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 2 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 4 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