Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Atnahs Pharma Netherlands B.V., Strawinskylaan 3127, 1077 ZX Amsterdam, Netherlands
Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.
Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with IV ibandronic acid.
Appropriate medical support and monitoring measures should be readily available when Bondronat intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.
Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bondronat for oncology indications (see section 4.8).
The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.
A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bondronat in patients with concomitant risk factors.
The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bondronat. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bondronat administration.
The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Bondronat treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
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.
Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat (see section 4.2).
As no clinical data are available, dose recommendations cannot be given for patients with severe hepatic insufficiency (see section 4.2).
Overhydration should be avoided in patients at risk of cardiac failure.
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.
Bondronat is essentially sodium free.
Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.
There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.
It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during breast-feeding.
There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).
On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bondronat has no or negligible influence on the ability to drive and use machines.
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw and ocular inflammation (see paragraph "description of selected adverse reactions"and section 4.4).
Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.
In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache.
Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with Bondronat 6 mg), and from post-marketing experience.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse Reactions Reported for Intravenous Administration of Bondronat:
Common: Infection
Uncommon: Cystitis, vaginitis, oral candidiasis
Uncommon: Benign skin neoplasm
Uncommon: Anaemia, blood dyscrasia
Very rare: Hypersensitivity†, bronchospasm†, angioedema†, anaphylactic reaction/shock†**
Not known: Asthma exacerbation
Common: Parathyroid disorder
Common: Hypocalcaemia**
Uncommon: Hypophosphataemia
Uncommon: Sleep disorder, anxiety, affection lability
Common: Headache, dizziness, dysgeusia (taste perversion)
Uncommon: Cerebrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia
Common: Cataract
Rare: Ocular inflammation†**
Uncommon: Deafness
Common: Bundle branch block
Uncommon: Myocardial ischaemia, cardiovascular disorder, palpitations
Common: Pharyngitis
Uncommon: Lung oedema, stridor
Common: Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder
Uncommon: Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis
Uncommon: Cholelithiasis
Common: Skin disorder, ecchymosis
Uncommon: Rash, alopecia
Very rare: Stevens-Johnson Syndrome†, Erythema Multiforme†, Dermatitis Bullous†
Common: Osteoarthritis, myalgia, arthralgia, joint disorder, bone pain
Rare: Atypical subtrochanteric and diaphyseal femoral fractures†
Very rare: Osteonecrosis of jaw†**, Osteonecrosis of the external auditory canal (bisphosphonat e class adverse reaction)†
Uncommon: Urinary retention, renal cyst
Uncommon: Pelvic pain
Common: Pyrexia, influenza-like illness**, oedema peripheral, asthenia, thirst
Uncommon: Hypothermia
Common: Gamma-GT increased, creatinine increased
Uncommon: Blood alkaline phosphatase increase, weight decrease
Uncommon: Injury, injection
** See further information below
† Identified in post-marketing experience
Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4). Cases of ONJ have been reported in the post marketing setting for ibandronic acid.
Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
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 national reporting system listed in Appendix V.
To avoid potential incompatibilities Bondronat concentrate for solution for infusion should only be diluted with isotonic sodium chloride solution or 5% glucose solution.
Bondronat should not be mixed with calcium containing solutions.
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