Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Bonefos tablets are contraindicated in patients with severe renal failure where creatinine clearance is below 10ml/min, hypersensitivity to the active substance or to any of the excipients listed in section 6.1 and in patients receiving concomitant treatment with other bisphosphonates.
Adequate fluid intake should be maintained during treatment.
Bonefos tablets should be administered with care to patients with renal impairment (see dose adjustment under “Posology and method of administration”). Adequate fluid intake must be maintained during clodronate treatment. This is particularly important when administering clodronate to patients with hypercalcaemia or renal impairment.
Renal function with serum creatinine, serum calcium and phosphate levels should be monitored before and during treatment.
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 primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive 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 osteonecrosis of the jaw 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 osteonecrosis of the jaw.
Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. 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.
Concomitant use with other bisphosphonates is contraindicated. Patients receiving NSAIDs in addition to sodium clodronate have developed renal dysfunction. However, a synergistic action has not been established. As aminoglycosides can cause hypocalcaemia, concomitant clodronate should be administered with caution.
Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate by 80% at the maximum.
Bonefos forms complexes with divalent metal ions, and therefore simultaneous administration with food, antacids and mineral supplements may impair absorption.
There is a limited amount of data from the use of clodronate in pregnant women. Bonefos is not recommended during pregnancy and in women of childbearing potential not using effective contraception. Although in animals clodronate passes through the placental barrier it is not known if it passes into the foetus in humans. Furthermore, it is not known if clodronate can cause foetal damage or affect reproduction in humans. Studies in animals have shown reproductive toxicity (see section 5.3).
It is unknown whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Bonefos.
In animal studies, clodronate did not cause foetal damage, but large doses decreased male fertility.
No clinical data on the effect of clodronate on fertility in humans are available.
None known.
The most common reported drug reaction is diarrhoea which is usually mild and occurs more commonly with higher doses.
These adverse reactions may occur when using Bonefos:
Common ≥1/100 to <1/10, Rare ≥1/10,000 to <1/1,000, Very rare <1/10,000, Frequency unknown
Common: Asymptomatic hypocalcemia
Rare: Symptomatic hypocalcemia. Increased levels of serum parathyroid hormone associated with decreased serum calcium levels. Increased levels of serum alkaline phosphatase*
Common: Diarrhoea**, Nausea**, Vomiting**
Common: Levels of transaminases increased – usually within normal range
Rare: Levels of transaminases increased to more than twice the normal range without associated abnormal hepatic function
Rare: Hypersensitivity reaction manifesting as skin reaction e.g. pruritus, urticaria, exfoliative dermatitis
Rare: Bronchospasm in patients with and without a previous history of asthma.
Frequency unknown: Impairment of respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disorder.
Frequency unknown: Impairment of renal function (elevation of serum creatinine and proteinuria), severe renal damage. Single cases of renal failure, in rare cases with fatal outcome, especially with concomitant use of NSAIDs, most often diclofenac.
Rare: Atypical subtrochanteric and diaphyseal femoral fractures. (bisphosphonate class adverse reaction; from post-marketing experience) (see Section 4.4).
Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).
Frequency unknown: Isolated cases of osteonecrosis of the jaw, primarily in patients previously treated with aminobisphosphonates such as zoledronate and pamidronate (see Section 4.4). 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.
Frequency unknown: Uveitis has been reported with Bonefos during post-marketing experience. Although the following reactions have been reported with other biphosphonates; conjunctivitis, episcleritis and scleritis, only conjunctivitis has been reported for Bonefos. This was in one patient concomitantly treated with another bisphosphonate. To date, episcleritis and scleritis (bisphosphonate class adverse reactions) have not been reported with Bonefos
* in patients with metastatic disease, may also be due to hepatic and bone disease.
** usually mild – use of the divided dose regimen rather than a single daily dose may improve gastro-intestinal tolerance.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
None stated.
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