Drug Interactions
Interactions with herbal products have not been established.
Clodronate has been reported to be associated with renal dysfunction when used simultaneously with NSAIDs, most often diclofenac.
The use of clodronate with other agents indicated for the reduction of calcium, such as corticosteroids, phosphate, calcitonin, mithramycin or loop diuretics, may result in increased hypocalcemic effect depending on tumour type and pathophysiological situation.
Due to increased risk of hypocalcemia, caution should be exercised when using clodronate together with aminoglycosides.
Bisphosphonates are not known to affect the antineoplastic activity of most anticancer agents, including carmustine, cyclophosphamide, doxorubicin and fluorouracil. However, concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine by up to 80%.
Clodronate i.v. solutions must not be mixed with calcium-containing solutions, such as Ringer's solution, since clodronate forms poorly soluble complexes with divalent cations.
For oral administration, simultaneous administration with food, liquids or drugs containing divalent cations (i.e., calcium, magnesium, aluminum or iron), such as antacids or iron preparations, leads to significantly reduced bioavailability of clodronate.
Clodronate is compatible with 0.9% saline and 5% dextrose injections.
The drug should be taken on an empty stomach, with a glass of plain water, at least two hours before or after food, because food may decrease the amount of clodronate disodium absorbed by the body.
Interactions with laboratory tests have not been established.
Information for the Patient
Bonefos
Dosage and Administration
The oral recommended daily maintenance dose following intravenous therapy is in the range of 1600 mg (four capsules) to 2400 mg (six capsules) given preferably as a single dose or in two divided doses. The maximal recommended daily dose is 3200 mg (eight capsules).
Caution should be exercised in determining dosage adjustment for patients with malignancy and severe skeletal disease, given the potential for wide variation in nonrenal clearance in such patients.
The contents of the ampoule must be diluted in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection and administered by infusion lasting at least two hours. The compatibility of BONEFOS with other admixed drugs or injection solutions has not been studied. Treatment should be continued until plasma calcium levels return to normal, which is generally achieved after two to five days of treatment. Treatment should not be prolonged beyond seven days. Adequate hydration should be ensured, and renal function and serum calcium levels should be monitored before and during treatment.
BONEFOS capsules should be swallowed whole, and should not be taken with food (see Warnings and Precautions). The drug should be taken on an empty stomach, with a glass of plain water, at least two hours before or after food.
Controlled studies have not been undertaken for retreatment with clodronate. Limited clinical experience has suggested that patients developing hypercalcemia following termination of therapy with clodronate 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 (300 mg/day).
| Degree of Renal Failure: Creatinine Clearance (mL/min) | Percent of Normal Dose |
| 50–80 | 75–100% |
| 12–50 | 50–75% |
| <12 | 50% |
One 5 mL ampoule should be diluted in 500 mL of 0.9% (9 mg/mL) saline injection or 5% (50 mg/mL) dextrose injection and administered as an infusion over at least two hours.
The diluted product may be stored for up to 24 hours at room temperature.
Since clodronate is eliminated mainly via the kidneys, it should be used with caution in patients with renal impairment. Dosage should be reduced in patients with renal impairment, and daily doses exceeding 1600 mg should not be used continuously (see Contraindications and Warnings and Precautions).
Limited data suggest that clodronate can be effectively removed from plasma by standard hemodialysis immediately following clodronate infusion but is poorly removed by peritoneal dialysis. No formal study has been conducted for a regimen recommendation of clodronate use in subjects undergoing hemodialysis or peritoneal dialysis.
In patients with increased bone resorption, but no hypercalcemia, the recommended starting dose is 1600 mg/day. The dose may be increased if this is deemed clinically appropriate. However, the daily dose should not exceed 3200 mg.
Adverse Reactions
Occasional mild to moderate abnormalities in renal function (increase in mean serum creatinine concentrations, transient proteinuria) occurred after i.v. clodronate therapy.
Gastrointestinal disturbances including nausea, vomiting, gastric pain and diarrhea were the most frequently reported adverse events with oral clodronate and occurred in approximately 10% of patients. These reactions were usually mild. In rare cases, treatment had to be discontinued. Difficulty in swallowing the capsule, irritation of the mouth and ulcerative pharyngitis were rarely reported.
Bisphosphonates are generally well tolerated, especially when taken properly by appropriately selected patients (see Dosage and Administration and Contraindications).
Impairment of respiratory function in patients with acetylsalicylic acid-sensitive asthma and hypersensitivity reactions manifesting as respiratory disorder have been reported.
Secondary hyperparathyroidism may develop as a result of BONEFOS therapy. This is a homeostatic response to the fall in serum calcium and will reverse upon discontinuation of therapy.
Impairment of renal function (elevation of serum creatinine and proteinuria) and severe renal damage have been reported, especially after rapid intravenous infusion of high doses of clodronate (see Dosage and Administration, Dosing Considerations, Renal Impairment).
Single cases of renal failure, in rare cases with fatal outcome, have been reported, especially with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), most often diclofenac.
Very rare instances of bronchoconstriction have been observed in patients with acetylsalicylic acid-sensitive asthma.
Some cases of skin disorders, usually manifesting as erythematous or maculopapular lesions, have been reported. Immediate hypersensitivity reactions seem to be rare. Local reaction may occur following extravasation.
Isolated cases of osteonecrosis of the jaw have been reported, primarily in patients who were previously treated with amino-bisphosphonates such as zoledronate and pamidronate. Osteonecrosis of the jaw has other well-documented multiple risk factors. It is not possible to determine if these events are related to bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroids), to the patient’s underlying disease or to other co-morbid risk factors (e.g., anemia, infection, pre-existing oral disease).
Severe bone, joint, and/or muscle pain has been reported in patients taking BONEFOS; however, such reports have been infrequent. The onset of symptoms varied from days to several months after starting BONEFOS.
During a 12-month study of 610 postmenopausal osteopenic women randomized to receive placebo or clodronate, elevations of aminotransferases were common, exceeding the normal range in up to 18% of clodronate-treated subjects versus up to 7% of placebo-treated subjects. Aminotransferases were elevated to more than twice the normal range in 1.8% (9/491) of clodronate-treated subjects. No serious adverse events due to liver disease were reported during the 12 months of follow-up. Changes in serum concentrations of alkaline phosphatase have been observed. In patients with metastatic diseases, alkaline phosphatase may also be elevated due to liver and bone metastases.
The following adverse reactions have been observed with both oral and intravenous treatment with clodronate, although the frequency of reactions may differ.
Asymptomatic hypocalcemia is a common adverse reaction which occurs in approximately 3% of treated patients. Symptomatic hypocalcemia is rare. Although not yet reported during BONEFOS (clodronate disodium) therapy, hyperphosphatemia has been known to occur with other bisphosphonates.
Indications and Clinical Use
No data is available. As older patients may have decreased renal function, please refer to Warnings and Precautions, Renal.
The safety and efficacy of BONEFOS in children have not been established.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
There is a lack of documented experience on acute overdosing with clodronate. An overdose of the intravenous preparation can result in renal damage. Renal function should be monitored. Overdosage may result in hypocalcemia. Careful monitoring for several days for signs and symptoms of hypocalcemia, in addition to monitoring of serum calcium levels, is recommended in cases where the dose given was too high in relation to initial serum calcium levels (see Warnings and Precautions).
Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and oral or parenteral calcium supplementation may be required to restore plasma calcium levels. Milk or antacids may be given to bind the unabsorbed clodronate following acute oral overdosage.
Dosage Forms, Composition and Packaging
Each yellow, hard gelatin capsule contains: anhydrous clodronate (as the tetrahydrate) 400 mg. Nonmedicinal ingredients: calcium stearate, colloidal anhydrous silica, gelatin, iron oxide (red and yellow), lactose, talc and titanium dioxide. High density polyethylene bottles of 120.
Each mL of i.v. infusion contains: clodronate tetrahydrate corresponding to anhydrous clodronate, 60 mg. Nonmedicinal ingredients: sodium hydroxide (to adjust the pH) and water for injection. Ampuls of 5 mL, packages of 5.
Warnings and Precautions
Administration of clodronate may aggravate renal function in some patients. Intravenous administration of doses notably higher than those recommended may cause severe renal damage, especially if the infusion rate is too high. Appropriate monitoring of the renal function during and after intravenous infusion is required. Since the drug is excreted by the kidneys, it is essential to establish that the excretion of the fluid load and of the drug would not present an excessive medical risk. Adequate fluid intake must be maintained during clodronate treatment. If during therapy there is deterioration of renal function, the intravenous infusion must be stopped.
Clodronate should be used with caution in patients with renal impairment. When the benefits of the use of clodronate in renal impairment outweigh the risks, dose adjustment should be considered, otherwise, the drug should be withheld. Data for dose adjustment in relation to renal function have been derived from a study involving 24 subjects with chronic renal impairment of varying severity and 24 healthy volunteers with normal renal function. Based on the results of this study, dose reductions are recommended depending on the degree of renal insufficiency (see Dosage and Administration). Serum creatinine and blood urea nitrogen should be monitored when the drug is administered intravenously in patients with impaired renal function.
Note: Caution should be exercised in determining dosage adjustment for patients with malignancy and severe skeletal disease, given the potential for wide variation in nonrenal clearance in such patients.
Intravenous or oral administration of clodronate may present a risk of hypocalcemia. When given intravenously, the drug tends to chelate blood calcium during therapy which may contribute to hypocalcemia. Asymptomatic hypocalcemia is a common adverse reaction which occurs in approximately 3% of treated patients. Symptomatic hypocalcemia is rare. Symptomatic hypocalcemia can be reversed by the administration of calcium gluconate.
The drug should be taken on an empty stomach, with a glass of plain water, at least two hours before or after food, because food may decrease the amount of clodronate disodium absorbed by the body.
The safety and efficacy of BONEFOS in children have not been established.
The safety and efficacy of BONEFOS in pregnant women has not been established (see Contraindications).
No data is available. As older patients may have decreased renal function, please refer to Warnings and Precautions, Renal.
The recommended daily dose of i.v. BONEFOS must be diluted in 500 mL of 0.9% sodium chloride injection USP or 5% dextrose injection USP and administered as a slow intravenous infusion lasting at least two hours. BONEFOS should not be mixed with other intravenous infusions. No other drugs or nutrients should be added to the diluted infusion solution (see Dosage and Administration). BONEFOS (clodronate disodium) should not be given as a bolus injection since rapid bolus injection may precipitate acute renal failure, severe local reactions and thrombophlebitis. Extravasation should be avoided. Local reactions may occur (see Adverse Reactions).
Patients must be adequately hydrated before and during the treatment period. This is particularly important when administering clodronate as an intravenous infusion and in patients with hypercalcemia and/or impaired renal function (see Adverse Reactions). Excess calcium impairs the renal concentrating mechanisms resulting in polyuria and excessive fluid loss. Nausea and lethargy caused by hypercalcemia can also reduce oral fluid intake leading to a 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 (see Warnings and Precautions, Renal).
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, 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 judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
The effect of BONEFOS on the ability to drive and use machinery is not known.
Hyperphosphatemia has not been reported during clodronate therapy. However, transient hypophosphatemia can occur following therapy with clodronate.
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 during treatment of hypercalcemia (see Adverse Reactions).
Calcium levels should be monitored throughout the treatment. Corrected (adjusted) serum calcium values may be calculated using established algorithms, such as:
Caadj=Car−0.71 (A−Am)
Caadj=adjusted calcium concentration (mg/100 mL)
Car=total calcium concentration (mg/100 mL)
A=albumin concentration (g/100 mL)
Am=mean normal albumin concentration of the given laboratory (g/100 mL)
Serum creatinine and blood urea nitrogen should be monitored when the drug is administered intravenously in patients with impaired renal function.
Increased serum parathyroid hormone 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.
Clodronate is eliminated mainly via the kidneys. A study examining the pharmacokinetics of clodronate in renally impaired subjects that enrolled a total of 60 subjects in 4 groups (18 subjects with mild, 12 with moderate, and 16 with severe renal insufficiency, and 14 healthy volunteers) demonstrates a clear increase in the mean clodronate serum AUC(0-24h) with decreasing renal function after daily oral clodronate administration. There was no increase in adverse events with worsening renal function. No dose adjustment is considered necessary for subjects with mild renal impairment. Dosage adjustment in patients with moderate and severe renal impairment is recommended (see Dosage and Administration).
There is no clinical experience with BONEFOS in lactating women and it is not known whether BONEFOS passes into breast milk (see Contraindications).
Storage and Stability
BONEFOS (clodronate disodium) capsules and intravenous infusion should be stored between 15 and 30°C.
The diluted intravenous solution may be stored for up to 24 hours at room temperature.
Action and Clinical Pharmacology
Volume of distribution is approximately 20 L. The substance which is bound to bone is about 20% of the absorbed amount. The binding of clodronate to serum proteins is variable, between 2%-36%.
Following a single oral dose, the absorption of clodronate is rapid and the peak serum concentration is reached within 30 minutes. Absorption is estimated at 1-3% of the ingested dose.
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. The most likely mechanism of action of clodronate appears to be suppression of osteoclast activity, resulting in reduction of bone resorption. However, clodronate may also have indirect inhibitory effects through osteoblastic cells, which control the recruitment and activity of osteoclasts.
Unabsorbed drug is excreted unchanged in the feces.
Clodronate is not metabolized.
After an i.v. dose, clodronate exhibits a plasma concentration profile which fits a two-compartment model with t½α approximately 0.3 h and t½β approximately 2 h. The t½ of the terminal elimination phase is approximately 13 h, and accounts for 10-15% of renal excretion. Total clearance is about 110 mL/min and renal clearance is approximately 90 mL/min.
In responsive patients, inhibition of increased bone resorption by clodronate leads to reduction of hypercalcemia of malignancy presenting with or without demonstrable skeletal metastases.
During and also after intravenous administration of clodronate the elevated serum calcium decreases, in some instances to hypocalcemic levels. The decrease in serum calcium concentration is rapid with significant reductions usually attained within two days after starting intravenous therapy and continuing for five to six days after discontinuing therapy.
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 BONEFOS (clodronate disodium) for treatment of hypercalcemia, 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).
Contraindications
Renal functional impairment when serum creatinine exceeds 440 μmol/L (5.0 mg/dL) (see Warnings and Precautions).
Severe inflammation of the gastrointestinal tract.
Pregnancy and lactation.
Concomitant treatment with other bisphosphonates
Hypersensitivity to bisphosphonates, clodronate disodium or to any ingredient in the formulation or component of the container. For a complete listing, see Summary Product Information and Dosage Forms, Composition and Packaging.
