Zometa 4 mg/5 ml concentrate for solution for infusion

One vial with 5 ml concentrate contains 4 mg zoledronic acid (anhydrous).

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

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion

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

- Treatment of tumour-induced hypercalcaemia (TIH).

Zometa must only be used by clinicians experienced in the administration of intravenous bisphosphonates.

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.

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

Adults and elderly

The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid. The concentrate must be further diluted with 100 ml sterile 0.9% w/v sodium chloride or 5% w/v glucose solution and given in no less than 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.

Treatment of 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 zoledronic acid. The concentrate must be further diluted with 100 ml sterile 0.9% w/v sodium chloride or 5% w/v glucose solution and given as a single intravenous infusion in no less than 15 minutes. Patients must be maintained well hydrated prior to and following administration of Zometa.

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 an 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 prior to treatment interruption.

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

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.

The use of Zometa in paediatric patients has 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).

• 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)

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 concomitantly.

The safety and efficacy of Zometa in paediatric patients have not been established (see section 5.1).

Renal insufficiency

Patients with TIH with 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.

As with other bisphosphonates, 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 drugs. While the risk is reduced with a dose of Zometa 4 mg 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 Zometa. 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 Zometa 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 (see section 4.2).

In view of the potential impact of bisphosphonates, including Zometa, 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 of the jaw

Osteonecrosis of the jaw has been reported in patients, predominantly those with cancer, receiving treatment with bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. 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. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. However, such reports have been infrequent. This category of drugs includes Zometa (zoledronic acid). 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 the same drug 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.

In clinical studies, Zometa has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see section 5.2), but no formal clinical interaction studies have been performed. Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required. Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.

In multiple myeloma patients, the risk of renal dysfunction may be increased when intravenous bisphosphonates are used in combination with thalidomide.

Pregnancy

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.

Lactation

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

No studies on the effects on the ability to drive and use machines have been performed.