.

Monitoring and Laboratory Tests

Serum calcium levels should be monitored throughout treatment with clodronate disodium.

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)] x 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.

Adverse Reactions

Adverse Drug Reaction Overview

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Listed in Table 1, are the crude incidence rates for the most common adverse events reported during therapy with CLASTEON 400 mg capsules and CLASTEON i.v. (concentrate for intravenous infusion).

ADVERSE EVENT ORAL
(N=390)
%(N)
I.V.
(N=188) %(N)
Digestive System
Vomiting --- 3.6(14)
Nausea 3.1(12) 1.1(2)
Diarrhea 1.8(7) 0.5(1)
Anorexia 1.0(4) ---
Metabolic and Nutritional
Hypocalcemia 1.5(6) ---
Creatinine Increased 1.3(5) ---
SGPT Increased 0.3(1) ---
Cardiovascular System
Heart Failure 1.3(5) ---
Respiratory System
Pneumonia 1.3(5) ---
Musculoskeletal System
Spontaneous Fracture 1.0(4) ---

Cardiovascular

Adverse events affecting the cardiovascular system were all assessed as unrelated to clodronate disodium therapy since alternative causalities were evident (e.g. heart failure prior to clodronate disodium therapy).

Endocrine and Metabolism

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

Immune

Patient surveillance encompassing about 2700 patient-years treated with clodronate disodium detected five cases of acute non-lymphocytic leukemia or myelodysplasia in patients without multiple myeloma, and two cases in patients with multiple myeloma (two patients with multiple myeloma also developed non-lymphocytic leukemia while receiving placebo). The causal relationship to clodronate disodium or to the underlying disease has not been established. Appropriate monitoring of hematological parameters, including white cell count is still advised.

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

Musculoskeletal

Adverse events reported as spontaneous fractures were all assessed as unrelated to clodronate disodium therapy since alternative causalities were evident (e.g. deficient immune state in patients suffering from advanced malignant diseases).

Respiratory

Adverse events affecting the respiratory system were all assessed as unrelated to clodronate disodium therapy since alternative causalities were evident (e.g. pneumonia).

A case of a bronchospastic reaction in a female patient suffering from an acetylsalicylic acidsensitive asthma bronchiole has been reported after administration of i.v. clodronate disodium.

Abnormal Hematologic and Clinical Chemistry Findings

Hypercalcemia of malignancy is frequently associated with abnormal elevation in serum creatinine and BUN. Transient increases in serum creatinine were observed during clodronate disodium 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 disodium.

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

Post-Market Adverse Drug Reactions

Cases of osteonecrosis (primarily involving the jaws) have been reported in patients treated with bisphosphonates. The majority of the reported cases are in cancer patients attendant to a dental procedure. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anemia, coagulopathies, infection, pre-existing oral disease).

Although causality cannot be determined, it is prudent to avoid dental surgery as recovery may be prolonged (see WARNINGS AND PRECAUTIONS, Skeletal/Muscle).

Uveitis and conjunctivitis have been reported with CLASTEON during post-marketing experience (see WARNINGS AND PRECAUTIONS).

Drug Interactions

Overview

Compatibility with i.v. solutions

CLASTEON should not be mixed with calcium-containing intravenous infusions. CLASTEON i.v. is a concentrate for intravenous 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 (1) 10 mL ampoule (for multiple infusion use) or five (5) 10 mL ampoules (for single infusion use) of CLASTEON 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 AND ADMINISTRATION).

Drug-Drug Interactions

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

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

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

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

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

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Since clodronate disodium binds to bone, CLASTEON may interfere with bone scintigraphy examinations.

Dosage And Administration

Dosing Considerations

CLASTEON should not be mixed with calcium-containing intravenous infusions.

Recommended Dose and Dosage Adjustment

CLASTEON i.v. (concentrate for intravenous infusion)

Single Infusion

Recommended dosage: The contents of five (5) 10 mL ampoules is administered by slow intravenous infusion over a period of not less than 4 hours.

Multiple Infusions

Recommended dosage: The contents of one (1) 10 mL ampoule is administered as a single daily dose over a period of 2 to 6 hours (see Administration).

Oral Clasteon

Recommended dosage

The oral recommended daily maintenance dose following intravenous therapy is in the range of 1600 mg (4 capsules) to 2400 mg (6 capsules) given in single or two divided doses. Maximal recommended daily dose is 3200 mg (8 capsules).

Oral doses higher than 3200 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

CLASTEON i.v. (concentrate for intravenous infusion)

CLASTEON i.v. may be administered either as a single infusion or as multiple infusions.

CLASTEON (clodronate disodium) 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.

Paravenous infiltration should be avoided. Local reactions may occur.

Single Infusion

Administration

Five (5) 10 mL ampoules of CLASTEON i.v. concentrate for intravenous infusion (300 mg/10 mL) is diluted aseptically with 500 mL of 0.9% w/v sodium chloride injections, USP or 5% w/v dextrose, USP and administered by slow intravenous 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 1500 mg dose, it is important to establish and maintain full hydration with oral or i.v. fluids.

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

Multiple Infusions

Administration: One (1) 10 mL ampoule of CLASTEON i.v. concentrate for intravenous infusion (300 mg/10 mL) is diluted aseptically with 500 mL of 0.9% w/v sodium chloride injection, USP or 5% w/v dextrose, USP and administered by slow intravenous 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 intravenous fluids be administered to establish or maintain full hydration.

Protect the diluted solution from temperatures below 15°C and above 30°C. The reconstituted solution of CLASTEON i.v. should be administered within 12 hours of preparation by slow intravenous 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 intravenous infusions should not exceed 10 days.

Response

In most cases, elevated serum calcium levels can be reduced to normal within 2 to 5 days, which ever method of infusion is used. Following normalization, treatment should be continued with CLASTEON (clodronate disodium) 400 mg capsules in order to maintain normocalcemia. Should the serum calcium level rise again during oral treatment, the intravenous infusion can be reintroduced.

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

Oral Clasteon

Administration

CLASTEON (clodronate disodium) 400 mg blue and white gelatin capsules should be administered whole with copious fluids, but not with milk. The patient should not eat one hour before or after CLASTEON intake.

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.

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 disodium or during oral administration may be retreated either with a higher oral dosage (up to 3200 mg/day) or with the i.v. infusion preparation as a single infusion (1500 mg/day) or multiple infusions (300 mg/day). Oral or i.v. treatment should be chosen dependant 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.

Overdosage

There is a lack of documented experience on acute overdosing with clodronate disodium. One case of total kidney failure, liver damage and unconsciousness has been reported after accidental ingestion of 20,000 mg (50 x 400 mg) of clodronate. An overdose of the intravenous 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 WARNINGS AND RECAUTIONS, Monitoring and Laboratory Tests). 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.

Action And Clinical Pharmacology

Mechanism of Action

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

Pharmacodynamics

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 disodium is also clearly shown in reduced urinary calcium and hydroxyproline excretion. During and also after intravenous administration of clodronate disodium, 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 tumour load, in the amount and type of osteolytic mediators produced by the tumour 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 2-3 weeks after termination of therapy with clodronate disodium.

Clodronate disodium 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 disodium, 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 disodium in adequately hydrated patients may also normalize suppressed plasma parathyroid hormone (PTH) levels and decrease urinary calcium, hydroxyproline and phosphate excretion.

Pharmacokinetics

Clodronate disodium is rapidly cleared from the blood. The mean value for plasma half-life after oral administration of clodronate disodium is 5.6 h. 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 disodium after oral administration is low (1 - 3%).

After i.v. dose, clodronate disodium exhibits a plasma concentration profile which fits a two-compartment model with a t½α approximately 0.3 h and a t½β approximately 2 h, and terminal elimination phase with t½ approximately 13 h. The latter accounts for 10 - 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 disodium 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.

Storage And Stability

CLASTEON (clodronate disodium) i.v. (concentrate for intravenous infusion) and blue and white gelatin capsules should be stored at room temperature (15-30°C). Protect from high humidity.

Storage of Diluted Solution

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

Dosage Forms, Composition And Packaging

CLASTEON (clodronate disodium) i.v. (concentrate for intravenous infusion) is supplied in 10 mL sterile ampoules containing 300 mg of clodronate disodium per ampoule. CLASTEON is available in boxes of 5 ampoules.

CLASTEON (clodronate disodium) blue and white gelatin capsules are supplied as 400 mg of clodronate disodium per capsule. CLASTEON capsules are available in blister packs of 120 capsules per box. Boxes of 120 capsules contain 12 blister strips (10 capsules/blister strip).

Quantitative composition of the concentrate for i.v. infusion:

COMPOSITION CONCENTRATION
(mg/10mL)
Disodium hydrogen carbonate 3.200 - 5.700

Quantitative composition of the capsules:

CAPSULES
Maize starch
Sodium starch glycolate
Talc
Magnesium stearate
Gelatin
Titanium oxide
Indigotin