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Rounding rituximab dose to nearest vial size

Samit Patel and Ann Le J Oncol Pharm Pract 2013 19: 218 originally published online 31 October 2012 DOI: 10.1177/1078155212462439 The online version of this article can be found at: http://opp.sagepub.com/content/19/3/218

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Original Article

Oncology Pharmacy Practice

J Oncol Pharm Practice 19(3) 218221 ! The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155212462439 opp.sagepub.com

Journal of

Rounding rituximab dose to nearest vial size

Samit Patel
Stanford Hosiptal and Clinics, Stanford, CA, USA

Ann Le
Stanford Hosiptal and Clinics, Stanford, CA, USA

Abstract Purpose: To determine the feasibility of dose-rounding rituximab by looking at the potential deviation from the prescribed dose to the dose rounded to the nearest vial size. Methods: This study is a retrospective chart review of all rituximab orders prescribed for hematologic or oncologic indications over a period of 24 months. The feasibility of dose-rounding rituximab to the nearest vial size was evaluated by looking at the potential deviation of the prescribed dose to the rounded dose. Physician opinion towards dose rounding rituximab was assessed through a survey. Results: From October 2008 through September 2010, 2028 orders of rituximab were prescribed and processed. Ninety-nine percent of all rituximab doses fell within 10% dose deviation if rounded to the nearest 100-mg vial size and 66.1% of all rituximab orders fell within 5% dose deviation. All responding physicians were comfortable with at least a 5% dose deviation, projecting a yearly savings of approximately US$37,000 through rounding down and capturing additional cost of approximately US$43,000 through rounding up. Conclusion: The projected savings of dose-rounding rituximab to the nearest vial size resulted in both substantial financial savings and reduced unnecessary wastage of unused drug.

Keywords Rituximab, rounding, vial size

Background
The development of monoclonal antibodies in the last few decades has advanced cancer therapy by providing more targeted therapy towards tumor cells. By interfering with specic receptors or antigens, monoclonal antibodies can incite antitumor activity through a variety of mechanisms activation of host immune response to tumor cells, delivery of cytotoxic molecules into tumor cells, or inhibition of downstream cell signaling pathways.1,2 There are currently over a dozen monoclonal antibodies approved by the U.S. Food and Drug Administration (FDA) for cancer treatment with many more in the pipeline. The rst monoclonal antibody to be approved for the treatment of a malignant indication was rituximab. Targeting CD20 surface receptors on normal and malignant B cells, rituximab is currently being used as both monotherapy and in

conjunction with other antineoplastic agents for the treatment of many other malignancies.2 Additionally, rituximab is utilized for the treatment of non-malignant indications including autoimmune disorders and chronic graft-versus-host disease.1,2 Monoclonal antibodies are considered to be a form of biological therapy. In order to preserve protein viability and decrease bacterial contamination, these drugs must be stored and prepared at specic manufacturer guidelines. All monoclonal antibodies are available as preservative-free single-use (or single-dose) vials that should not be reused for additional doses, with the exception of trustumab.312 This can lead to
Corresponding author: Samit Patel, Stanford Hosiptal and Clinics, 300 Pasteur Drive, Stanford, CA 94305, USA. Email: SaPatel@stanfordmed.org

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Patel and Le considerable drug waste when doses that do not use an entire vial are prescribed. With the development of newer and more expensive biological therapies, drug waste translates to considerable economic loss. The nancial and clinical impact of dose-rounding of chemotherapy (including monoclonal antibodies) has been reported to be benecial, leading to signicant cost savings without any signicant associated increase in toxicity.1316 The purpose of this study is to assess the feasibility of dose-rounding rituximab to the nearest available vial size and to potentially develop institution based guidelines for the dosing of all monoclonal antibodies. In addition, we conducted a physician opinion survey to assess the general consensus of dose-rounding rituximab.

219 orders were rounded up or down to the nearest vial size, 99.4% of all rituximab doses would fall within 10% deviation from original dose ordered. From our survey of 51 hematology and oncology physicians, we received 19 responses. Four physicians reported that they do not prescribe rituximab often. Six physicians (40%) reported to be comfortable with a 5% or less dierence in dose deviation if rounding to the nearest vial. Five physicians (33%) reported to be comfortable with a 10% or less dierence in dose deviation. The remaining four physicians (27%) were comfortable with a greater than 10% dose deviation.

Discussion
Rituximab, like many monoclonal antibodies is available only as single-use vials.1 According to the Centers for Disease and Control Prevention (CDC), singleuse vials are designed for use in a single patient for a single case/procedure/injection.3 The United States Pharmacopeia (USP) Chapter 797 standards for sterile compounding also follow a similar denition as singleuse vials may not contain proper preservatives to protect against contamination and instability.17,18 Utilization of single-use vials for multiple patients by health care personnel have resulted in reported cases of contamination and spread of infection.19 However, most of these cases were not performed in a clean room or under aseptic technique, which may have further compromised the integrity of the vials and nal parental product.20 Interestingly, USP Chapter 797 standards for sterile compounding allow single-use vials to be used up to 6 hours from initial needle puncture if initial puncture was performed in an ISO Class 5 air environment or better.17,18 This can lead to considerable confusion regarding whether or not the remainder of the vials may be used a second time within the 6 hour time frame. If this were the case, scheduling patients on the same day would be vastly benecial. The Centers for Medicare and Medicaid Services (CMS) has a dierent perspective on the issue of dose rounding. When clinically appropriate, they encourage ecient utilization of drugs and biologics through methods such as scheduling two or more patients who are receiving the same drug on the same day. When such strategies are not feasible and the remainder of single-use vials must be discarded, CMS provides payment for the amount of drug or biologic discarded in addition to the amount administered. For example, if a patient is prescribed 645 mg of rituximab, the infusion center can additionally bill CMS for the 55 mg of rituximab wasted.21 Although this practice provides strong nancial incentive for cancer centers to bill for wasted drug, this may hinder the practice of rounding to nearest vial sizes.

Methods
This study was a retrospective chart review of electronic medical records from October 2008 through September 2010 of all rituximab orders prescribed for hematologic or oncologic indications at Stanford Hospital and Clincs. We looked at the potential deviation from the prescribed dose to the dose of the nearest vial size. Data collected include patient demographics and dose prescribed. Drug cost data was obtained from the pharmacy departments purchasing division. Patients actively enrolled in clinical research trials were excluded. Additionally, medical oncologists and hematologists at this institution were surveyed to assess their acceptability with percent dose deviation when doses of rituximab are rounded to the nearest vial size.

Results
Over a period of 24 months, there were 2028 rituximab orders processed through the pharmacy for a hematologic or oncologic indication. We performed a theoretical analysis of rounding rituximab doses, which ranged between 100 mg and 1300 mg. Dose was rounded up or down, based on 100 mg vials sizes. The percent dose deviation was calculated for each dose and the least of the two was taken. For example, a 105 mg dose would be rounded down to 100 mg (4.8% dose deviation) rather than rounded up to 200 mg (90.5% dose deviation). Dose deviation after rounding analysis was evaluated and compared. Of these orders, 153 required no rounding. Seven hundred and eighty nine orders could be rounded down to the nearest vial size. The remaining 1086 orders could be rounded up to the nearest vial size. When rounded up or down, 66.1% of all rituximab orders were less than 5% deviation of the actual dose while 25.7% of all orders were within 6 10%. Less than 1% of all rounded doses deviated greater than 10% of actual dose. In total, if these

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220 Both safety and ecacy should be considered when dose rounding is undertaken. Rituximabs anticancer properties are dependent on the binding and saturation of CD20 receptors on malignant cells. Early phase I dose-escalating trials of rituximab for treatment of non-Hodgkins lymphoma have demonstrated no dose-limiting toxicity for doses ranging from 10 mg/m2 up to 500 mg/m2. In addition, there has not been any established relationship between dose and frequency or severity of adverse events.22,23 While the lack of increased toxicity with dose escalating rituximab can be extrapolated to support minimal risk associated with dose rounding up, there is no data addressing clinical ecacy with rounding down. A physician opinion survey was used to determine the maximal dose deviation for clinical ecacy. We have shown that of the physicians that responded to our survey, all responders considered at least a 5% deviation in dose to be acceptable. Over a 12 month period, this potentially allowed for 66.1% of all rituximab orders to be rounded: 313 orders rounded down and 357 orders rounded up. This could result in saving 6712 mg of rituximab from being wasted due to rounding down and 7735 mg of rituximab being utilized. While rounding up may seem like a potential increase in utilization, this is actually a reduction in wastage. Based upon our acquisition cost of US$563.22 per 100 mg vial of rituximab, we projected a saving of approximately US$37,803 through rounding down and capturing additional cost of $43,568 through rounding up. Of note, most of the survey responders were comfortable with at least 10% dose deviation (60%), projecting a potential saving of approximately US$55,861 through rounding down and capturing additional cost of US$90,595 through rounding up. Over recent years, pharmacy departments have looked to minimize cost through maximizing labor eciency and closely monitoring inventory and procedures. Through our daily experience compounding medications, we have noticed that rituximab vials, like many other injectable medications, contain a small amount overll. Anecdotally, we have discovered this to be approximately 23 mg per 100 mg vial. This fortuitously allows us to occasionally prepare some doses of rituximab without having to open another vial which would result in wasting of the remaining unused drug. For example, a 720 mg dose of rituximab can be prepared with only seven 100 mg vials.

Journal of Oncology Pharmacy Practice 19(3) indication. Based on our potential calculated cost savings, cost capturing and our physician opinion consensus of rounding to the nearest vial within 5% of actual dose calculated, our study shows that dose rounding can have tremendous nancial implications if applied to other monoclonal antibodies on the market. However, it is important to evaluate the safety, ecacy and pharmacokinetic data of these agents. In addition, with the substantial surge in cost of new biological agents entering the market, eorts to minimize unnecessary drug waste has become more important than ever. Funding
This research received no specic grant from any funding agency in the public, commercial or not-for-prot sectors.

References
1. Rituxan (rituximab) package insert. South San Francisco, CA: Genentech, Inc., 1997. 2. Oldham RK and Dillman RO. Monoclonal antibodies in cancer therapy: 25 years of progress. J Clin Oncol 2008; 26(11): 17741777. 3. Centers of Disease Control and Prevention (CDC). Occupational exposure to antineoplastic agents, www.cdc.gov (accessed 11 November 2011). 4. Campath (alemtuzumab) package insert. Cambridge, MA: Genzyme Corporation, 2009. 5. Avastin (bevacizumab) package insert. South San Francisco, CA: Genentech, Inc., 2004. 6. Adcetris (brentuximab vedotin) package insert. Bothell, WA: Seattle Genetics, Inc., 2011. 7. Erbitux (cetuximab) package insert. Princeton, NJ: Bristol-Myers Squibb, 2004. 8. Zevalin (ibritumomab) package insert. Irvine, CA: Spectrum Pharmaceuticals, Inc., 2009. 9. Yervoy (ipilimumab) package insert. Princeton, NJ: Bristol-Myers Squibb, 2011. 10. Arzerra (ofatumumab) package insert. Research Triangle Park, NC: GlaxoSmithKline, 2011. 11. Vectibix (panitumumab) package insert. Thousand Oaks, CA: Amgen, Inc., 2006. 12. Herceptin (trastuzumab) package insert. South San Francisco, CA: Genentech, Inc., 2003. 13. Field K, Zelenko A, Kosmider S, et al. Dose rounding of chemotherapy in colorectal cancer: an analysis of clinician attitudes and the potential impact on treatment costs. Asia Pac J Clin Oncol 2010; 6(3): 203209. 14. 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(3): 246251. 15. Fasola G, Aita M, Marini L, et al. Drug waste minimization and cost-containment in Medical Oncology: twoyear results of a feasibility study. BMC Health Serv Res 2008; 8: 70. 16. Dooley MJ, Singh S and Michael M. Implications of dose rounding of chemotherapy to nearest vial size. Support Care Cancer 2004; 12(9): 653656.

Conclusion
Our retrospective analysis evaluated the feasibility of dose rounding a biological agent. We chose to evaluate only rituximab when it was prescribed for a malignant

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Patel and Le
17. United States Pharmacopeial Convention. Pharmaceutical compounding sterile preparations. Revision Bulletin. 2008. 18. Pharmaceutical compounding-sterile preparations. (general information chapter 797). In: The United States pharmacopeia, 27th rev., and the national formulary, 22nd edn. Rockville, MD: The United States Pharmacopeial Convention, 2004, pp.23502370. 19. Centers of Disease Control and Prevention (CDC). Injection safety, www.cdc.gov (accessed 11 November 2011). 20. Grohskopf LA, Roth VR, Feikin DR, et al. Serratia liquefaciens bloodstream infections from contamination of epoetin alfa at a hemodialysis center. N Engl J Med 2001; 344(20): 14911497.

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21. Centers for Medicare and Medicaid Services. Medicare claims processing manual. Chapter 17 Drugs and biologicals transmittal 40 Discarded drugs and biologicals, https://www.cms.gov/manuals/downloads/clm104c17.pdf (accessed 7 November 2011). 22. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDECC2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkins lymphoma. J Clin Oncol 1997; 15(10): 32663274. 23. Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84(8): 24572466.

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