liposomal cytarabine suspension (DepoCyte ) is not recommended for use within NHS Scotland for the intrathecal treatment of lymphomatous meningitis.

Transcription

1 Scottish Medicines Consortium Re-Submission liposomal cytarabine 50mg suspension for injection (DepoCyte) No. (164/05) Napp Pharmaceuticals 6 July 2007 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full resubmission liposomal cytarabine suspension (DepoCyte ) is not recommended for use within NHS Scotland for the intrathecal treatment of lymphomatous meningitis. There is limited clinical evidence to support a claim of superior efficacy for liposomal cytarabine over existing therapy. Effects on symptom improvement and quality of life were not well defined. The manufacturer did not present a sufficiently robust economic analysis and its justification of the treatment s cost in relation to its health benefits was not sufficient to gain acceptance by SMC. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium 1

2 Indication Intrathecal treatment of lymphomatous meningitis. In the majority of patients such treatment will be part of symptomatic palliation of the disease. It should be administered only under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Dosing information 50mg administered intrathecally (via lumbar puncture or intraventricularly via an Ommaya reservoir) every 14 days for two doses (induction therapy), then every 14 days for three doses plus an additional dose 28 days later (consolidation therapy), then every 28 days for four doses (maintenance therapy). Product availability date Launched in UK in April Summary of evidence on comparative efficacy Lyposomal cytarabine is a formulation of cytarabine arabinoside (free cytarabine) that is encapsulated in lipid based particles. It has a prolonged half life in the cerebrospinal fluid (CSF) thereby extending the duration and distribution of its cytotoxic actions in the neuraxis. Due to the rarity of lymphomatous meningitis there has only been one randomised clinical study carried out with liposomal cytarabine. In this open-label clinical study, 35 patients with lymphomatous meningitis and Karnofsky performance score (KPS) >50% were randomised, with stratification for acquired-immunodeficiency syndrome (AIDS)-related LM and 33 were entered into a four-week induction phase where they were treated with intrathecal (IT) liposomal cytarabine 50mg every two weeks or IT free cytarabine 50mg twice a week. Unless already receiving dexamethasone, all patients received dexamethasone 4mg orally or intravenously twice daily on days 1 to 5 of each treatment cycle to help counteract the development of arachnoiditis (characterised by headache, nausea, vomiting, fever, neck rigidity, neck and back pain, meningism, CSF pleocytosis, with or without altered consciousness). Patients who achieved a complete response continued their respective drugs in a consolidation phase, with liposomal cytarabine given every two weeks for six weeks then every four weeks for one dose and free cytarabine given every week for four weeks then every two weeks for four doses. Patients remaining in remission continued their respective drug every four weeks for sixteen weeks in a maintenance phase. A complete response was defined as negative cerebrospinal fluid (CSF) cytology by the end of the induction phase at all sites that were positive at baseline and no neurological progression. A confirmed complete response required the above criteria plus confirmation of negative CSF cytology at all previously positive sites within 15 days of treatment initiation. If negative cytology was achieved after more than 15 days, but within the induction period, it was classed as a complete response (unconfirmed). A late response was defined by the same criteria as a complete response, but occurred after the induction phase. All patients receiving at least one dose of study drug were included in the treated population for analysis. The efficacy-evaluable population included all patients who received at least one dose of liposomal cytarabine or four doses of free cytarabine and remained in the study for at least twelve days. 2

3 In this population, the confirmed complete response rate with liposomal cytarabine was significantly greater than with free cytarabine (38% versus 0%), and the complete response rate was also greater with liposomal cytarabine when compared with free cytarabine (38% versus 18%). The total number of patients experiencing any response was significantly greater in the liposomal cytarabine group than in the free cytarabine group (81% versus 27%). These results are detailed below together with results for the treated population. The clinical effectiveness section outlines why the European Medicines Agency (EMEA) considers that this study did not provide compelling evidence to support a claim that liposomal cytarabine has superior efficacy over free cytarabine. Number (%) of responders with liposomal cytarabine and free cytarabine in patients with lymphomatous meningitis Liposomal cytarabine Number (%) (CI) Treated Evaluated N=17 N=16 Confirmed complete response 6* (35%) 6* (38%) (14 to 62) (15 to 65) Complete response 6 (35%) 6 (38%) (14 to 62) (15 to 65) Late response 1 (6%) 1 (6%) (0 to 29) (0 to 30) Any response 13* (76%) 13* (81%) (50 to 93) (54 to 96) Free cytarabine Number (%) (CI) Treated Evaluated N=17 N= (0 to 21) (0 to 29) 2 (13%) 2 (18%) (2 to 38) (0 to 52) 1 (6%) 1 (9%) (0 to 30) (0 to 41) 3 (19%) 3 (27%) (4 to 46) (6 to 61) * p 0.05 for liposomal cytarabine versus free cytarabine, Fischer s exact test. CI = 95% confidence intervals of the percentage. The time to neurological progression was defined as the period between study drug initiation and the development of neurological progression, assessed by the physician s global assessment of neurological status, or death. The study was not powered or designed to detect a statistically significant difference between the groups for this endpoint and none was found. Median times to neurological progression with liposomal cytarabine and free cytarabine in the treated populations were 77 and 48 days, respectively, and in the evaluable populations were 76.5 and 58.5 days, respectively. The study was not powered or designed to detect statistically significant differences between treatment groups in quality of life assessments and none were found. KPS data were only available for the induction phase for 16 and 8 patients in the liposomal cytarabine and free cytarabine groups, respectively, with insufficient data for the other study periods and the other types of quality of life assessments in the trial. During the induction phase, KPS improved from baseline for 31% (n=5) and 25% (n=2) patients in the liposomal cytarabine and free cytarabine groups, respectively, with 50% (n=8) and 13% (n=1) in the respective groups having no change and 19% (n=3) and 63% (n=5) in the respective groups experiencing deterioration in their scores. As part of the resubmission process, limited information on two retrospective reports was submitted and considered. 3

4 Summary of evidence on comparative safety The EMEA s European Public Assessment Report (EPAR) for liposomal cytarabine notes that the safety data for this preparation did not demonstrate any new toxicities when compared with free cytarabine. However, there does not appear to be an improved safety profile for liposomal cytarabine when compared with free cytarabine. Summary of clinical effectiveness issues The main clinical study appears to indicate that liposomal cytarabine has superior efficacy to free cytarabine in clearing the CSF of malignant cells. However, the EMEA considered that it did not provide compelling evidence to support a claim of this nature due to limitations in its methodology and the small sample size, which is inevitable due to the rarity of the disease. The response rate with free cytarabine in this trial was lower than that observed with this drug in published case studies. Whilst the strict criteria for response may have contributed to this, it is possible that there is another reason for this observation. Three patients in the free cytarabine group had negative CSF cytology at the end of induction but as they did not have samples taken from all sites that were positive at baseline they were classified as nonresponders. If all three patients had been responders, the response rates for free cytarabine (6 out of 14 (43%) in the evaluable population and 6 out of 16 (38%) in the treated population) would be in the range of previously published results for this drug in the treatment of lymphomatous meningitis. It is feasible, therefore, that there is in fact no significant difference between the response rates in the two treatment regimens in the main clinical study being presented. The main aim of treatment for lymphomatous meningitis is palliation and an attempt to delay time to neurological progression thereby improving the quality of remaining life. Treatment generally aims to relieve symptoms such as cranial nerve palsies, focal sensory and / or motor deficits, headache and encephalopathy. Liposomal cytarabine offers the benefit of a reduction in the number of administrations when compared with free cytarabine and methotrexate and as a consequence could offer quality of life benefits by reducing the number of visits to hospital for terminally ill patients. However, the main clinical study described previously did not provide data on the relative efficacy of liposomal cytarabine and free cytarabine in relation to symptom improvement and quality of life data were limited. Furthermore, it is likely that patients will still need to attend hospital regularly due to the requirement for concomitant treatment. Thus relative benefits in terms of symptom control and quality of life with the use of liposomal cytarabine in clinical practice have not been demonstrated. Summary of comparative health economic evidence The manufacturer submitted a cost-utility analysis comparing liposomal cytarabine with free cytarabine for the treatment of lymphomatous meningitis. Cytarabine is an appropriate comparator, although methotrexate is also used in Scotland. An incremental cost per QALY gain of 22,915 for liposomal cytarabine was estimated by the manufacturer. The acquisition cost of liposomal cytarabine was estimated at an average of over 6,400 per treatment course compared to 39 for free cytarabine. However, due to the need for fewer doses of liposomal cytarabine compared to free cytarabine, the cost 4

5 associated with drug administration was estimated to be much lower reducing the cost differential to 3,400. Based on data from the single small randomised trial a survival analysis estimated a gain of 113 days in mean time to disease progression for liposomal cytarabine, although mean time from progression to death was 74 days less for liposomal cytarabine patients. Utility for the non-disease progression and disease progression stages were estimated using a time trade off exercise conducted with 6 Belgium clinicians at 0.65 and 0.26 respectively. In sensitivity analysis assuming a higher utility for disease progression of 0.45 increased cost-utility to 31,145 per QALY gained. An important weakness was that the estimated time to progression benefit is based on limited clinical evidence that the EMEA considered was not compelling evidence of superior efficacy for liposomal cytarabine over free cytarabine. The difference in estimates of mean time to progression were greater than the difference in median time to progression presented in the clinical section of the submission, but are likely to be associated with the impact of outliers. Without superior efficacy, liposomal cytarabine would not be considered costeffective due to higher net costs. In addition, the incremental cost-effectiveness results were subject to high uncertainty with a range based on 95% confidence intervals for the costeffectiveness ratio estimated as between 4,068 per QALY gained to liposomal cytarabine being less effective and more costly than free cytarabine (i.e. dominated). The other potential benefit of liposomal cytarabine is the hospital resource savings due to lower frequency of drug administration compared to free cytarabine. However, a concern was that the resource use for administration via a lumbar puncture used in the analysis could overestimate the value to the NHS of the released resources. The result was sensitive to this value; a sensitivity analysis requested from the manufacturer demonstrated that if the cost of lumbar puncture drug administration was reduced by 50% the cost effectiveness ratio for liposomal cytarabine would be 32,732 per QALY gained. In addition, the additional disutility associated with more frequent drug administration for free cytarabine using lumbar puncture was not adequately addressed in the analysis. Given these weaknesses, in conclusion, the manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. Summary of patient and public involvement Patient Interest Group Submission: Lymphoma Association Additional information: guidelines and protocols All Wales Medicines Strategy Group recommendation on the use of liposomal cytarabine (DepoCyte ), within NHS Wales, 14 th February The Minister for Health and Social Services endorsed AWMSG recommendation that liposomal cytarabine (DepoCyte ) should not be supported in NHS Wales for the treatment of lymphomatous meningitis. Additional information: previous SMC advice Scottish Medicines Consortium assessment of cytarabine liposomal suspension for injection (DepoCyte ), for the intrathecal treatment of lymphomatous meningitis, 8 th April SMC advised NHS Boards and Area Drug and Therapeutic Committees (ADTCs) that cytarabine liposomal suspension for injection (DepoCyte ) is not recommended for use within NHS Scotland for the intrathecal treatment of lymphomatous meningitis. Intrathecally administered 5

6 cytarabine liposomal suspension cleared malignant cells from the cerebrospinal fluid, however effects on symptom improvement were not well defined and the cost-effectiveness compared to cytarabine solution has not been demonstrated. Additional information: comparators Cytarabine and methotrexate solutions for injection can be administered IT for the treatment of lymphomatous meningitis. Additional information: costs Liposomal cytarabine suspension is transported in a box containing a temperature monitoring device to ensure that it is refrigerated, but not exposed to temperatures below 2 0 C. The cost of providing one 50mg vial in this way is (plus VAT). The transporting box can accommodate up to five vials. In the past, as the number of vials per order increased the cost per vial decreased. However, this offer changed on the 1 st January A discount now only applies when ordering 5 or more vials, when the cost per vial drops to 875 (plus VAT). As stringent storage precautions associated with liposomal cytarabine may result in hospitals procuring only one vial per order, the one vial cost is used below. Cost per treatment cycle of IT chemotherapy for lymphomatous meningitis Drug Dose Regimen Cost per cycle a ( ) Liposomal cytarabine suspension Free cytarabine solution Induction: 50mg every 2 weeks (2 doses) Consolidation: 50mg every 2 weeks (3 doses), then every 4 weeks (for 1 dose) Maintenance: 50mg every 4 weeks (4 doses) For 30 weeks 10 to 30mg / m 2 three times a week until CSF findings return to normal Cost per course b ( ) 1224 c 12,240 c 3.90 d 351 d Methotrexate solution 200 to 500mcicrograms / kg every 2 to 5 days until CSF findings return to normal or 12mg / m 2 every week for two weeks then every four weeks until CSF findings return to normal 2.62 e 110 to 275 e or 24 e Doses are for general comparison and do not imply therapeutic equivalence. Costs assume that one dose is administered from each vial and that residual drug is discarded each time (i.e. no vial sharing). (a) each cycle is equivalent to one dose; (b) as cost per course is based on a 30 week course for liposomal cytarabine an equivalent course length has been used for comparators; (c) based on cost of one vial per order; (d) based on a body surface area (BSA) of 1.7m 2 and cost of a 100mg/5ml vial ( 3.90) in the 53 rd edition of the British National Formulary (BNF); (e) based on a body weight of 70kg or BSA of 1.7m 2 and cost of a 50mg/2ml vial ( 2.62) in the 53 rd edition of the BNF. 6

7 Additional information: budget impact The manufacturer estimated a net annual budget impact of 114k in 2007 up to 127k in 2011 based on 33 patients eligible for treatment in 2007, increasing to 37 patients by This net budget impact was stated by the manufacturer to be a worst cost scenario as it assumes all eligible patients with LM switch from free cytarabine to liposomal cytarabine. 7

8 Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. This assessment is based on data submitted by the applicant company up to and including 14 June Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. The undernoted references were supplied with the submission. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999;17(10): SkyePharma. A Randomized Clinical Study to Determine the Efficacy and Safety of DepoFoam Encapsulated Cytarabine (SKY0101) Versus Standard Therapy for the Treatment of Neoplastic Meningitis in Patients with Leukemia, Lymphoma or Solid Tumors (Protocol DTC ) Howell S, B. Liposomal cytarabine for the treatment of lymphomatous meningitis. Biological Therapy of Lymphoma 2003;6: European Medicines Agency. European public assessment report for DepoCyte;