Zoledronic Acid 4Mg/5Ml Concentrate Solution for Prevention of Skeletal

New Medicines Committee Briefing May 2014

Zoledronic acid 4mg/5ml concentrate solution for prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with Myeloma. *Update*

Zoledronic acid to be reviewed for use within:

Primary Care

Secondary Care  Summary:

Zoledronic acid is licensed for the treatment of adult patients with tumour-induced hypercalcaemia and 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 bone1.

MRC Myeloma IX trial showed zoledronic acid to have treatment benefits beyond bone health in multiple myeloma patients2.

Zoledronic acid is superiority to pamidronate in the treatment of hypercalcemia in malignancy3.

A Cochrane review in multiple myeloma found bisphosphonate reduced pathological vertebrate fractures, skeletal-related events (SREs) and pain but no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronte or clodronate) for any outcome. Zoledronate appeared superior to placebo and etidronate in improving overall survivial4.

Guidelines for the diagnosis and management of multiple myeloma 2013 recommend zoledronic acid as the bisphosphonate of choice in the treatment of hypercalcaemia5.

Update: May 2014

Oncology: Consultant submitting application: Dr K Karunanithi Clinical Director: Dr A Stewart

Dr Karunanithi Dr Kamaraj Karunanithi and Grace Gough (lead Pharmacist for Cancer) have requested that zoledronic acid be considered for inclusion into the Joint Formulary for the prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with Myeloma. Dr Karunanithi states that zoledronic acid would replace pamidronate as the first line option for treatment of these indications in myeloma patients; however pamidronate would remain on the formulary for other indications. Zoledronic acid will be prescribed by UHNS prescribers for patients who will remain under the care of the UHNS Haematology team but the infusions will be administered in community clinics by the Staffordshire and Stoke on Trent Partnership (SSOTP). Any out of area patients will be treated in the chemotherapy day unit.

Dr Karunanithi noted two main advantages to using zoledronic acid as: 1. Reduced risk of skeletal related events (SRE): Osteolytic disease is the most common complication of myeloma leading to devastating skeletal-related events, such as pathological fractures and spinal cord compression, which will often require radiation or surgery depending on severity. SREs are a major cause of morbidity leading to increased cost not only for the surgical and radiological interventions but also increased length of in-patient stay. Complications such as spinal cord compression require extensive interventions including MRI scans to diagnose, complex interventions and extensive nursing care. Even when patients are discharged there can be increased demands on the community nursing teams due to this increased morbidity. Any reduction in SREs will be a cost saving to the health economy. 2. Reduced administration time: Zoledronic acid is given as a 15 minute infusion as appose to pamidronate that is infused over 2 hours in patients with normal renal function and 4 hours with renal function from 30- 60mls/min. As myeloma can affect renal function there are numerous patients that have to receive the 4 hour infusion. This means that there is a saving of between 105 mins and 225 minutes of chair and nursing time per patient. This increase in capacity could be used to increase the number of patient receiving treatment each day which would increase income for the provider

Cost:

Cost incl VAT Cost excl VAT

DISODIUM PAMIDRONATE!30mg/10mL!CONC.FOR INFUSION (1vial) £1.78 £1.48 DISODIUM PAMIDRONATE!60mg/20mL!CONC.FOR INFUSION (1 vial £3.42 £2.85 ZOLEDRONIC ACID!4mg!INJECTION (1 vial) £10.20 £8.50

Estimated number of patients who will be treated with zoledronic acid per year: Number of patient’s currently receiving pamidronate in the community for this indication = 40

Number patient’s currently receiving pamidronate in the trust for this indication = 5

Total currently on treatment = 45

Pamidronate is given as a 4 weekly infusion for 2 years only

Zoledronic acid is given as a 4 weekly infusion for 2 years and is then given as a 2 monthly infusion until progression (average duration of treatment 5 years)

Number of new patient’s per year = approximately 15

Proposal is to start all new patients on zoledronic acid and convert a percentage of existing patient’s that are at high risk of skeletal related events (bone disease at the time of diagnosis) from pamidronate to zoledronic acid

Hence staggered uptake

year 1 year 2 year 3 year 4 year 5 Number of patients starting monthly infusions 20 15 15 15 15 Number of patients finishing monthly infusions 0 0 15 15 15 Number of patients on monthly infusions1 20 35 35 35 35 Number of monthly administrations 240 420 420 420 420 Number of Patients starting 2 monthly infusion 0 5 15 15 15 Cumulative number of patients on 2 monthly 0 5 20 35 50 infusions number of 2 monthly administrations 0 30 120 210 300 Total number of administrations 240 450 540 630 720 Cost of pamidronate2 £1,248 £2,340 £2,808 £3,276 £3,744 Cost of zoledronic acid3 £2,448 £4,590 £5,508 £6,426 £7,344 Cost Pressure £1,200 £2,250 £2,700 £3,150 £3,600 Assumptions

1. The number of patient’s in year 1 will be 15 new patients and 5 existing high risk patients, then 15 new patients each year 3

2. Pamidronate cost is based on 90mg dose including VAT (£5.20 per dose) 3. Zoledronic acid cost is based on 4mg dose including VAT (£10.20 per dose)

Expenditure:

Disodium pamidronate & Zoledronic acid Usage and Expenditure at UHNS Cancer Directorate only April 13 - March 14 Sum of Drug name Sum of Cost Qty DISODIUM PAMIDRONATE!30mg/10mL!CONCENTRATE FOR INFUSION 454 £806.29 DISODIUM PAMIDRONATE!60mg/20mL!CONCENTRATE FOR INFUSION 5 £17.10 ZOLEDRONIC ACID!4mg!INJECTION 5 £254.62

Efficacy:

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF MULTIPLE MYELOMA 20135

Haemato-oncology Task Force of the British Committee for Standards in Haematology (BCSH), UK Myeloma Forum

4 Management of common medical emergencies in myeloma patients

4.2 Hypercalcaemia

Up to 30% of myeloma patients present with hypercalcaemia occurring mostly in the context of active disease. Acute hypercalcaemia can present with central nervous system dysfunction (confusion, coma and obtundation), muscle weakness, pancreatitis, constipation, thirst, polyuria, shortening of the Q-T interval on electrocardiogram and acute renal insufficiency. Alternative causes of hypercalcaemia should be considered eg. hyperparathyroidism. Treatment of the underlying disease should be initiated as soon as possible along with active treatment of hypercalcaemia to minimize long-term renal damage. The mainstays of treatment are hydration and intravenous bisphosphonates.

Mild hypercalcaemia (corrected calcium 2.6-2.9 mmol/l) may be corrected with oral and/or intravenous rehydration.

Moderate to severe hypercalcaemia (corrected calcium ≥ 2.9mmol/l) requires intravenous rehydration with normal saline. Adequate urine output should be ensured and use of intravenous loop diuretics, such as furosemide, should be considered to avoid volume overload and heart failure and promote urinary calcium excretion.

All patients with moderate to severe hypercalcaemia should receive a bisphosphonate. A randomized controlled trial in patients with hypercalcaemia of malignancy has shown that zoledronic acid is superior to

pamidronate3. If the calcium remains high after 72 h a further dose of zoledronic acid may be given. Dose modifications are required in renal impairment and reduced dose pamidronate (30mg) may be more appropriate in patients with severe renal impairment. Patients with refractory hypercalcaemia may require corticosteroids and calcitonin.

Recommendations (mostly grade C; level III evidence)

• in mild hypercalcaemia (corrected calcium 2.6-2.9 mmol/l) re-hydrate with oral and /or iv fluids (Grade A1)

• in moderate-severe hypercalcaemia (corrected calcium >2.9 mmol/l) re-hydrate with intravenous fluids and give furosemide if required (Grade B1)

• zoledronic acid is the bisphosphonate of choice in the treatment of hypercalcaemia (Grade B1)

Scottish Medicine Compendium6:

Zoledronic acid is recommended for restricted within NHS Scotland. SMC recommends zoledronic acid to be restricted to prescribing by oncologists for patients with breast cancer and multiple myeloma. SMC noted that zoledronic acid provides an alternative to other bisphosphonates licensed for prevention of skeletal related events. It may offer some minor advantages in terms of administration. SMC stated that at local level the decision will rest on weighing up the additional cost against other options available for improving the delivery of oncology services.

Cochrane Review

Cochrane Review: Bisphosphonates in multiple myeloma: a network meta-analysis 4

The aim of the meta-analysis was to assess the evidence related to benefits and harms associated with use of various types of bisphosphonates in the management of patients with multiple myeloma. The primary objective was to determine whether adding bisphosphonates to standard therapy improved overall survival (OS) and progression-free survival (PFS), and decreased skeletal-related morbidity. The secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcaemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcaemia.

Any RCT assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in multiple myeloma were eligible for inclusion. 16 RCTs were included comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients.

Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I2 = 55%, P = 0.01) for OS. To explain this heterogeneity a meta-regression was performed assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs.

Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I2 = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I2 = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I2 = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcaemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcaemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.

The authors concluded that use of bisphosphonates in patients with myeloma reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 multiple myeloma patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 myeloma patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 myeloma patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. The authors found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.

MRC Myeloma IX Trial: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma2.

Summary: Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has also shown potential anticancer benefits in preclinical and clinical studies.

Morgan GJ et al. in a randomised controlled trial compared zoledronic acid with clodronic acid as first-line bisphosphonate treatment aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3-4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression.

The primary endpoints were overall survival, progression-free survival, and overall response rate while secondary endpoints included skeletal-related events and toxic effects. Overall survival and progression-free survival were calculated from first randomisation to death or to progression or death, respectively. Differences were assessed between-groups with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive

chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). Responses and disease progression were defined according to international response criteria. Briefly, complete response was defined as negative immunofixation (100% M-protein reduction), and very good partial response was defined as at least 90% M-protein reduction with positive immunofixation. Safety was assessed by continuous monitoring of adverse events. Serum creatinine was monitored monthly during induction chemotherapy and, thereafter, monthly for zoledronic acid and every 3 months for clodronic acid. Serious adverse events were defined as treatment emergent if they were judged by the treating physician to be potentially related to study drugs. Data for skeletal-related events, defined as vertebral fractures, other fractures, spinal cord compression, need for radiation or surgery to bone lesions, and new osteolytic bone lesions, were recorded until disease progression.

Outcome: Zoledronic acid reduced mortality by 16% (95% CI 4-26) compared to clodronic acid (hazard ratio [HR] 0.84, 95% CI 0.74-0.96; p=0.0118), and extended median overall survival by 5.5 months (50.0 months, IQR 21.0 to not reached vs 44.5 months, IQR 16.5 to not reached; p=0.04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0.88, 95% CI 0.80-0.98; p=0.0179), and increased median progression-free survival by 2.0 months (19.5 months, IQR 9.0-38.0 vs 17.5 months, IQR 8.5- 34.0; p=0.07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0.43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0.18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment- emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).

Morgan G.J et al. found consistency with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits.

Zoledronic Acid Is Superior to Pamidronate in the Treatment of Hypercalcemia of Malignancy: A Pooled Analysis of Two Randomised, controlled Clinical Trials.Error! Bookmark not defined.

Major P. et al in 2 identical, concurrent, parallel, randomised, double-blind, double-dummy, multi-centre trials compared the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM). This trial was a pooled analysis of patients with moderate to severe HCM (corrected serum calcium >3 mmol/L [12 mg/L]) who were either treated with a single dose of zoledronic acid (4mg or 8 mg) via 5 mins infusion or pamidronate (90 mg) via 2hrs infusion.

The clinical end points were rate of complete response by day 10, response duration and time to relapse. 287 patients were randomised and evaluated for safety (86, 98 and 103 for zoledronic acid 4mg, 8mg and pamidronate 90mg, respectively). 275 were evaluated for efficacy (86, 90 and 99 for zoledronic acid 4mg, 8mg and pamidronate 90mg, respectively).

Both doses of zoledronic acid were superior to pamidronate in the treatment of hypercalcemia. The complete response rates by day 10 were 88.4% (p=0.002), 86.7% (p=0.015), and 69.7% for zoledronic acid 4mg and 8 mg and pamidronate 90mg, respectively. Normalisation of corrected serum calcium occurred by day 4 in approximately 50% of patients treated with zoledronic acid and 33% of the pamidronate-treated patients. The

median duration of complete response favoured zoledronic acid 4mg and 8 mg over pamidronate 90mg with response durations of 32, 43, and 18 days respectively.

Safety: The most common adverse events were fever, anaemia, nausea, constipation and dyspnoea which occurred with similar frequency among zoledronic acid and pamidronate groups. Adverse events suspected to be drug related included fever, hypophosphatemia and asymptomatic hypocalcemia. Zoledronic acid group reported more renal adverse events compared to pamidronate group

The authors concluded that zoledronic acid is superior to pamidronate in treatment of HCM while maintaining a similar safety profile.

Advantages of using zoledronic acid as the first line bisphosphonate for patients with myeloma

 The Myeloma IX Trial showed that zoledronic acid reduced the risk of SRE by 26% compared to the comparator clodronate. Any reduction in SREs will be a tremendous advantage to the patient and the health economy because SREs are a major source of morbidity in patients with myeloma. SREs lead to increased hospital stays complex, surgical interventions radiotherapy and increased nursing requirement.  Zoledronic acid has been shown to be the only bisphosphonate that has shown to have an effect of increasing overall survival in myeloma patients. This is an obvious advantage for patients. The Myeloma-IX study showed that zoledronic acid prolonged the median overall survival of the patients by 5.5 months over clodronate. This was mainly the result of the beneficial effect of zoledronic acid in patients who had bone disease at baseline. Patients presenting with bone disease who received zoledronic acid had a survival advantage of 10 months.  The 15 minute infusion is much more convenient than the 2-4 hour infusion required when administering pamidronate. This will increase capacity in the clinics and allow more patients to be treated without increasing staffing. This means that there is a saving of between 105 mins and 225 minutes of chair and nursing time per patient. This increase in capacity could be used to increase the number of patient receiving treatment each day which would increase income for the provider

Current Formulary Status:

NICE TA160, TA161 6.6 DRUGS AFFECTING BONE METABOLISM  NMC Section Review: September 2008

 NICE TA160 rd Raloxifene 2 3 line for secondary prevention of osteoporotic fractures in postmenopausal women  NICE TA161  MTRAC

6.6.1 Calcitonin and parathyroid hormone Calcitonin (Salmon)/

Salcatonin  NICE TA161 Restriction: In line with NICE Guidance only Teriparatide  MTRAC

6.6.2 Bisphosphonates and other drugs affecting bone metabolism  NICE TA160 Alendronic acid 1st line for Osteoporosis  NICE TA161  MTRAC Disodium etidronate 2nd line for Osteoporosis  NICE TA160

(also Didronel PMO)  NICE TA161  NICE TA160 Risedronate 2nd line for Osteoporosis and Paget’s disease  NICE TA161  MTRAC  NICE TA160 Strontium 2 3rd line for Osteoporosis  NICE TA161  MTRAC Ibandronic acid oral Restriction: For the prevention of skeletal events in breast cancer and metastatic bone  MTRAC

(Bondronat®) disease only  FF Article Restriction: Initiation under direction of oncology/haematology only

Sodium clodronate 2 Tablets Only  NICE 204 Restriction: In line with NICE Guidance only Denosumab  NICE 265 Disodium pamidronate Ibandronic acid IV Restriction: Specialists with an interest in Osteoporosis  MTRAC Zoledronic acid IV Restriction: Specialists with an interest in Osteoporosis

Update References:

1 Zoledronic acid 4 mg / 5 ml concentrate for solution for infusion. Intrpharm Labouratories. Summary of Product Characeristics. Date of revision of the text 28/03/2014. Accessed via www.emc.medicines.org.uk 30/04/14 2 Morgan G.J. et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010; 376: 1989–99 3 Major P. et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcaemia of malignancy: a pooled analysis of 2 randomised, controlled clinical trials. J Clin Oncol 2001; 19(2): 558-67 4 Mhaskar R. et al. Bisphosphonates in myeloma: a network meta-analysis (Review). The Cochrane Library 2012 issue 5. 5 Jenny M. Bird et al. on behalf of the Haemato-oncology Task Force of the British Committee for Standards in Haematology (BCSH), UK Myeloma Forum GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF MULTIPLE MYELOMA 2013. Accessed via http://www.bcshguidelines.com 30/04/14 6 Zoledronic Acid (Zometa®), Scottish Medicines Consortium (No. 29/02), May 2003. Accessed via www.scottishmedicines.org.uk

Produced by Sr Maria Chidiamara Njoku Primary Care/Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: 01782 674541 E-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.

DRUGS AND THERAPEUTICS COMMITTEE BRIEFING NOVEMBER 2006

Intravenous zoledronic acid (Zometa®) for treatment of hypercalcaemia of malignancy and management of skeletal metastases in patients with breast cancer or multiple myeloma.

Intravenous zoledronic acid is to be reviewed for use within:

Primary Care

Secondary Care  Summary

. Zoledronic acid is licensed for the treatment of tumour-induced hypercalcaemia and for the prevention of skeletal related events in patients with advanced malignancies involving bone.

. Clinical trials of zoledronic acid in multiple myeloma and breast cancer have not been powered to show any superiority to pamidronate in the prevention of skeletal related events therefore there is no evidence to shown benefit of zoledronic acid over pamidronate.

. A Cochrane review of the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with advanced breast cancer concluded that bisphosphonate treatment reduced the risk of developing a skeletal event by 17%. Zoledronic acid was associated with a reduction in risk of developing a skeletal event of 41% compared to pamidronate 33%.

. Guidelines on multiple myeloma treatment recommend that bisphosphonates are prescribed for all patients with myeloma requiring chemotherapy. They concluded that intravenous pamidronate and zoledronic acid are equivalent in efficacy and therefore choice of treatment will depend on patient and physician preference.

Background

. Zoledronic acid is licensed for the treatment of tumour-induced hypercalcaemia and for the prevention of skeletal related events in patients with advanced malignancies involving bone. It is the only bisphosphonate licensed as a preventative therapy of skeletal related events although pamidronate is licensed for the treatment of osteolytic lesions and bone pain with bone metastases associated with breast cancer or multiple myeloma.

. It is recommended that bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases. The SPC states that in deciding to treat patients with bone metastases for the prevention of skeletal related events, it should be considered that the onset of treatment effect is 2-3 months.1

. The application for use of zoledronic acid in hypercalcaemia of malignancy and management of skeletal metastases in breast cancer patients was submitted by Dr Brunt, Consultant Oncologist, UHNS. This would be used as an alternative to disodium pamidronate and sodium clodronate. From the original application it is estimated that, per annum, six patients would be prescribed zoledronic acid for the treatment of hypercalcaemia of malignancy and three for skeletal effects related to breast cancer.

. The original application for the use of zoledronic acid in multiple myeloma patients was received by Dr Stewart, Consultant Haematologist.

. The current bisphosphonate alternatives included within the formulary are shown below:

6.6.2 Bisphosphonates and other drugs affecting bone metabolism Alendronic acid MTRAC Disodium etidronate (also Didronel PMO) Risedronate Restriction: Paget’s disease only MTRAC Sodium clodronate 2 Restriction: Initiation under direction of oncology/haematology only Tablets Only Disodium pamidronate

Licensed Indications

. Intravenous zoledronic acid is licensed for the prevention of skeletal related effects (pathological fractures, spinal compression, radiation or surgery to bone) in patients with advances malignancies involving bone.1 o The recommended dose is 4mg zoledronic acid every 3 to 4 weeks (patients should also be prescribed an oral calcium supplement of 500mg and 400IU vitamin D daily).

. It is also licensed for the treatment of tumour-induced hypercalcaemia. o The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥12.0mg/dL or 3mmol/L) is 4mg zoledronic acid.

NICE and other guidance

. There is no NICE guidance relating to zoledronic acid treatment.

. The Scottish Medicines Consortium reviewed zoledronic acid in May 2003 and recommended restricted use within NHS Scotland. Prescribing should be restricted to oncologists for patients with breast cancer and multiple myeloma as an alternative to other bisphosphonates licensed for prevention of skeletal related events.2

MTRAC

. There is no published MTRAC relating to zoledronic acid treatment.

Efficacy

Breast Cancer

. A Cochrane Review of the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with advanced breast cancer and in women with early breast cancer, was reviewed in 2005. 3 The authors identified 21 randomised studies for inclusion and reported the following results: o In women with advanced breast cancer, bisphosphonate treatment reduced the risk of developing a skeletal event by 17% (RR 0.83; 95% CI 0.78 to 0.89; p<0.00001). o Intravenous pamidronate (90mg) reduces the rate of skeletal events, delays the time to a skeletal event and significantly reduced the risk of developing a skeletal event in comparison to placebo. The reduction in risk of developing a skeletal event with 90mg intravenous pamidronate is 33% (RR 0.77; 95% CI 0.69 to 0.87). o Intravenous zoledronic acid also reduces the rate of skeletal events, delays the time to a skeletal event and significantly reduces the risk of an event occurring in comparison to placebo. The reduction in risk of developing a skeletal event with 4mg zoledronic acid is 41% (RR 0.59; 95% CI 0.42 to 0.82). o Bisphosphonates did not produce a significant reduction in women with advanced breast cancer without clinically evident bone metastases.

. The American Society of Clinical Oncology updated guidance on the role of bisphosphonates and bone health issues in women with breast cancer in 2003.4 For breast cancer patients who have evidence of bone destruction on plain radiographs, intravenous pamidronate 90mg delivered over 2 hours or zoledronic acid 4mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence to support the use of one bisphosphonate over the other. Other recommendations in the guidelines include: o Starting bisphosphonates in women with an abnormal bone scan and an abnormal CT or MRI scan showing bone destruction, but normal

plain radiographs, is considered reasonable by panel consensus based on the findings in women with lytic or mixed lytic/blastic changes on plain radiographs. o Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction on radiographs, CT scans or MRI is not recommended. o Once initiated, intravenous bisphosphonates should be continued until evidence of substantial decline in a patients’ general performance status. The panel stresses that clinical judgement must guide what is a substantial decline. There is no evidence addressing the consequence of stopping bisphosphonates after one or more adverse skeletal events. o The panel recommends that the current standards of care for cancer pain management must be applied throughout bisphosphonate therapy and is required by good clinical practice. These standards of care for pain management include analgesics, corticosteroids, interventional procedures, NSAIDs, systemic radiopharmaceuticals and local radiation therapy. Among other therapeutic options, intravenous pamidronate or zoledronic acid may be of benefit among women with pain caused by bone metastases to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, because it was associated with modest pain control benefit in controlled trials. o There is insufficient evidence to support a role for intravenous bisphosphonates as an adjunctive therapy to radiation therapy in women with pain as a result of metastatic bone disease when systemic chemotherapy and/or hormonal therapy is not being employed. The role of bisphosphonates in this setting has not been determined. In women already treated with local radiotherapy who have recurrent or persistent pain, bisphosphonates are an attractive but little studied therapy.

. Two randomised trials have shown that zoledronic acid can be given safely over a short interval and produces similar antiresorptive effects as administering 90mg of pamidronate, as assessed by bone markers… o The first randomised phase II study, compared zoledronic acid to pamidronate in 280 patients with lytic bone metastases from either multiple myeloma (n = 108) or breast cancer (n = 172).5 Patients were randomly assigned to nine monthly infusions of 0.4mg, 2.0mg or 4.0mg zoledronic acid in a 5 minute infusion, or to 90mg pamidronate as a 2 hour infusion. The primary end-point was to determine a dose(s) of zoledronic acid that reduced the need for radiation to less than 30% of treated women although all skeletal related events (SRE’s) were also reported. SRE’s were an aggregate of all sites and number of pathologic fractures, spinal cord collapse/compression and need for therapeutic radiation therapy, including pain and impending fracture. The

duration of follow up was not reported and the trial was not powered to show any superiority of zoledronic acid over pamidronate. Radiation was required in a similar proportion of patients (18% to 21%) receiving pamidronate and zoledronic acid 2.0mg or 4.0mg, whereas more patients (24%) receiving 0.4mg zoledronic acid underwent radiotherapy. Similarly, the proportion of patients with any SRE was lower in the 2.0mg and 4.0mg zoledronic acid and pamidronate groups (30% to 35%) compared with the 0.4mg zoledronic acid group (46%). The results of this trial did not provide disease specific data and only reported overall results. o A larger phase III, double-blind, randomised trial compared 4 or 8mg doses of zoledronic acid to 90mg pamidronate every 3 to 4 weeks in multiple myeloma or breast cancer patients with lytic disease.6 Due to increases in creatinine that occurred more frequently in patients receiving zoledronic acid, the infusion time was increased from 5 to 15 minutes during the trial. Despite this change, renal problems occurred more often in patients randomly assigned 8mg zoledronic acid and as a result the dose was reduced to 4mg. Again the trial was powered to show equivalence of zoledronic acid to pamidronate. The intention to treat analysis included 1,648 patients with metastatic breast cancer or multiple myeloma (zoledronic acid 4mg, n= 563; zoledronic acid 4/8mg, n= 524; pamidronate, n= 556). Primary endpoint analysis of the proportion of breast cancer patients with at least 1 SRE during the trial showed no significant difference between the zoledronic acid or pamidronate treatment groups (44% to 47%). Secondary end-points of pain and performance status showed similar effects to those in prior studies. In all treatment groups, about 50% of patients reported an adverse event; however, less than 5% of those events were classified as drug-related. Seven percent of patients discontinued therapy due to an adverse effect. The frequency of serious renal-related adverse events was 1.9% in the higher dose (8mg) zoledronic acid group compared with 0.5% in the 4mg zoledronic acid group and 0.2% in the pamidronate group.

. Included in the Cochrane review was one study of zoledronic acid compared to pamidronate in breast cancer patients who had at least 1 bone metastasis.7 This was a sub-group analysis of the previous trial analysing the breast cancer strata only. A total of 1,130 patients with advanced breast carcinoma and at least 1 bone metastasis were included in the trial, 47% of which had at least 1 osteolytic lesion (lytic sub-group). Patients were randomised to zoledronic acid 4mg (n = 378), 4/8mg zoledronic acid (n = 364) or 90mg pamidronate (n = 388). During the 13 month trial, the proportion of patients with an SRE was similar between the treatment groups (43% in the 4mg zoledronic acid, 45% in the 4/8mg zoledronic acid and 45% in the pamidronate group). In the lytic sub-group, 4mg zoledronic acid produced an additional 17% relative reduction in the proportion of patients with an SRE compared with pamidronate (48% vs. 58% in the pamidronate group) although this did not reach statistical significance (p=0.058).

Multiple Myeloma

. Guidelines on the diagnosis and management of multiple myeloma published in 2005 by the UK Myeloma Forum gives the following recommendations:8 o Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident. o Treatment should be continued for at least 2 years; it is current practice to continue treatment indefinitely although there are a few reported data on longer-term use. o Oral clodronate (1600mg/day or equivalent dose), intravenous pamidronate and intravenous zoledronic acid may be used. Monthly i.v. pamidronate and zoledronic acid are equivalent in efficacy and therefore the choice of treatment will depend on patient and physician preference. o There is insufficient data to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma.

. The published trials of zoledronic acid in multiple myeloma patients include the Rosen et al and Berenson et al studies described above, which included both multiple myeloma and breast cancer patients.5, 6 These showed that i.v. zoledronic acid was as effective as pamidronate when used for multiple melyoma patients. The Berenson et al study was exclused from the Cochrane review as no disease-specific data was reported. Overall results are described above. Rosen et al reported on multiple myeloma patients treated with zoledronic acid or pamidronate. There was no significant difference in the percentage of patients having at least one SRE with zoledronic acid or pamidronate (47% to 49%).

. A Cochrane review published in 2002 on bisphosphonates in multiple myeloma studied trials of bisphosphonates against placebo or no treatment in multiple myeloma patients.9 The primary objective of this review was to determine whether adding bisphosphonates to standard therapy in multiple myeloma decreases skeletal-related morbidity (pathological fractures), skeletal-related mortality and overall mortality. Secondary objectives were to determine the effects on pain, quality of life and incidence of hypercalcaemia. There were no trials on the use of zoledronic acid vs. placebo or no treatment found for inclusion in the review. Data from 1113 patients in 11 placebo- controlled trials of clodronate, pamidronate or etidronate and from a preliminary report of a trial of ibandronate were included. The meta-analysis concluded that adding bisphosphonates to the treatment of myeloma reduces vertebral fractures and pain but not mortality, reduction of non-vertebral fracture or incidence of hypercalcaemia. Overall it was calculated that you need to treat 10 (95% CI 7 to 20) patients with multiple myeloma to prevent one vertebral fracture and 11 (7 to 28) to prevent one patient experiencing pain.

Hypercalcaemia

. The efficacy of zoledronic acid in the treatment of moderate to severe hypercalcaemia of malignancy has been compared with that of pamidronate in 2 randomised, double-blind, parallel-group trials from which data were pooled for analysis (n = 287).10 Zoledronic acid (4mg or 8mg) was administered via a 5 minute intravenous infusion and pamidronate (90mg) was given as a 2-hour intravenous infusion. The primary end-point was normocalcaemia defined as calcium levels <2.7mmol/L, duration of response and time to relapse. Both dose levels of zoledronic acid were significantly more effective than pamidronate according to response rates at days 7 and 10 (p<0.015). There was no significant difference in proportion of patients experiencing response with zoledronic acid 4mg versus 8mg. The median time to relapse with zoledronic acid was 13 days (4mg) or 23 days (8mg) longer than that for pamidronate (p=0.001 and p=0.007, respectively).

Safety and adverse effects

. IV zoledronic acid must only be used by clinicians experienced in the administration of intravenous bisphosphonates.

. For administration the concentrated solution for infusion (4mg/5mL zoledronic acid) should be further diluted with 100mL sodium chloride 0.9% w/v or 5% w/v glucose. The infusion should be over no less than 15 minutes. Patients must be adequately hydrated prior to and following administration of intravenous zoledronic acid.

. IV zoldreonic acid is contraindicated in pregnancy, lactating women and patients with significant hypersensitivity to zoledronic acid or any other bisphosphonate.

. The safety and efficacy of zoledronic acid in paediatric patients has not been established.

. Patients with severe renal impairment should only be considered for treatment after careful evaluation of the potential risks and benefits. For patients with mild to moderate renal failure in the prevention of skeletal events a dose reduction is recommended dependent on creatinine clearance as described in the Summary of Product Characteristics. In the treatment of tumour-induced hypercalcaemia no dosage adjustment is required in patients with serum creatinine <400mmol/L. Patients should have their serum creatinine level checked before each dose of zoledronic acid. If any deterioration is seen, treatment should be withheld and resumed only when creatinine levels have returned to within 10% of the baseline value.

. Standard hypercalcaemia-related metabolic parameters such as serum levels of calcium, phosphate and magnesium should be carefully monitored after initiating zoledronic acid therapy. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occurs short-term supplemental therapy may be necessary.

Adverse effects:

. Frequencies of adverse reactions are mainly based on data collection from chronic treatment. Adverse reactions to zoledronic acid are similar to those reported for other bisphosphonates and can be expected to occur in approximately one third of patients.

. Intravenous administration is most commonly associated with a flu-like syndrome in about 9% patients including bone pain (9.1%), fever (7.2%), fatigue (1.4%) and rigors (2.9%). Occasionally cases of arthralgia and myalgia in approximately 3% of patients have been reported.

. A fall in serum phosphate levels may accompany treatment however this is usually asymptomatic and does not require treatment.

. Gastrointestinal reactions such as nausea (5.8%) and vomiting (2.6%) have been reported following administration. Occasional local reactions to the infusion site, such as swelling, redness and/or pain, have been observed in less than 1% of patients.

. As with other bisphosphonates, zoledronic acid 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 zoledronic acid and other bisphosphonates as well as the use of other nephrotoxic drugs.

. From post-marketing surveillance rare cases of osteonecrosis (primarily of the jaws) have been reported in patients treated with bisphosphonates. Many had signs of local infection including osteomyelitis and the majority of reports refer to cancer patients following tooth extractions or other dental surgeries. It is advisable that patients avoid invasive dental procedures if possible.

Drug Interactions

. Caution is advised when bisphosphonates are administered with aminoglycosides as both agents may have an additive effect resulting in lower serum calcium level for longer periods than required.

. Caution is also indicated when zoledronic acid is used with other potentially nephrotoxic drugs.

. Attention should be paid to the possibility of hypomagnesaemia developing during treatment.

Dosage Forms

. Zometa® 4mg/5mL concentrate for solution for infusion.

References

1. Zometa® Summary of Product Characeristics. Novartis, February 2006 [Accessed 29/6/06 via www.emc.medicines.org.uk] 2. Zoledronic Acid (Zometa®), Scottish Medicines Consortium (No. 29/02), May 2003. 3. Pavlakis, Schmidt & Stockler. Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews 2005, Issue 3 4. Hillner et al. American Society of Clinical Oncology 2003 Update on the role of bisphosphonates and bone heath issues in women with breast cancer. J Clin Oncol 2003; 21(21): 4042-4057. 5. Berenson et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91: 1191-1200. 6. Rosen et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7: 377-387. 7. Rosen et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004; 100: 36-43. 8. Smith et al. Guidelines on the diagnosis and management of multiple myeloma 2005. B J Haematology 2005; 132: 410-451. 9. Djulbegovic et al. Bisphosphonates in multiple myeloma. Cochrane Database of systematic reviews 2002; Issue 4. Produced10. Major by et: al . ZoledronicSamantha acid Leigh is superior to pamidronate in the treatment of hypercalcaemia ofMedicines malignancy: Management a pooled Interface analysis Support of 2 Pharmacist randomised, controlled clinical trials. J ClinUniversity Oncol 2001; Hospital 19(2 of North Staffordshire Telephone: 01782 552903 e-mail: [email protected]

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