Drug Class Description
Bisphosphonate

Generic Name
Zoledronic

Drug Description
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).

Presentation
Concentrate for solution for infusion

Indications
- 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).

Adult Dosage
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 boneAdults and elderlyThe 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 TIHAdults and elderlyThe 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 impairmentTIH: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.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 (CrCl) should be determined. CrCl 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 CrCl < 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 CrCl 30–60 ml/min, the following Zometa dose is recommended:Baseline Creatinine Clearance (ml/min)Zometa Recommended Dose*> 604.0mg50-603.5mg*40-493.3mg*30-393.0mg**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 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. Zometa treatment should be resumed at the same dose as that prior to treatment interruption.Instructions for preparing reduced doses of ZometaWithdraw an appropriate volume of the concentrate needed, as follows:4.4 ml for 3.5 mg dose4.1 ml for 3.3 mg dose3.8 ml for 3.0 mg doseThe 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 not been studied. Zometa should not be used in that patient population until further data becomes available.

Child Dosage
Not recommended.

Contra Indications
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.

Special Precautions
GeneralPatients 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, shortterm supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.The safety and efficacy of Zometa in paediatric patients have not been established.Renal insufficiencyPatients 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.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 insufficiencyAs 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 jawOsteonecrosis 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 painIn 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.

Interactions
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, 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.

Adverse Reactions
Frequencies of adverse reactions for Zometa 4 mg are mainly based on data collection from chronic treatment. Adverse reactions to Zometa are similar to those reported for other bisphosphonates and can be expected to occur in approximately one third of patients. Intravenous administration has been most commonly associated with a flu-like syndrome in about 9% of patients, including bone pain (9.1%), fever (7.2%), fatigue (4.1%) and rigors (2.9%). Occasionally cases of arthralgia and myalgia in approximately 3% have been reported. No information is available on the reversibility of these adverse effects.Frequently, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels (in approximately 20% of patients), which is asymptomatic not requiring treatment. The serum calcium may fall to asymptomatic hypocalcaemic levels in approximately 3% of patients.Gastrointestinal reactions, such as nausea (5.8%) and vomiting (2.6%) have been reported following intravenous infusion of Zometa. Occasionally local reactions at the infusion site such as redness or swelling and/or pain were also observed in less than 1% of the patients.Anorexia was reported in 1.5% of patients treated with Zometa 4 mg.Few cases of rash or pruritus have been observed (below 1%).As with other bisphosphonates, cases of conjunctivitis in approximately 1% have been reported.There have been some reports of impaired renal function (2.3%), although the aetiology appears to be multifactorial in many cases.Based on pooled analysis of placebo-controlled studies, severe anaemia (Hb < 8.0 g/dl) was reported in 5.2% of patients receiving Zometa 4 mg versus 4.2% on placebo.The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies following predominantly chronic treatment with zoledronic acid:Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100), rare (1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.Blood and lymphatic system disordersCommon: AnaemiaUncommon: Thrombocytopenia, leukopeniaRare: PancytopeniaNervous system disordersCommon: HeadacheUncommon: Dizziness, paraesthesia, taste disturbance, hypoaesthesia, hyperaesthesia, tremorPsychiatric disordersUncommon: Anxiety, sleep disturbanceRare: ConfusionEye disordersCommon: ConjunctivitisUncommon: Blurred visionVery rare: Uveitis, episcleritisGastrointestinal disordersCommon: Nausea, vomiting, anorexiaUncommon: Diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouthRespiratory, thoracic and mediastinal disordersUncommon: Dyspnoea, coughSkin and subcutaneous tissue disordersUncommon: Pruritus, rash (including erythematous and macular rash), increased sweatingMusculoskeletal, connective tissue and bone disordersCommon: Bone pain, myalgia, arthralgia, generalised painUncommon: Muscle crampsCardiovascular disordersUncommon: Hypertension, hypotensionRare: BradycardiaRenal and urinary disordersCommon: Renal impairmentUncommon: Acute renal failure, haematuria, proteinuriaImmune system disordersUncommon: Hypersensitivity reactionRare: Angioneurotic oedemaGeneral disorders and administration site conditionsCommon: Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing)Uncommon: Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increaseLaboratory abnormalitiesVery Common: HypophosphataemiaCommon: Blood creatinine and blood urea increased, hypocalcaemiaUncommon: Hypomagnesaemia, hypokalaemiaRare: Hyperkalaemia, hypernatraemiaIn one 3 year, randomised, double-blind controlled trial that eva luated 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 34 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.Post-marketing experienceThe 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.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.

Manufacturer
Novartis

Drug Availability
(POM)

Updated
12 August 2009