Update Section 4.4 and 4.8 to include wording on acute phase reactions

Update Section 5.1 to include 12-month date for the open-label extension of the paediatric study

• Section 4.2: Updated to include the following recommendation: Aclasta should not be used in children and adolescents below 18 years of age. There are no data available for children under 5 years of age. Currently available data for children aged 5 to 17 years are described in section 5.1.
• Section 5.1: Updated to include detailed results of the study.

·         “Anti‑angiogenic medicinal products” has been added to the existing concomitant risk factors in SPC sections 4.4 and 4.8 based on recent publications which demonstrate that anti-angiogenic medicinal products are associated with ONJ

·         The current wording on ONJ focuses mainly on cancer patients. A general statement that “Osteonecrosis of the jaw has been reported in patients treated with zoledronic acid” is added in section 4.4. Specific information of ONJ in patients with cancer‑indication is deleted in section 4.4, but maintained in section 4.8.

·         The information on hydration and calcium intake, currently under the subheading on Paget`s disease in Section 4.2, has been moved to the beginning of Section 4.2 as hydration intake and calcium intake are important for all patients treated with Aclasta.

Section 4.2: Addition of information regarding periodic review of the need for continued treatment

Section 4.4: Addition of information regarding atypical femoral fractures which have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. 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.

Section 4.8: Addition of "Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)" as a rare undesirable effect

Patients with renal impairment

Use of Aclasta should not be used in patients with creatinine clearance < 35 ml/min is not recommended due to limited clinical experience in this population (see section 4.4).

In Section 4.4 the following warning re use in opatients with renal impairment:

Renal impairment has been observed following the administration of Aclasta (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after Aclasta administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal adverse reactions:

·             Creatinine clearance should be measured before each Aclasta dose.

·             Aclasta should not be used in patients with creatinine clearance < 35 ml/min (see section 5.2).

·             Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.

·             Monitoring of serum creatinine should be considered in at-risk patients.

·             Aclasta should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).

·             Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Aclasta.

·             A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).The dose of 5 mg zoledronic acid must be administered over at least 15 minutes.

Aclasta is not recommended in patients with severe renal impairment (creatinine clearance < 35 ml/min) due to limited clinical experience in this population. Patients should have their serum creatinine level measured before receiving Aclasta.

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important in the elderly and for patients receiving diuretic therapy. Caution is indicated when Aclasta is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration), see section 4.5.

In Section 4.5 the following text added:

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

In Section 4.8 the following post marketing AEs added (frequency unknown):
Scleritis and orbital inflammation, Hypotension (some of the patients had underlying risk factors), Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects), Renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period (see sections 4.4 and 4.8 Class effects), Dehydration secondary to post-dose symptoms such as fever, vomiting and diarrhoea.

In Section 5.2, the following text added:

Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 l/h, independent of dose, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.