Novartis Pharmaceuticals UK Ltd

Reports of ONJ have been received in patients treated with Zometa and concomitant anti-angiogenic medicinal products.

The following text has been added to Section 4.8 as shown below in blue text:

Description of selected adverse reactions

Renal function impairment

Zometa has been associated with reports of renal dysfunction. In a pooled analysis of safety data from Zometa registration trials for the prevention of skeletal-related events in patients with advanced malignancies involving bone, the frequency of renal impairment adverse events suspected to be related to Zometa (adverse reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung and other solid tumours (3.2%). Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zometa or other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of 4 mg zoledronic acid (see section 4.4).

The use of Zometa in paediatric patients has not been studied in 2 clinical trials in the treatment of severe osteogenesis imperfecta (see section 5.1). Zometa should not be used in the paediatric population because safety and efficacy in children have not been established (see sections 4.4 and 5.1). Zometa should not be used in that patient population until further data becomes available.

Section 4.3 insertions underlined and deletions in red:

4.3     Contraindications

·             Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients in the formulation of Zometa

·             Breast-feeding (see section 4.6)Zometa concentrate is contraindicated in breast-feeding women and in patients with clinically significant hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of Zometa.

Section 4.4 new paragraph added under the general heading and reference to section 5.1 in last paragraph under the general heading:

Zometa contains the same active substance as found in Aclasta (zoledronic acid). Patients being treated with Zometa should not be treated with Aclasta concomitantly.

Section 4.6 Pregnancy and Lactation headings added.

Section 4.8 Deletions shown in red relating to Table 1 and addition of final paragraph underlined. 

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies following predominantly chronic treatment with zoledronic acid:

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (³1/10), common (³1/100, <1/10), uncommon (³1/1,000, <1/100), rare (³1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)including isolated reports.

In one 3-year, randomised, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid 5 mg once yearly vs. placebo in the treatment of postmenopausal osteoporosis (PMO), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in other trials with zoledronic acid, including those with Zometa (zoledronic acid) 4 mg every 3‑4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.

Post-marketing experience

The following adverse reactions have been reported during post-approval use of Zometa.

Cases of osteonecrosis (primarily of the jaws) have been reported, predominantly in cancer patients treated with bisphosphonates, including Zometa. Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaws has multiple documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4).

In very rare cases, the following events have been reported: hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors, atrial fibrillation, somnolence, bronchoconstriction, anaphylactic reaction/shock, urticaria, scleritis and orbital inflammation. Because these reports are from a population of uncertain size and are subject to confounding factors, it is difficult to assess causality and to estimate event incidence rates.

Paediatric population

Safety findings in the paediatric population are summarised in section 5.1.

Section 5.1 Addition of paragraphs and table to the end of the section:

Paediatric population

Clinical trial results in the treatment of severe osteogenesis imperfecta in paediatric patients aged 1 to 17 years

The effects of intravenous zoledronic acid in the treatment of paediatric patients (age 1 to 17 years) with severe osteogenesis imperfecta (types I, III and IV) were compared to intravenous pamidronate in one international, multicentre, randomised, open-label study with 74 and 76 patients in each treatment group, respectively. The study treatment period was 12 months preceded by a 4- to 9-week screening period during which vitamin D and elemental calcium supplements were taken for at least 2 weeks. In the clinical programme patients aged 1 to < 3 years received 0.025 mg/kg zoledronic acid (up to a maximum single dose of 0.35 mg) every 3 months and patients aged 3 to 17 years received 0.05 mg/kg zoledronic acid (up to a maximum single dose of 0.83 mg) every 3 months. An extension study was conducted in order to examine the long-term general and renal safety of once yearly or twice yearly zoledronic acid over the 12-month extension treatment period in children who had completed one year of treatment with either zoledronic acid or pamidronate in the core study.

The primary endpoint of the study was the percent change from baseline in lumbar spine bone mineral density (BMD) after 12 months of treatment. Estimated treatment effects on BMD were similar, but the trial design was not sufficiently robust to establish non-inferior efficacy for Zometa. In particular there was no clear evidence of efficacy on incidence of fracture or on pain. Fracture adverse events of long bones in the lower extremities were reported in approximately 24% (femur) and 14% (tibia) of zoledronic acid-treated patients vs 12% and 5% of pamidronate-treated patients with severe osteogenesis imperfecta, regardless of disease type and causality but overall incidence of fractures was comparable for the zoledronic acid and pamidronate-treated patients: 43% (32/74) vs 41% (31/76). Interpretation of the risk of fracture is confounded by the fact that fractures are common events in patients with severe osteogenesis imperfecta as part of the disease process.

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 6. The following conventional classification is used: very common (³1/10), common (³1/100, <1/10), uncommon (³1/1,000, <1/100), rare (³1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 6: Adverse reactions observed in paediatric patients with severe osteogenesis imperfecta¹

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 Zometa 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).

Section 5.2 Additional paragraph inserted at the end of the section:

Special populations

Paediatric patients

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.

The following has been added to section 4.2  Posology and method of administration of the SmPC:

Zometa reconstituted solution must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer’s solution, and should be administered as a single intravenous solution in a separate infusion line.

Section 4.3 Contraindications has been rephrased as follows:

Zometa powder for solution for infusion is contraindicated in breast-feeding women and in patients with clinically significant hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of Zometa

Section 4.6 Pregnancy and lactation has been rephrased as follows:

There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Zometa should not be used during pregnancy.

It is not known whether zoledronic acid is excreted into human milk. Zometa is contraindicated in breast-feeding women (see section 4.3).

Section 4.8  Undesirable effects has the following additional information:

In very rare cases, the following events have been reported: hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors, atrial fibrillation, somnolence, bronchoconstriction, anaphylactic reaction/shock, and urticaria. Because these reports are from a population of uncertain size and are subject to confounding factors, it is difficult to assess causality and to estimate event incidence rates.

Section 5.3 Preclinical safety data contains the following additional information:

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.

Section 6.2 Incompatabilities has the following additional information:

Zometa reconstituted solution must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer’s solution, and should be administered as a single intravenous solution in a separate infusion line.

The Summary of Product Characteristics has been updated to include the following changes:

• Section 4.8: Addition of the following information: "In one 3 year, randomised, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid 5 mg once yearly vs. placebo in the treatment of postmenopausal osteoporosis (PMO), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in other trials with zoledronic acid, including those with Zometa (zoledronic acid) 4 mg every 3 4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown."

• Section 4.9: Addition of information regarding monitoring of renal function and serum electrolyte levels, along with re-wording of information regarding use of calcium gluconate in cases of hypocalcaemia in overdose situations, as outlined below in italics:

"Clinical experience with acute overdose of Zometa is limited. Patients who have received doses higher than those recommended should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated."

• Additional efficacy and safety data from a phase III trial of Zometa compared to placebo for the treatment of bone metastases in Japanese women with breast cancer (including figure 1)

• Reported rate of ONJ updated