nt finding in repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound's pharmacological antiresorptive activity.
The safety margins relative to renal effects were narrow in the long-term repeat-dose parenteral animal studies but the cumulative no adverse event levels (NOAELs) in the single dose (1.6 mg/kg) and multiple dose studies of up to one month (0.06–0.6 mg/kg/day) did not indicate renal effects at doses equivalent to or exceeding the highest intended human therapeutic dose. Longer-term repeat administration at doses bracketing the highest intended human therapeutic dose of zoledronic acid produced toxicological effects in other organs, including the gastrointestinal tract, liver, spleen and lungs, and at intravenous injection sites.
Reproduction toxicity
Zoledronic acid was teratogenic in the rat at subcutaneous doses 0.2 mg/kg. Although no teratogenicity or foetotoxicity was observed in the rabbit, maternal toxicity was found. Dystocia was observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat.
Mutagenicity and carcinogenic potential
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol
Sodium citrate
Water for injections
6.2 Incompatibilities
This medicinal product must not be allowed to come into contact with any calcium-containing solutions and it must not be mixed or given intravenously with any other medicinal product in the same infusion line.
6.3 Shelf life
Unopened bottle: 3 years.
After first opening: From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. The refrigerated solution should then be equilibrated to room temperature prior to administration.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
100 ml solution in a transparent, colourless, plastic (cycloolefinic copolymer) bottle closed with a fluorocarbon polymer coated bromobutyl rubber stopper and an aluminum cap with a flip-off component of polypropylene.
Pack size
One bottle as a unit pack or multi-packs comprising 4 or 5 packs, each containing one bottle.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Additional information on handling of Zometa, including guidance on the preparation of reduced doses using the Zometa ready-to-use bottle, is provided in section 4.2.
Aseptic techniques must be followed during the preparation of the infusion. For single use only.
Only clear solution free from particles and discolouration should be used.
Healthcare professionals are advised not to dispose of unused Zometa via the domestic sewage sy
