The type of adverse reactions observed in this population were similar to those previously seen in adults with advanced malignancies involving the bone (see section 4.8). The adverse reactions ranked under headings of frequency, are presented in Table 7. The following conventional classification is used: 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).

Table 7: Adverse reactions observed in paediatric patients with severe osteogenesis imperfecta1

Nervous system disorders
 
  Common:
 Headache
 
Cardiac disorders
 
  Common:
 Tachycardia
 
Respiratory, thoracic and mediastinal disorders
 
  Common:
 Nasopharyngitis
 
Gastrointestinal disorders
 
  Very common:
 Vomiting, nausea
 
  Common:
 Abdominal pain
 
Musculoskeletal and connective tissue disorders
 
  Common:
 Pain in extremities, arthralgia, musculoskeletal pain
 
General disorders and administration site conditions
 
 
 Very common:
 Pyrexia, fatigue
 
 
 Common:
 Acute phase reaction, pain
 
Investigations
 
 
 Very common:
 Hypocalcaemia
 
 
 Common:
 Hypophosphataemia
 

1 Adverse events occurring with frequencies < 5% were medically assessed and it was shown that these cases are consistent with the well established safety profile of Zometa (see section 4.8)

In paediatric patients with severe osteogenesis imperfecta, zoledronic acid seems to be associated with more pronounced risks for acute phase reaction, hypocalcaemia and unexplained tachycardia, in comparison to pamidronate, but this difference declined after subsequent infusions.

The European Medicines Agency has waived the obligation to submit the results of studies with zoledronic acid in all subsets of the paediatric population in the treatment of tumour-induced hypercalcaemia and prevention of skeletal-related events in patients with advanced malignancies involving bone (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

 Single and multiple 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients with bone metastases yielded the following pharmacokinetic data, which were found to be dose independent.

After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of pea