Drug: Aprepitant (Emend ) Date of Review: 4/01/10

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1 CAMBRIDGESHIRE JOINT PRESCRIBING GROUP Business Case Evaluation and Recommendation Document Drug: Aprepitant (Emend ) Date of Review: 4/01/10 Business Case Decision and date: DOUBLE RED, 20 January 2010 CJPG noted that there was a lack of consistency in the patient populations in which the drug was being used that meant its use could not readily be evaluated. It was also noted that optimal doses of the alternative anti-emetic agents, which were used in the trials were not utilised, within the submitting Trust. Not funded: Referred to Anglia Cancer Network SACT group for review as part of the Anglia Cancer Network Anti-emetic guidelines Priority assigned: Medium Business Case Indication: Nausea and vomiting for highly emetogenic or refractory chemotherapy regimens Licensed Indication: Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Place in therapy: Used in exceptional circumstances in refractory nausea and vomiting for germ cell cisplatin containing regimes only with cisplatin >60mg/m 2 Treatment alternatives: see-anti-emetics guidelines ondansetron, metoclopramide levomethopromazine, haloperidol, high dose dexamethasone. Stopping criteria: if ineffective Patient Numbers from Business case - CPCT 50 Equates to 100 for CPCT Patient Numbers from Business case - PPCT 13 Equates to 26 for PPCT NICE evaluation date: - None Points to consider: Aprepitant is a neurokinin receptor antagonist and should be used as an adjunct to dexamethasone and a 5HT3 antagonist in preventing nausea and vomiting associated with moderately and highly emetogenic chemotherapy (British National Formulary 58). Page 1 of 5

2 The drug has a novel mechanism of action which is synergistic with currently used drugs (5HT3 antagonists and steroids) Patients who were audited for aprepitant use within CUHFT were: % of patients receiving aprepitant on highly emetogenic cisplatin-based chemotherapy regimes ( 70mg/m 2 cisplatin per cycle), AND % of patients receiving aprepitant who were refractory to standard dual 5HT3 and dexamethasone therapy. Audit showed that patients were treated with aprepitant outside of the audit criteria (86% of sarcoma patients), e.g. patients on etoposide and ifosfomide or VIDE. Clinicians have suggested that if the chemotherapy regime is known to be highly emetogenic better practice may be to start the patient on aprepitant from cycle 1 with no need to demonstrate refractory symptoms first. There is likely to be a significant increase in the number of patients who receive aprepitant when receiving emetogenic chemotherapy. Aprepitant appears to have the most benefit in the prevention of delayed CINV and in the prevention of emesis rather than nausea. Studies have investigated its use in breast cancer patients also. The number of patients requiring treatment with aprepitant is likely to rise by 10% a year. Noted that palonosetron is as effective as other anti-emetics in preventing emesis when given as a single intravenous injection following highly emetogenic chemotherapy in the acute phase and moderately emetogenic chemotherapy in the acute and delayed phases post-chemotherapy. Highly emetogenic chemotherapy includes: ABVD (Doxorubicin, bleomycin, vincristine and dacarbazine) Anthracycline single agent in combination with cyclophosphamide (AC) and taxanes Dacarbazine Any cisplatin containing regimen (including <60mg/m 2 ) Any ifosfamide containing regimen The Scottish Medicines Consortium (SMC) rejected the use of aprepitant in patients being treated with moderately emetogenic chemotherapy as the aprepitant regimen showed a significant difference compared to the standard regimen in terms of the primary end-point of complete response (no N and V) for the acute phase only. No superiority for the aprepitant regimen could be demonstrated for the prevention of nausea. The SMC accepted aprepitant for restricted use within NHS Scotland for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based chemotherapy. It should be initiated only by appropriate hospital-based specialists. NNT for percentage complete response vs standard therapy (i.e. no emesis and no rescue therapy) on days 1 to 5 post cisplatin = 5 Clinical efficacy 1 A multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). Patients (530 patients radomised, of whom 260 patients in the aprepitant group and 261 patients in the standard therapy group were included in the efficacy analyses) receiving cisplatin 70 mg/m 2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 post cisplatin, analysed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. The percentage of patients with complete response on days 1 to 5 was significantly higher in the Page 2 of 5

3 aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]) as well as in separate analyses of both the acute phase (89.2% v 78.1%; p <0.001), and even more notably, the delayed phase (75.4% v 55.8%; p <0.001). Interactions between treatment and region, or treatment and concomitant chemotherapy, were not significant (p> 0.10), though a significant treatment-bysex interaction was noted (p <0.001). Within the aprepitant group, the percentages of females (77.6%) and males (69.8%) with complete response overall were similar, whereas in the standard therapy group overall, the percentage of females who had complete response (38.8%) was less than that of males with complete response (60.5%). This interaction was not found to be significantly qualitative (p > 0.5, by Gail and Simon s test), indicating that the two treatment groups could be combined across sexes for the statistical analyses. Of the 16 deaths that occurred, seven (2.7%) were in the aprepitant group, and nine (3.4%) were in the standard therapy group. None of the adverse events resulting in death were considered drugrelated by the investigator. The most commonly reported serious adverse events in the aprepitant and standard therapy groups, respectively, included dehydration (1.9% v 1.1%), febrile neutropenia (2.3% v 1.9%), neutropenia (2.7% v 0%), and thrombocytopenia (1.5% v 0%). Clinical practice implications: Aprepitant is given orally as 3 capsules, once daily for three days with the 1 st dose 30 minutes prior to start of chemotherapy on day 1 of each cycle Most alternatives for highly emetogenic chemotherapy are given I/V, however aprepitant is used as adjunctive treatment to I/V preparations. Use of aprepitant may reduce the number of hospital admissions for nausea and sickness. There may a reduction in use of syringe driver treatments which includes pump, maintenance of pump and drug costs as well as nursing time to reconstitute syringe driver anti-emetics. Avoidance of hospital emergency admissions resulting from uncontrolled vomiting associated with chemotherapy. Allows more patients to be treated at the optimum effective chemotherapy dose. Important common side effects include anorexia and raised LFTs Commissioning implications: What are the economic considerations for this business case? The cost of a pack of three capsules of aprepitant (three day pack (1x125mg + 2x80mg capsules)) is inc. VAT. The likely number of cycles of chemotherapy per patient is 6 - therefore the cost of treating one patient with aprepitant will be The cost of treating 100 CPCT patients per six cycles with aprepitant could be 100 x = 30,174 And the cost of treating 26 PPCT patients could be 26 x = 7,845. Aprepitant is usually used in combination with a 5HT3 antagonist and a steroid. The drug costs of treating patients, being treated with moderately emetogenic chemotherapy, with an aprepitant regimen could be as follows: Page 3 of 5

4 Anti-emetic drug regime comparison for moderately emetogenic chemotherapy Aprepitant Dose 125mg po on day 1 then 80mg on days 2 and 3 Dexamethasone 12mg po on day 1 Ondansetron 8mg po bd on day 1 Standard anti-emetic regimen (as per clinical study) Dexamethasone 20mg po on day 1 Cost per cycle 65 inc.vat 33 inc VAT Ondansetron 8mg po bd on day 1-3 The SMC felt the economic case for aprepitant in the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy has not been demonstrated. The drug costs of treating patients, being treated with highly emetogenic chemotherapy, with an aprepitant regimen are as follows: Anti-emetic drug regime Dose comparison for highly emetogenic chemotherapy Aprepitant 125mg po on day 1 then 80mg on days 2 and 3 Dexamethasone 12mg po on day 1 followed by oral dexamethasone 8 mg once daily on days 2 to 4 Ondansetron 32mg I/V on day 1 Standard anti-emetic regimen from clinical trial Dexamethasone 20mg po on day 1 followed by oral dexamethasone 8 mg twice daily on days 2 to 4 Ondansetron 32mg I/V on day 1 Cost per cycle inc.vat 60 inc. VAT The costs of using apripetant as an adjunct to standard anti-emetic therapy for patients taking highly-emetogenic chemotherapy are: For 100 CPCT patients x 6 x = 65,094 inc. VAT And the cost of treating 26 PPCT patients could be 26 x 6 x = 16,924 inc. VAT. There may be a reduction in hospital admissions through emergency services for chemotherapyrelated uncontrolled vomiting. Cost of an admission for this indication is 252/day, Estimated average length of admission for this indication is 3 days ( 756). Estimate that the use of aprepitant will avoid 2 patient admissions per month ( 756 X 2= 1512). Estimated total cost savings from avoiding inpatient admissions for Nausea & Vomiting = 18,144 per year. An economic evaluation of the benefit of patients remaining at the most-effective chemotherapy treatment doses is not currently available. What are the risks / benefits of commissioning? Risks are that there could be significant prescribing creep initial indications were that there would be approximately 7 patients for whom aprepitant may be used by CUHFT for CPCT and PPCT. Page 4 of 5

5 The business case indicates that there may be 63 patients for CPCT and PPCT who may be given aprepitant. The patient numbers are concordant with those submitted by the manufacturer to the SMC in their evaluation of the drug but do not represent the total number of providers for the PCT. The manufacturer, in its economic model, indicated that patient numbers would increase by 10% a year. The evidence for use of aprepitant is in breast cancer and respiratory cancer patients. The business case is for germ cell and sarcoma patients. Are there options to reduce costs through redesign? Possibly if patient pathways for sarcoma and germ cell chemotherapy are altered to reduce use of highly emetogenic chemotherapy regimens. This would require a cost-effectiveness evaluation and appropriate use of network approved chemotherapy regimens. Submitting trust CUHFT Therapeutic Area Oncology Date sent Date of review Date of completion 30/12/09 4/1/ References: 1 Hesketh PJ, Grunberg et al. The Oral Neurokinin-1 Antagonist Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients Receiving High-Dose Cisplatin The Aprepitant Protocol 052 Study Group. Journal of Clinical Oncology ; 21: Warr DG, Hesketh PJ, Gralla RJ et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. Journal of Clinical Oncology 2005; 23 : Herrstedt J, Muss HB, Warr DG et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005; 104: European Medicines Agency. European Public Assessment Report; Emend-H-527-II-09 Scientific Discussion. Accessed on 15/11/05: 5 Scottish Medicines Consortium. Aprepitant 125mg, 80mg capsules (Emend ) Merck Sharp and Dohme Ltd No. 242/06. New indication: prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy Page 5 of 5