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drug-monograph
clodronate
Other Names
Bonefos®, Ostac®, Clasteon®
Appearance
Oral use- capsule;
Injection- Clear, colorless solution mixed into larger bags of fluids
Funding Program
ODB Limited Use
B - Mechanism of Action and Pharmacokinetics
Clodronate is a first generation bisphosphonate. Bisphosphonates bind to hydroxyapatite in bone and inhibit osteoclast resorption and thus bone resorption. Clodronate has been shown to prevent or delay skeletal-related events and decrease bone pain, as well as normalize calcium levels in the presence of hypercalcemia.
Absorption
| Bioavailability | Oral: 1 to 3% bioavailability; reduced when administered with food or calcium |
Distribution
Clodronate is rapidly accumulated in bone after parenteral administration.
| Cross blood brain barrier? | no information found |
| PPB | 2 - 36 % |
Metabolism
Not metabolized
| Active metabolites | no |
| Inactive metabolites | no |
Elimination
Excreted unchanged by the kidneys. About 20% of absorbed dose binds to bone and is released slowly.
| Urine | 60-80% of absorbed dose as unchanged drug within 24 hours. |
| Feces | 5% of IV dose |
| Half-life | Dependent on rate of bone turnover |
C - Indications and Status
Health Canada Approvals:
- Management of hypercalcemia of malignancy
- As an adjunct in the management of osteolysis resulting from bone metastases of malignant tumours
D - Adverse Effects
Emetogenic Potential:
Not applicable
Extravasation Potential: Mild irritant
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Thrombophlebitis (rapid infusion) | I | |||
| Dermatological | Rash (rare) | I E | |||
| Gastrointestinal | Anorexia (1%) | I | |||
| Diarrhea (up to 10% with PO) | I | ||||
| Gastrointestinal pain (10%) (gastric) | I E | ||||
| Nausea, vomiting (4%) | I | ||||
| Hepatobiliary | ↑ LFTs (2%) (> 2 x ULN) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Metabolic / Endocrine | ↓ Ca (3%) | E | |||
| Hyperparathyroidism (secondary, reversible) | I | ||||
| ↓ PO4 (transient) | I | ||||
| Musculoskeletal | Fracture (1%) (including atypical) | E | |||
| Musculoskeletal pain (infrequently severe) | E D | ||||
| Osteonecrosis of jaw (rare) | E | ||||
| Neoplastic | Leukemia (secondary) (rare) | D | |||
| MDS (rare) | D | ||||
| Ophthalmic | Uveitis , episcleritis, conjunctivitis (rare) | E D | |||
| Renal | Proteinuria (transient) | E | |||
| Renal failure (rare) | I E | ||||
| Respiratory | Bronchospasm (in ASA sensitive asthmatics; theoretical) | I | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
Administration of clodronate may aggravate renal function in some patients, especially with IV use, concomitant NSAIDs or in the presence of dehydration, hypercalcemia or pre-existing renal dysfunction. Vigorous rehydration for patients with hypercalcemia is mandatory.
Gastrointestinal disturbances including nausea, vomiting, gastric pain and diarrhea are the most frequent adverse events reported during clodronate therapy, particularly with the oral form. A reduction in dosage, a change to IV clodronate or a temporary interruption of therapy may assist in the management of patients where these symptoms are relevant.
Osteonecrosis of the jaw has been reported, with an increased risk in patients who smoke, have comorbid or dental diseases, poorly fitting dentures, have had invasive dental procedures, are receiving steroids, radiotherapy, chemotherapy and parenteral bisphosphonate formulations. Patients should be advised to have dental examinations prior to starting therapy and to avoid invasive dental procedures on treatment. The start of treatment or a new course of treatment should be delayed in patients with unhealed, open soft tissue lesions in the mouth. In multiple myeloma patients, consider either discontinuing treatment after 2 years for stable responding patients or decreasing frequency to every three monthly.
Atypical fractures of the femur (subtrochanteric or diaphyseal) have been reported with bisphosphonate use, primarily in patients receiving long-term treatment. These fractures are often bilateral, occur with minimal or no trauma, with symptoms including thigh or groin pain weeks or months before a complete fracture. Imaging features of stress features may be seen weeks to months before presentation with a completed femoral fracture. Poor healing of these fractures has also been reported.
E - Dosing
Refer to protocol by which patient is being treated. All patients should be adequately hydrated prior to and during treatment with clodronate. Dehydration must be vigorously corrected with normal saline prior to treatment, especially in patients with hypercalcemia; in general, at least 3 L/day should be administered initially and hydration continued until normocalcemia has been achieved. Overhydration should be avoided especially in patients with cardiac risk factors.
Calcium and Vitamin D supplements should be considered in patients who have normal calcium levels with no history of hypercalcemia.
Delay treatment in patients with unhealed soft tissue mouth lesions.
Adults:
Intravenous:
- Hypercalcemia: 300mg IV daily in 500mL NS or D5W, over at least 2-6 hours; may be repeated if required on days 2-5
- Other usage: q3-4 weeks; 1500mg IV in 500mL NS or D5W, over at least 4 hours, as single dose
For hypercalcemia, elevated calcium levels are usually reduced to normal within 2 to 5 days. After normalization, maintenance treatment may be continued with the oral capsules to maintain normocalcemia.
Oral:
1600mg to 2400mg daily given in single or two divided doses The dose may be increased (up to 3200mg/day) if deemed clinically appropriate. Doses over 1600 mg daily should not be used for prolonged periods.
Dosage with Toxicity:
Dosage in myelosuppression: No dosage adjustment required
|
Toxicity
|
Action
|
Atypical fractures of the femur |
Consider discontinuing
|
Ocular symptoms other than uncomplicated conjunctivitis |
Refer to ophthalmologist; consider discontinuing |
|
Osteonecrosis of the jaw
|
Refer to dentist or dental surgeon; hold until recovery |
|
Severe or intolerable GI symptoms
|
Consider discontinuing; switch to IV bisphosphonate |
Dosage with Hepatic Impairment:
No adjustment required.
Dosage with Renal Impairment:
Clodronate is renally excreted and should be discontinued if renal function deteriorates during treatment.
Creatinine Clearance |
PO: % of normal dose |
IV: % of Normal dose |
50-80 mL/min |
100% |
75-100% |
30-49 mL/min |
75% |
50-75% |
12-29mL/min |
50% |
50-75% |
< 12mL/min |
50% OR discontinue |
50% OR discontinue |
Dosage in the elderly:
Use with caution due to the risk of renal impairment.
Children:
Safety and efficacy have not been established.
F - Administration Guidelines
Intravenous
- Clodronate should not be given as a bolus injection since acute renal failure, severe local reactions and thrombophlebitis may occur.
- Mix in 500mL solution (D5W, NS) and infuse over at least 2 hours (for 300mg IV daily up to 7-10 days), or over at least 4 hours (for single dose of 1500 mg IV). Should not be mixed in any diluents other than NS or D5W.
- Do not use Ringer's lactate or other calcium-containing solutions.
- Do not admix with any other drug.
- May infuse using ambulatory infusion device.
- All patients should be adequately hydrated prior to and during treatment with clodronate.
- Store unopened vials at room temperature (15-30°C)
Oral
- Oral clodronate should be swallowed whole, administered with copious amounts of water, and on an empty stomach, 2 hours before or after food or any oral drugs/supplements for optimal absorption. Patient should remain upright for half an hour after taking oral clodronate.
- If given BID, the second dose should be taken between meals, more than two hours after and more than one hour before eating, drinking (other than plain water), or taking any other oral drugs.
- Clodronate should not be taken with milk or food containing calcium or other divalent ions (i.e. Mg, Al, Ca, Fe), as clodronate absorption may be impaired.
- Store capsules at room temperature (15-30°C).
G - Special Precautions
Contraindications:
Other Drug Properties:
- Patients with moderate to severe renal impairment (serum creatinine > 440 umol/L)
- Patients with a hypersensitivity to clodronate or other bisphosphonates
- Patients with severe inflammation of the GI tract
- Patents on concomitant treatment with other bisphosphonates as combined effects are unknown
- Patients with mild renal impairment
- Patients must have adequate fluid intake during clodronate treatment, but overhydration should be avoided
- Patients with risk factors for ONJ (see adverse effects description section)
Other Drug Properties:
- Carcinogenicity: No
- Mutagenicity: No
- Fetotoxicity: Yes
Clodronate is contraindicated in pregnancy and lactation. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
- Excretion into breast milk: Unknown
- Fertility effects: Probable
H - Interactions
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Calcium-containing IV solutions | ↓ absorption | Chelate to clodronate | Avoid |
| Antacid or drug containing calcium, iron, magnesium or aluminum | ↓ absorption | Chelate to clodronate | Avoid. Take clodronate 2 hours before or after meals and other drugs. |
| Aminoglycosides, corticosteroids, phosphate, calcitonin, mithramycin, loop-diuretics | ↑ hypocalcemia | Additive hypocalcemic effect | Caution or avoid. Monitor serum calcium. |
| NSAID's, especially diclofenac | ↑ potential of renal dysfunction | Possible additive action | Caution or avoid. Monitor serum creatinine |
| Estramustine | ↑ toxicity | Increased levels of estramustine (up to 80%) | Use with Caution |
I - Recommended Clinical Monitoring
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Recommended Clinical Monitoring
| Monitor Type | Monitor Frequency |
|---|---|
| Dental examination with appropriate preventative dentistry should be considered prior to treatment. Regular dental check-ups. Avoid invasive dental surgeries while on treatment. | |
Corrected serum calcium* (daily during iv infusion), albumin, and phosphate -- *Corrected Ca (mmol/L) = Measured Ca (mmol/L) + (0.02 X [40-Measured Albumin (g/L)]) |
Baseline and as clinically indicated |
Renal function tests, especially with IV use |
Baseline and at each visit |
Clinical toxicity assessment (GI, hydration, osteonecrosis, dental, hypersensitivity, ophthalmic, musculoskeletal pain) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Suggested Clinical Monitoring
| Monitor Type | Monitor Frequency |
|---|---|
CBC, in patients with anemia, leukopenia or thrombocytopenia |
Baseline and as clinically indicated |
| Liver function tests | Baseline and intermittent |
J - Supplementary Public Funding
New Drug Funding Program (NDFP Website )
- Clodronate (IV) - Metastatic Breast Cancer
- clodronate - For the prevention and treatment of osteolytic lesions in patients with multiple myeloma (capsules)
- clodronate - For the treatment of bony metastases in patients with breast cancer (capsules)
- clodronate - For the control and prophylaxis of hypercalcemia of malignancy (capsules)
K - References
CCO Practice Guideline: Use of Bisphosphonates in Patients with Bone Metastases from Breast Cancer
CCO Practice Guideline: The Role of Bisphosphonates in the Management of Skeletal Complications for Patients with Multiple Myeloma
Diel I J, Solomayer E, Costa S D et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. NEJM 339(6): 357-63.
Lacy MO, Dispenzieri A, Gertz MA, et al. Mayo Clinic Consensus Statement for the Use of Bisphosphonates in Multiple Myeloma. Mayo Clin Proc 2006; 81(8):1047-1053.
O'Rourke NP, McCloskey EV, Vasikaran S, et al. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. British Journal of Cancer 1993;67(3):560-3.
Plosker GL, Goa KL. Clodronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs (1994); 47(6): 945-82.
Product Monograph: Bonefos® (clodronate). Bayer Inc., March 30, 2017.
Product Monograph: Clasteon® (clodronate). Sunovion Pharmaceuticals Inc., September 22, 2011.
June 2020 Archived. Not on QBP
L - Disclaimer
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
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Last Updated: July 21, 2026
