Zometa^® 4 mg/5 ml concentrate for solution for infusion

One vial with 5 ml concentrate contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate.

One ml concentrate contains 0.8 mg zoledronic acid (as monohydrate).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion

Clear and colourless solution.

- Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone.

- Treatment of adult patients with tumour-induced hypercalcaemia (TIH).

Zometa must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zometa should be given the package leaflet and the patient reminder card.

Posology

Prevention of skeletal related events in patients with advanced malignancies involving bone

Adults and older people

The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid 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 TIH

Adults and older people

The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥ 12.0 mg/dl or 3.0 mmol/l) is a single dose of 4 mg zoledronic acid.

Renal impairment

TIH:

Zometa treatment in TIH patients who also have severe renal impairment should be considered only after eva luating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine > 400 µmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in TIH patients with serum creatinine < 400 µmol/l or < 4.5 mg/dl (see section 4.4).

Prevention of skeletal related events in patients with advanced malignancies involving bone:

When initiating treatment with Zometa in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should be determined. CLcr is calculated from serum creatinine using the Cockcroft-Gault formula. Zometa is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CLcr < 30 ml/min. In clinical trials with Zometa, patients with serum creatinine > 265 µmol/l or > 3.0 mg/dl were excluded.

In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CLcr 30–60 ml/min, the following Zometa dose is recommended (see also section 4.4):

* Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr = 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 Zometa 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 < 124 µmol/l), an increase of 0.5 mg/dl or 44 µmol/l;

- For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 µmol/l), an increase of 1.0 mg/dl or 88 µmol/l.

In the clinical studies, Zometa treatment was resumed only when the creatinine level returned to within 10% of the baseline value (see section 4.4). Zometa treatment should be resumed at the same dose as that given prior to treatment interruption.

Paediatric population

The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been established. Currently available data are described in section and 5.1 but no recommendation on a posology can be made.

Method of administration

Intravenous use.

Zometa 4 mg concentrate for solution for infusion, further diluted in 100 ml (see section 6.6), should be given as a single intravenous infusion in no less than 15 minutes.

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

Instructions for preparing reduced doses of Zometa

Withdraw an appropriate volume of the concentrate needed, as follows:

- 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 instructions on the dilution of the medicinal product before administration, see section 6.6. The withdrawn amount of 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 over no less than 15 minutes.

Zometa concentrate 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.

Patients must be maintained well hydrated prior to and following administration of Zometa.

• Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in section 6.1

• Breast-feeding (see section 4.6)

General

Patients must be assessed prior to administration of Zometa to ensure that they are adequately hydrated.

Overhydration should be avoided in patients at risk of cardiac failure.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating Zometa therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.

Zometa contains the same active substance as found in Aclasta (zoledronic acid). Patients being treated with Zometa should not be treated with Aclasta or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.

Renal insufficiency

Patients with TIH and evidence of deterioration in renal function should be appropriately eva luated with consideration given as to whether the potential benefit of treatment with Zometa outweighs the possible risk.

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.

Zometa has been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zometa and other bisphosphonates as well as use of other nephrotoxic medicinal products. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 15 minutes, deterioration in renal function may still occur. 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. Increases in serum creatinine also occur in some patients with chronic administration of Zometa at recommended doses for prevention of skeletal related events, although less frequently.

Patients should have their serum creatinine levels assessed prior to each dose of Zometa. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of zoledronic acid are recommended. In patients who show evidence of renal deterioration during treatment, Zometa should be withheld. Zometa should only be resumed when serum creatinine returns to within 10% of baseline. Zometa treatment should be resumed at the same dose as that given prior to treatment interruption.

In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data in patients with severe renal impairment (in clinical trials defined as serum creatinine ≥ 400 µmol/l or ≥ 4.5 mg/dl for patients with TIH and ≥ 265 µmol/l or ≥ 3.0 mg/dl for patients with cancer and bone metastases, respectively) at baseline and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30 ml/min), the use of Zometa is not recommended in patients with severe renal impairment.

Hepatic insufficiency

As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.

Osteonecrosis

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials and in the post-marketing setting in patients receiving Zometa.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth, except in medical emergency situations. A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.

The following risk factors should be considered when eva luating an individual's risk of developing ONJ:

- Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate.

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

- Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids.

- History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting dentures.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Zometa.

While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to zoledronic acid administration. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of other anatomical sites

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Additionally, there have been sporadic reports of osteonecrosis of other sites, including the hip and femur, reported predominantly in adult cancer patients treated with Zometa.

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking Zometa. However, such reports have been infrequent. The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with Zometa or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending eva luation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be eva luated for an incomplete femur fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients treated with Zometa. Cardiac arrhythmias and neurologic adverse events (including convulsions, hypoaesthesia and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, the hypocalcaemia may be life-threatening (see section 4.8). Caution is advised when Zometa is administered with medicinal products known to cause hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (see section 4.5). Serum calcium should be measured and hypocalcaemia must be corrected before initiating Zometa therapy. Patients should be adequately supplemented with calcium and vitamin D.