Zometa 4 mg Injection

Treatment of tumour - induced hypercalcaemia (TIH). ZOMETA u00ae slows progression of skeletal conditions in adult patients when used in conjunction with appropriate antineoplastic therapy in patients with advanced carcinoma of the breast, prostate, lung and myeloma.

Treatment of Tumour - induced Hypercalcaemia (TIH):

Adults and elderly: The recommended dose in hypercalcaemia (albumin - corrected serum calcium u2265 12,0 mg/dL or 3,0 mmol/L) is 4 mg. The concentrate must be diluted with 100 mL sterile 0,9 % w/v sodium chloride or 5 % w/v glucose solution and given as a single intravenous infusion of no less than 15 minutes. Patients must be maintained well - hydrated prior to and following administration of ZOMETA.

Skeletal conditions in patients with advanced malignancies involving bone: Adults and elderly: The recommended dose is 4 mg. 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 an intravenous infusion lasting no less than 15 - minutes 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 patients with renal impairment: Patients with HCM: ZOMETA u00ae 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).

Skeletal related events in patients with advanced malignancies involving bone: Skeletal - related events (SREs) are complications associated with bone metastases and may include fractures, spinal cord compression, bone pain, and frequently hypercalcemia. They are associated with intractable bone pain, fractures, bladder and bowel disturbances, anxiety, depression, and decreased survival. When initiating treatment with ZOMETA in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine levels and creatinine clearance (CrCl) should be determined. CrCl is calculated from serum creatinine levels using the Cockcraft - 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 CrCl 265 micromol/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 CrCl 30 u2013 60 mL/min, the following ZOMETA dose is recommended (see also section 4.4).

Table 1: Baseline Creatinine Clearance (ml/min) ZOMETA Recommended Dose *

• > 60 4,0 mg
• 50 to 60 3,5 mg*
• 40 to 49 3,3 mg*
• 30 to 39 3,0 mg*

*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 ZOMETA u00ae 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 u2265 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 u2265 1,0 mg/dl or 88,4 mmol/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 should be resumed at the same dose as that prior to treatment interruption.

Paediatric population: The safety and efficacy of ZOMETA in paediatric patients have not been established.

Instructions on preparing reduced doses of ZOMETA: 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 ZOMETA, 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.

Instructions for use and handling: ZOMETA 4 mg/5 ml concentrate for solution for infusion is for intravenous use only. 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 or 5 % w/v glucose solution). If refrigerated, the solution must be allowed to reach room temperature before administration (see section 4.2).

Hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of ZOMETA u00ae 4 mg Concentrate for solution for infusion. Pregnancy, and breast - feeding women (see section 4.6). Severe impairment of renal function.

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. ZOMETA should not be given together with other bisphosphonates since the combined effects of these medicines are unknown.

Standard hypercalcaemia - related metabolic parameters, such as serum levels of calcium, phosphate, magnesium as well as serum creatinine should be carefully monitored after initiating ZOMETA therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occur, 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.

Renal impairment: Patients with HCM with evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued 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 to 3 months. Bisphosphonates as a class, including ZOMETA, have 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 or other bisphosphonates as well as use of nephrotoxic drugs, or using a shorter infusion time than currently recommended. While the risk is reduced with a dose of ZOMETA 4 mg administered over no less than 15 minutes, deterioration in renal function may still occur. 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. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of ZOMETA.

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 only be resumed when the creatinine level returns to within 10 % of the baseline value (see section 4.2). In view of the potential impact of bisphosphonates, including ZOMETA on renal function, the lack of extensive clinical safety data in patients with severe renal impairment (in clinical trials defined as serum creatinine u2265 400 micromol/l or u2265 4,5 mg/dl for patients with HCM and u2265 265 micromol/l or u2265 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 (see section 4.3).

Hepatic insufficiency: Only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population (see section 4.3).

Osteonecrosis of the jaw (ONJ): Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment regimens including bisphosphonates such as 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.

Post - marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Patients should maintain good oral hygiene and should have dental examination with preventive dentistry prior to treatment with bisphosphonates. Patients should be advised of the reports of osteonecrosis of the jaw so that dental symptoms developing during treatment can be fully assessed before commencing dental procedures. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate (e.g. ZOMETA) therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphate (e.g. ZOMETA) 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.

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 ZOMETA - treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of ZOMETA therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. During ZOMETA treatment 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.

Musculoskeletal pain: In post - marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including 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 re - challenged with the same drug or another bisphosphonate.

Hypocalcaemia: Hypocalcaemia has been reported in patients treated with ZOMETA. Cardiac dysrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcaemia. In some instances, the hypocalcaemia may be life - threatening. Caution is advised when ZOMETA is administered with other hypocalcaemia causing medicines, 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. While not observed with ZOMETA, administration of bisphosphonates as a class has been associated with bronchoconstriction in acetylsalicylic acid - sensitive asthmatic patients.

Paediatric use: The safety and efficacy of Zometa in paediatric patients have not been established.

Use in the elderly: Clinical studies of Zometa in hypercalcemia of malignancy, multiple myeloma and bone metastases included patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in elderly patients receiving Zometa as compared to younger adult patients. Because decreased renal function occurs with bisphosphonates including Zometa more commonly in the elderly, special care should be taken to monitor renal function.

Caution is advised when ZOMETA is administered with aminoglycosides, calcitonin or loop diuretics, since these medicines 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 medicines. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment. Caution is advised when Zometa is administered with anti - angiogenic drugs as an increase in incidence of ONJ has been observed in patients treated concomitantly with these drugs. In multiple myeloma patients, the risk of renal dysfunction may be increased when intravenous bisphosphonates, such as ZOMETA, are used in combination with thalidomide.

Observed interactions to be considered: Caution is advised when Zometa is administered with anti - angiogenic medicines as an increase in incidence of ONJ have been observed in patients treated concomitantly with these medicines.

Absence of interactions: In clinical studies, ZOMETA has been administered concomitantly with commonly used anticancer medicines, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. ZOMETA shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro, but no formal clinical interaction studies have been performed. No dose adjustment for ZOMETA is needed when co - administered with thalidomide, except in patients with mild to moderate renal impairment at baseline (see section 4.2). Co - administration of thalidomide (100 or 200 mg once daily) with ZOMETA (4 mg given as a 15 minute infusion) did not significantly change the pharmacokinetics of zoledronic acid and the creatinine clearance of patients with multiple myeloma.

The safety of ZOMETA in pregnant and lactating women has not been established. Women of child - bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the foetus while receiving ZOMETA. There may be a risk of foetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant (see section 4.3) while receiving bisphosphonate therapy. It is not known whether ZOMETA is excreted into human milk (see section 4.3). Women receiving Zometa should not breastfeed their infants. In animal reproduction studies zoledronic acid was administered subcutaneously to rats and rabbits. It was found to be teratogenic at doses u2265 0,2 mg/kg bodyweight in rats. In rabbits, there was no teratogenicity or foetotoxicity but maternotoxicity was found. In the absence of adequate available experience in human pregnancy, ZOMETA should not be used during pregnancy (see section 4.3). The fertility was decreased in rats dosed SC with 0.1 mg/kg/day zoledronic acid (0.1 times the maximum human exposure of 8 mg, based on BSA), and pre - implantation loss was increased at 0.01 mg/kg/day. Reversible testicular atrophy occurred in rats at 0.003 mg/kg/day SC for 12 months (0.004 times the maximum human exposure of 8 mg, based on BSA). In dogs, testicular and prostatic atrophy and oligospermia were observed at 0.2 mg/kg/day IV for 3 months (0.6 times the maximum human exposure of 8 mg, based on BSA), and testicular atrophy and/or mineralisation at 0.03 mg/kg IV dosed every 2 - 3 days for 6 months (0.1 times the maximum human exposure of 8 mg, based on BSA). Female dogs had decreased weights of ovaries and uterus, correlated with anoestrus and, in some animals, with vaginal epithelial degeneration at 0.01 mg/kg/day IV (0.03 times the maximum human exposure of 8 mg, based on BSA).

Cases of dizziness, blurred vision and somnolence have been reported with the use of zoledronic acid. The patients should therefore be careful when driving, using machinery or performing other tasks that need full attention. It is not always possible to predict to what extent ZOMETA may interfere with the daily activities of a patient. Patients should ensure that they do not engage in the above activities until they are aware of the extent to which ZOMETA affects them. Within three days after ZOMETA administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions).

There is no experience of acute intoxication with ZOMETA. 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.