Bonefos骨膦

Bonefos

clodronic acid

Manufacturer:

Bayer

Distributor:

Zuellig
/
Firma Chun Cheong
Full Prescribing Info
Contents
Disodium clodronate.
Description
One Bonefos 400 mg capsule contains 400 mg disodium clodronate.
Excipients/Inactive Ingredients: lactose monohydrate, talc, calcium stearate, colloidal anhydrous silica.
Shell: hard gelatin capsule, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172).
Action
Pharmacology: Pharmacotherapeutic action: Bonefos is intended for the treatment of bone diseases. Bonefos contains disodium clodronate as an active ingredient. Clodronate is chemically defined as a bisphosphonate and is an analogue of the natural pyrophosphate. Bonefos has a strong affinity for mineralized tissues such as bone, where it inhibits bone resorption.
Toxicology: Preclinical safety data: Acute toxicity: Studies with single doses in mice and rats gave the following LD50 values: See Table 1.

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In mice and rats, clinical signs of acute toxicity comprised decreased motor activity, convulsions, unconsciousness and dyspnea. In the mini-pig, an intravenous dose of 240 mg/kg was toxic after two or three infusions.
Systemic tolerance: Repeated dose toxicity studies lasting from 2 weeks to 12 months have been performed on rats and mini-pigs. A few deaths were reported in all these studies. Intravenous administration was lethal to rats at daily doses of 140 and 160 mg/kg after 1-7 days. In the mini-pig, an intravenous daily dose of 80 mg/kg after 7-13 days caused vomiting and general weakness before death. At oral daily doses of 100-480 mg/kg in rats and 800 mg/kg in mini-pigs no test substance related mortality was noted.
In toxicity studies, the effect of clodronate was observed in the following organs (the observed changes within brackets): bone (sclerosis related to the pharmacological effects of clodronate), gastrointestinal tract (irritation), blood (lymphopenia, effects on hemostasis), kidneys (dilated tubules, proteinuria), and liver (elevation of serum transaminases).
Reproduction toxicity: In animal studies, clodronate did not cause fetal damage, but large doses decreased male fertility. After one month of subcutaneous administration of clodronate to newborn rats, skeletal changes resembling osteopetrosis were found, which are related to the pharmacological effects of clodronate.
Genotoxic potential, tumorigenicity: Clodronate has not shown genotoxic potential. No carcinogenic effects have been observed in studies with rats and mice.
Indications/Uses
Treatment of hypercalcemia and osteolytic bone metastases due to malignancy.
Dosage/Direction for Use
Clodronate is eliminated mainly via the kidneys. Therefore, adequate fluid intake must be maintained during clodronate treatment.
Bonefos capsules should be swallowed whole.
A daily dose of 1600 mg is recommended to be taken as a single dose. When higher daily doses are used, the part of the dose exceeding 1600 mg is recommended to be taken separately (as a second dose) as recommended as follows.
The single daily dose and the first dose of two should preferably be taken in the morning on an empty stomach together with a glass of water. The patient should then refrain from eating, drinking (other than plain water), and taking any other oral drugs for one hour.
When twice daily dosing is used, the first dose should be taken as recommended previously. The second dose should be taken between meals, more than two hours after and one hour before eating, drinking (other than plain water), or taking any other drugs.
Clodronate should in no case be taken with drinks, food or drugs containing calcium or other divalent cations because they impair the absorption of clodronate.
Children: Safety and efficacy in pediatric patients have not been studied.
Elderly: There are no special dosage recommendations for the elderly. Clinical trials have included patients over 65 years and no adverse effects specific to this age group have been reported.
Adult patients with normal renal function: Treatment of hypercalcemia due to malignancy: Intravenous clodronate is recommended for the start of the treatment of hypercalcemia. Subsequently, an oral dosage of 1600-3200 mg clodronate daily may be used. However, if oral therapy is used, a high starting dose of 2400-3200 mg should be used and, depending on the individual response, this can be reduced gradually to 1600 mg daily.
Treatment of osteolysis due to malignancy: When oral therapy is used to treat increased bone resorption without hypercalcemia, the recommended starting dose is 1600 mg daily. If clinically necessary, the dose may be increased, but is not recommended to exceed 3200 mg daily.
Patients with renal failure: Clodronate is eliminated mainly via the kidneys. Therefore, it should be used with caution in patients with renal failure; daily doses exceeding 1600 mg should not be used continuously.
The clodronate dose should be reduced as follows: See Table 2.

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Overdosage
Symptoms: Increases in serum creatinine and renal dysfunction have been reported with high intravenous doses of clodronate.
Treatment: Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium should be monitored.
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Concomitant treatment with other bisphosphonates.
Special Precautions
Adequate fluid intake shall be maintained during Bonefos treatment. This is particularly important when Bonefos is used in connection with hypercalcemia or renal failure.
Bonefos is eliminated mainly via the kidneys. It should therefore be used with caution in connection with renal failure; daily doses exceeding 1600 mg should not be used continuously.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including both intravenous and oral bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids.
Preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor dental hygiene) and invasive dental procedures should be avoided while patients are being treated with bisphosphonates.
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. So far, these fractures have not been reported with Bonefos. These transverse or short oblique, fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported.
Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Effects on ability to drive or use machines: Not known.
Use In Pregnancy & Lactation
Pregnancy: Although in animals clodronate passes through the placental barrier, it is not known if it passes into the fetus in humans. Furthermore, it is not known if clodronate can cause fetal damage or affect reproduction in humans. Therefore, clodronate should not be used for pregnant women, unless the therapeutic advantages clearly outweigh any risks.
Lactation: It is not known whether clodronate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from clodronate, breast feeding under the treatment with clodronate is not recommended.
Adverse Reactions
The most common reported drug reaction is diarrhea which is usually mild and occurs more commonly with higher doses.
These adverse reactions may occur in connection with both oral and intravenous treatment, although the frequency of reactions may differ. (See Table 3.)

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Post-marketing experience: Eye disorders: Uveitis has been reported with Bonefos during post-marketing experience. The following reactions have been reported with other bisphosphonates: Conjunctivitis, episcleritis and scleritis. Conjunctivitis was only reported with Bonefos in one patient concomitantly treated with another bisphosphonate. So far, episcleritis and scleritis have not been reported with Bonefos (bisphosphonate class adverse reaction).
Respiratory, thoracic and mediastinal disorders: Impairment of respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disorder.
Renal and urinary disorders: Impairment of renal function (elevation of serum creatinine and proteinuria), severe renal damage especially after rapid intravenous infusion of high doses of clodronate.
Single cases of renal failure, in rare cases with fatal outcome have been reported especially with concomitant use of NSAIDs, most often diclofenac.
Musculoskeletal and connective tissue disorders: Isolated cases of osteonecrosis of the jaw have been reported, primarily in patients who were previously treated with amino-bisphosphonates like zoledronate and pamidronate (see also Precautions). Severe bone, joint, and/or muscle pain has been reported in patients taking Bonefos. However, such reports have been infrequent and in randomised placebo controlled studies no differences are apparent between placebo and Bonefos treated patients. The onset of symptoms varied from days to several months after starting Bonefos.
During post-marketing experience the following reactions have been reported with other bisphosphonates: Atypical subtrochanteric and diaphyseal femoral fractures. So far, these reactions have not been reported with Bonefos (bisphosphonate class adverse reaction) (see also Precautions).
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Drug Interactions
Concomitant use with other bisphosphonates is contraindicated.
Clodronate has been reported to be associated with renal dysfunction when used simultaneously with non-steroidal anti-inflammatory analgesics (NSAIDs), most often diclofenac.
Due to increased risk of hypocalcemia, caution should be taken when using clodronate together with aminoglycosides.
Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate by 80% at the maximum.
Clodronate forms poorly soluble complexes with divalent cations. Therefore, clodronate should not be administered intravenously with solutions containing divalent cations (e.g. Ringer's solution). In addition clodronate tablets/capsules should not be taken with food or drugs containing divalent cations (e.g. antacids or iron preparations).
Storage
Store the medicine at room temperature (+15°C to +25°C).
Shelf life: Five years.
ATC Classification
M05BA02 - clodronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Presentation/Packing
Cap 400 mg (pale yellow hard gelatin capsule size 1, marked "Bonefos") x 60's.
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