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Dose rounding of ipilimumab in adult metastatic melanoma patients results in significant cost savings
Anthony Jarkowski III, Jill S Nestico, Karen L Vona and Nikhil I Khushalani J Oncol Pharm Pract published online 19 March 2013 DOI: 10.1177/1078155213476723 The online version of this article can be found at: http://opp.sagepub.com/content/early/2013/03/18/1078155213476723

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Original Article

Oncology Pharmacy Practice

J Oncol Pharm Practice 0(0) 14 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213476723 opp.sagepub.com

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Dose rounding of ipilimumab in adult metastatic melanoma patients results in significant cost savings*
Anthony Jarkowski III
James P Wilmot Cancer Center at the University of Rochester Medical Center, Rochester, NY, USA

Jill S Nestico
Roswell Park Cancer Institute, Buffalo, NY, USA

Karen L Vona
Roswell Park Cancer Institute, Buffalo, NY, USA

Nikhil I Khushalani
Roswell Park Cancer Institute, Buffalo, NY, USA

Abstract Purpose: To assess cost savings incurred with a dose rounding process that was implemented for ipilimumab. Secondarily, to assess response rates, patient tolerance, and adverse effects associated with ipilimumab upon implementation of dose rounding. Methods: All patients with a diagnosis of metastatic melanoma and who received at least one dose ipilimumab were included for analysis. Doses of ipilimumab were calculated based upon the actual body weight (in kg) of the patient at the FDA approved regimen of 3 mg/kg every 21 days 4 doses. The exact total mg dose was then rounded to the nearest 50 mg vial size. The potential effect on cost was calculated in US dollars for both the calculated and rounded doses. Waste, in mg, was defined as the amount of drug that may have been discarded if the calculated dose was used for therapy. The acquisition cost applied was US$120 per mg. Results: 22 patients have received at least one dose of ipilimumab. 11 patients have completed therapy and received all four induction doses. 9 patients discontinued therapy early and 2 patients were still actively receiving induction at the time of this analysis. A total of 63 doses were given. The maximum potential cost savings by giving ipilimumab to the nearest 50 mg over the period was 155,400. Conclusions: Dose rounding of ipilimumab to the nearest 50 mg has the potential to result in a significant cost savings by eliminating drug waste.

Keywords Melanoma, immunotherapy, ipilimumab, cost savings, dose rounding

Introduction
The oncologic time bomb, as predicted in the late 1990s, is upon us, with cancer costs soaring to an estimated 124 billion dollars in 2010. In 1990, costs were estimated at 27 billion dollars, rising to 90 billion dollars in 2008, and projected to reach 157 billion dollars by 2020, representing a 600% increase over the past

* Research was previously published in abstract format and presented in poster format at the Hematology Oncology Pharmacists Association (HOPA) annual meeting in March 2012 in Orlando, FL, USA.

Corresponding author: Anthony Jarkowski III, Department of Pharmacy, James P Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Email: Anthony_Jarkowski@urmc.rochester.edu

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2 three decades.1 One of the main drivers in the increasing expenditure of oncology care is drug cost. While newly developed therapies and drugs are revolutionizing the outcomes associated with cancer care, they can be extremely expensive and at times considered futile given the cost-eectiveness. The United Kingdoms NICE (National Institute for Clinical Excellence) has declined to approve a number of new anti-cancer agents due to a perceived lack of cost-eectiveness. For example, one course (three doses) of the vaccine, sipuleucel-T for hormone-refractory prostate cancer costs $US$93,000 per patient with a value of extending overall survival by approximately 4 months.2 Ipilimumab, a newly approved anti-cytotoxic t-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, was the rst drug to show a survival benet in patients with metastatic melanoma.3 At the approved dosing regimen of 3 mg/kg actual body weight (ABW) every 3 weeks 4 doses, the acquisition cost alone for an 80 kg person would be US$115,200 (based on an acquisition cost of US$120 per mg). Other newly approved expensive intravenous therapies include brentuximab for relapsed Hodgkins lymphoma and anaplastic large T-cell lymphoma and ofatumumab for chronic lymphocytic leukemia. The vast majority of anticancer agents are administered on a per weight basis (i.e. mg/kg) or based on body surface area (i.e. per m2). It is a common practice for oncology clinicians to calculate doses of chemotherapy/targeted agents to the nearest milligram. Intravenous cancer agents are typically supplied in xed drug amount vials, allowing the use of partial vials for a given patient. Some drugs, and the majority of monocloncal antibodies, are packaged preservativefree, allowing only for single time uses with a short expiration.4 When expensive new drugs, such as monoclonal antibodies or other biologics, are made preservative-free and used infrequently, unused partial vials that have expired can amount to a large amount of drug waste. With the rising costs of oncology care and a number of newly introduced expensive therapies, cost containment strategies are important. Drug waste as a consequence of unused or partially used vials can be costly. In the literature, dose rounding of both chemotherapy and biologic anticancer agents has resulted in cost savings.47 It is common clinical practice not to alter the administered dose of chemotherapy from cycle to cycle unless there is a change of greater than 510% in ABW. This practice is thought not to have an impact on the therapeutic ecacy of cancer therapy, although with limited to no data to date.6 For this reason, when ipilimumab was FDA approved for advanced melanoma in March 2011, we adopted dose rounding for the administration of this biological agent.

Journal of Oncology Pharmacy Practice 0(0) The aim of this project was to assess cost savings incurred with implementation of dose rounding for ipilimumab. Secondarily, we aimed to assess response rates, patient tolerance, and adverse eects associated with ipilimumab upon implementation of dose rounding.

Methods
Upon FDA approval in March 2011, the number of doses of ipilimumab and the patients receiving ipilimumab were tracked. Height, weight, ipilimumab dose given (in mg), number of doses received, side eects, and response data were collected. Patients with a diagnosis of metastatic melanoma who received at least one dose of ipilimumab were included for analysis. The initial decision to use ipilimumab and dosing strategies were made by the Soft Tissue Medicine service at Roswell Park Cancer Institute (RPCI). Ipilimumab was dosed at 3 mg/kg of actual body weight (ABW) every 21 days 4 doses. The exact total mg as calculated per weight in kg was rounded to the nearest 50 mg. One to 24 mg was rounded down to the nearest 100 mg integer and 2549 mg was rounded to the nearest 50 mg integer. Waste, in mg, was dened as the amount of drug that would have been discarded if the calculated dose was applied to the treatment regimen. Ipilimumab (YERVOY) is supplied in 50 and 200 mg single-use vials (5 mg/mL). The prescribing information for ipilimumab states to discard partially used or empty vials of YERVOY.8 Ipilimumab vials contain no preservatives and diluted solutions are good for up to 24 h.8 Each mg of ipilimumab costs US$120, as supplied by the pharmacy departments purchasing group. Per the institutes billing department, ipilimumab is billed per J-code, with 1 J-code representing 1 mg of ipilimumab. Adverse eects were documented per Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Best responses were graded by the investigators via clinical criteria and computed tomography (CT) scans after completion of the patients course of induction therapy. The project was reviewed and approved by the Institutional Review Board at Roswell Park Cancer Institute to allow for data collection from patient records. Cost savings were evaluated from March 2011 to February 2012.

Results
Twenty-two patients with metastatic melanoma were treated with at least 1 dose of ipilimumab, with two patients still receiving active induction therapy at the time of analysis. Individual characteristics of each

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Jarkowski et al.
Table 1. Individual patient characteristics of the dosing regimen.
Calculated Potential No. of Weight dose Rounded waste $ saved/ doses Total $ ID# (kg) (mg) dose (mg) dose given saved 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 74.2 88.8 114.1 111.8 85.8 92.9 90.2 94.3 61.2 74 95.8 79.6 76.6 77.3 118.6 95.9 95.4 69.2 106.4 223 266 342 335 257 279 270 283 184 222 287 239 230 232 356 288 286 207 319 218 400 275 200 250 350 350 250 300 250 300 200 200 300 250 250 250 350 300 300 200 300 200 400 300 27 34 8 15 43 21 30 17 16 28 13 11 20 18 44 12 14 43 31 32 0 25 3240 4080 960 1800 5160 2520 3600 2040 1920 3360 1560 1320 2400 2160 5280 1440 1680 5160 3720 3840 0 3000 4 4 4 4 1 4 1 4 2 1 3 2 4 4 3 4 4 1 3 2 3 1 12,960 16,320 3840 7200 5160 10,080 3600 8160 3840 3360 4680 2640 9600 8640 15,840 5760 6720 5160 11,160 7680 0 3000

Discussion
Ipilimumab is a valuable option in the expanding therapeutic armamentarium for metastatic melanoma. Like many commercially available monoclonal antibodies, it is supplied only as a single-use vial, which can result in signicant drug waste when partial vials are utilized. Our experience shows that dose rounding of ipilimumab to the nearest 50 mg can result in a signicant cost savings to the institution. While the Centers for Medicare and Medicaid Services do allow billing for wasted drug, system constraints at our site did not allow for this to be easily accomplished at the time of this study.10 There is a theoretical concern that dose-rounding of cytotoxic drugs may compromise ecacy and safety of the agent. However, available literature suggests that this practice is safe and indeed leads to costcontainment in an era of rising health care costs, albeit with limited data regarding the true impact on ecacy.5,6,11,12 Our dose rounding protocol does not appear to impact toxicity or ecacy, but we acknowledge that this is a small data-set and may not be representative of the entire population. Investigator graded response rate in our cohort was 5%, as compared to 10.9% in the phase III clinical trial.3 As is now well known, responses to ipilimumab may be delayed and patients may have disease progression by traditional radiological criteria at rst evaluation.13 Of note, in a dose-nding Phase II study of ipilimumab in melanoma, the 3 mg/kg dose produced a response rate of 4.2%, comparable to our data set.14 It is also important to be aware that a number of our patients were heavily pre-treated, with many previously undergoing multiple lines of therapy and some stopped induction therapy prior to completion because of rapid disease progression and/or because of decreasing performance status. The patterns of toxicity we observed were also similar to that reported for ipilimumab. Rounding of ipilimumab doses to the nearest 50 mg vial did not signicantly change the mg/kg dose, as the lowest mg/kg dose received was 2.7 and highest was 3.3, representing a 10% variation in dose, a generally accepted practice for monoclonal antibodies. There is signicant inter-patient pharmacodynamic and pharmacokinetic variability with many oncologic targeted therapies and cytotoxic chemotherapies.5 The anticancer activity of biologic therapy typically relies on several factors such as characteristics of the patient (i.e. CYP enzymes, protein binding capacity), characteristics of the cancer (i.e. drug eux pumps), drug to target interactions, and neutralizing antibody formation (1.1% of patients treated with ipilimumab8). Also biologic therapies often have alternate surrogates of dose response rather than a true maximum tolerated

20 72.8 21a 133.3 22a

a

91.6

Still receiving induction therapy at the time of manuscript preparation.

patients dosing regimen are listed in Table 1. Dose rounding was undertaken in 21 patients and one patient did not require any dose rounding. Nine patients doses were rounded down; 12 patients were rounded up on dose. A total of 63 doses were given over the time frame, with a mean number of 2.86 doses received per patient. Fifty-ve (11/20) percent of patients received all four induction doses. Of 20 patients who completed or stopped their given course of ipilimumab, one patient had a documented clinical response; one patient had stable disease (SD), while the rest had disease progression at the time of rst disease evaluation. The patient with a noted clinical response had their dose rounded down, while the one patient with SD had their dose rounded up. Signicant grade 3 or 4 adverse events attributed to ipilimumab included dermatitis (n 3) and colitis (n 1). One patient each developed grade II pancreatitis and grade II hypophysitis. All of these were successfully managed per published guidelines.9 The maximum potential cost savings for the 63 doses of ipilimumab given over the period was US$155,400. A detailed breakdown of cost savings for each patient is provided in Table 1.

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4 dose traditionally examined for chemotherapy, for example, the degree of receptor saturation.5 For these reasons, we have concluded that a small variation in dose such as 0.3 mg/kg ($10% variation in dose) should not have a signicant clinical impact on the patient. It is estimated that approximately 9000 individuals will succumb to melanoma in 2012 in the US alone.15 Even if we conservatively estimate that a third of these patients (n 3000) will receive ipilimumab as part of their therapeutic regimen at a mean of 3 doses each, the potential for annual cost savings from dose rounding of ipilimumab will equate to nearly US$22 m. Further pharmacoeconomic studies will be needed to validate this assumption.

Journal of Oncology Pharmacy Practice 0(0)

3. Hodi FS, ODay SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711723. 4. Patel S and Le A. Rounding rituximab dose to nearest vial size. J Oncol Pharm Pract 2012. Published online ahead of print. 5. Winger BJ, Clements EA, DeYoung JL, et al. Cost savings from dose rounding of biologic anticancer agents in adults. J Oncol Pharm Pract 2011; 17: 246251. 6. Dooley M, Singh S and Michael M. Implications of dose rounding of chemotherapy to the nearest vial size. Support Care Cancer 2004; 12: 653656. 7. Fasola G, Aita M, Marini L, et al. Drug waste minimisation and cost-containment in Medical Oncology: twoyear results of a feasibility study. BMC Health Serv Res 2008; 8: 70. 8. Yervoy (ipilimumab) package insert. Princeton, NJ: Bristol-Myers Squibb, 2011. 9. Weber JS, Ka hler KC and Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: 26912697. 10. Centers for Medicare and Medicaid Services. Medicare claims processing manual. Chapter 17 Drugs and biologicals transmittal Discarded drugs and biologicals. http://www.cms.gov/Regulations-and-Guidance/ Guidance/Manuals/Downloads/clm104c12.pdf (accessed March 2012). 11. Jenkins P and Wallis R. Dose-rounding of adjuvant chemotherapy for breast cancer: an audit of toxicity. J Oncol Pharm Pract 2010; 16: 251255. 12. Johnson KB, Lee CKK, Spooner SA, et al. Automated dose-rounding recommendations for pediatric medications. Pediatrics 2011; 128: e422e428. 13. Wolchok JD, Hoos A, ODay S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 74127420. 14. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11: 155164. 15. Siegel R, Naishadham D and Jemal A. Cancer statistics, 2012. CA: Cancer J Clin 2012; 62: 1029.

Conclusion
Dose rounding of ipilimumab in melanoma can result in signicant cost savings without any apparent compromise of safety and ecacy in this small cohort. Future research should focus on examining this strategy in a larger population and with other drugs to assist in reigning in rising drug costs. Funding
This research received no specic grant from any funding agency in the public, commercial, or not-for-prot sectors.

Conflict of interest
None.

References
1. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol 2011; 12: 933980. 2. Fong MK, Hare R and Jarkowski A. A new era for castrate resistant prostate cancer: a treatment review and update. J Oncol Pharm Pract 2012; 18: 343354.

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