ZOBONE Concentrate for solution for infusion Ref.[50459] Active ingredients: Zoledronic acid

Posology

For the treatment of:

Skeletal conditions in patients with advanced malignancies involving bone:

Adults and elderly:

The recommended dose in the treatment of the above, is 4 mg ZOBONE SOLUTION FOR INFUSION solution, which should be further diluted with 100 mL 0,9% w/v sodium chloride or 5% w/v glucose solution, given as a 15-minute intravenous infusion every 3 to 4 weeks.

Patients should also be administered an oral calcium supplement of 500 mg and 400-IU vitamin D daily.

The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months.

Treatment of tumour-induced hypercalcaemia (TIH):

Adults and elderly:

The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥12,0 mg/dL or 3,0 mmol/L) is 4 mg, which should be diluted with 100 mL sterile 0,9% w/v sodium chloride or 5% w/v glucose solution, given as a single 15-minute intravenous infusion.

Patients must be maintained well-hydrated prior to and following administration of ZOBONE SOLUTION FOR INFUSION.

Special populations

Renal impairment

Adjustment of dosage or infusion time is not required in patients with mild or moderate renal impairment (serum creatinine less than 400 μmol/L or less than 4,5 mg/dL, or calculated creatinine clearance by Cockcroft-Gault formula of more than 30 mL/min).

Patients with HCM

ZOBONE SOLUTION FOR INFUSION treatment in patients with hypercalcaemia of malignancy (HCM) and who also have severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 micromol/L or >4,5 mg/dL were excluded. No dose adjustment is necessary in HCM patients with serum creatinine <400 micromol/L or <4,5 mg/dl (see section 4.4).

In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CrCl 30–60 mL/min, the following ZOBONE SOLUTION FOR INFUSION dose is recommended (see also section 4.4).

Table 1:

^* Doses have been calculated assuming target AUC of 0,66 (mg.hr/L) (CrCl = 75 mL/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 mL/min.

Following initiation of therapy, serum creatinine should be measured prior to each dose of ZOBONE SOLUTION FOR INFUSION and treatment should be withheld if renal function has deteriorated. In the clinical trials, renal deterioration was defined as follows:

• For patients with normal baseline serum creatinine (<1,4 mg/dL or 123,76 mmol/L), an increase of ≥0,5 mg/dl or 44,2 mmol/L.
• For patients with an abnormal baseline creatinine (>1,4 mg/dL or 123,76 mmol/L), an increase of ≥1,0 mg/dL or 88,4 mmol/L. It is reported that, ZOBONE SOLUTION FOR INFUSION treatment should be resumed only when the creatinine level returned to within 10% of the baseline value (see section 4.4). ZOBONE SOLUTION FOR INFUSION should be resumed at the same dose as that prior to treatment interruption.

Paediatric population

The safety and efficacy of ZOBONE SOLUTION FOR INFUSION in children aged less than 18 years has not been established.

Instructions for preparing reduced dose of ZOBONE SOLUTION FOR INFUSION: Withdraw an appropriate volume of the reconstituted solution

(4 mg/5 mL) as needed:

4,4 mL for 3,5 mg dose

4,1 mL for 3,3 mg dose

3,8 mL for 3,0 mg dose

For information on the reconstitution and dilution of ZOBONE SOLUTION FOR INFUSION see Instructions for use and handling.

The withdrawn amount of liquid concentrate must be further diluted in 100 mL of sterile 0,9% w/v sodium chloride solution or 5% w/v glucose solution. The dose must be given as a single intravenous infusion of no less than 15 minutes.

In patients with mild to moderate renal impairment, reduced doses are recommended (see section “Posology” above and section 4.4).

If refrigerated, the solution must be allowed to reach room temperature before administration (see section 6.6).

There is no reported evidence of acute intoxication with ZOBONE SOLUTION FOR INFUSION. Patients who have received doses higher than those recommended should be carefully monitored. In the event of clinically significant hypocalcaemia, reversal may be achieved with an infusion of calcium gluconate.

Treatment should be supportive and symptomatic.

ZOBONE SOLUTION FOR INFUSION: 24 months.

Store at or below 25 °C. Do not refrigerate.

ZOBONE SOLUTION FOR INFUSION is stable when exposed to light before use.

KEEP OUT OF REACH OF CHILDREN.

Dilution instructions:

The Zoledronic acid SUN solution is stable for 24 hours at 2°C–8°C after further dilution in 100 ml physiological saline or 5% w/v glucose solution.

After aseptic dilution, from a microbiological point of view, the medicine should be used immediately. If not used immediately, the total time between dilution, storage in a refrigerator at 2°C-8°C and end of administration must not exceed 24 hours.

The refrigerated solution should then be equilibrated to room temperature prior to administration.

This medicine does not require any special storage conditions.

For storage conditions of the diluted solution for infusion, see section 6.3.

ZOBONE SOLUTION FOR INFUSION can withstand the effects of high (40°C) and low (-10°C to -20°C) temperature variations that may be encountered during shipping and handling, for 24 hours.

After dilution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8ºC.

The stability has been demonstrated throughout the entire concentration range (between 38,1 μg/mL and 28,9 μg/mL) for 24 hours at 2-8°C.

The diluted solution is stable for 24 hours stored at 2-8°C when reconstituted (see section 6.3).

ZOBONE SOLUTION FOR INFUSION:

Clear colourless solution in 5 mL colourless tubular glass vial with grey rubber stopper sealed with baby blue flip top aluminum seal.

Vial: 5 ml clear Type-I Neutral glass vial.

Stopper: Grey bromobutyl flange rubber stopper.

Seal: White aluminium seal and baby blue flip top aluminium seal.

Pack size: Packed in unit pack containing 1x 5 ml single vial.

Prior to administration, 5,0 mL concentrate from one vial or the volume of the concentrate withdrawn as required must be further diluted with 100 mL of calcium-free infusion solution (0,9% w/v sodium chloride solution or 5% w/v glucose solution).Additional information on handling of ZOBONE SOLUTION FOR INFUSION, including guidance on preparation of reduced doses, 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 ZOBONE SOLUTION FOR INFUSION via the domestic sewage system.

Any unused medicine or waste material should be disposed of in accordance with local requirements.

After aseptic dilution, it is preferable to use the diluted medicine immediately. If not used immediately, the duration and conditions of storage prior to use are the care provider’s responsibility. The total time between dilution, storage in a refrigerator at 2-8°C and end of administration must not exceed 24 hours. Do not freeze the reconstituted solution.