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  1. 1. REGULATORY COMPLIANCE The ESA APPRISE Oncology Program A History of REMS Requirements, a Review of the Data, And an Approach to Compliance in the Hospital David J. Reeves, PharmD, BCOP; Amanda K. Quebe, PharmD; and Ranita Patel, PharmDHistory of the REMS Program drugs, including the erythropoiesis-stimulating agents (ESAs), On September 27, 2007, President George W. Bush signed requires elements to ensure safe use with or without aninto law the Food and Drug Administration Amendments Act implementation system (Table 3, page 425). The FDA seeksof 2007 (FDAAA), which authorized the FDA to require a Risk input from patients and health care practitioners when devel-Evaluation and Mitigation Strategy (REMS) program for drugs oping the program design to ensure that it will not be undulyand biological agents.1 REMS programs are intended to sup- burdensome to patients or the health care system.2port the safe use of products for which the risks and benefitsneed to be carefully weighed in general or in specific patient The Use of Erythropoiesis-Stimulating Agentspopulations. The FDA can require a REMS program at the time In Oncologyof a product’s approval. If a safety problem is detected after ESAs have been widely used in cancer patients on the basisapproval, the REMS can be required at any time during a of data showing that they decreased transfusion requirements.drug’s life cycle. A 2006 meta-analysis of more than 9,000 patients receiving The decision about whether to require a REMS program is ESAs, with and without concurrent antineoplastic therapy,based on the estimated patient population likely to be exposed reported a 36% decreased need for red blood cell transfusions.5to the product, the seriousness of the condition being treated Unfortunately, the authors also found a 67% increase in throm-by the drug, the expected benefit and duration of treatment, boembolic events (transient ischemic attacks, stroke, pul-and the safety risk created by use of the drug.2 The results of monar y emboli, deep-vein thrombosis, and myocardialthis analysis determine the need for and the components of the infarction) for those receiving ESAs, conflicting with results ofREMS. a previous publication.6 This earlier analysis, published in The FDAAA legislation authorized several individual 2005,6 also indicated a trend toward increased survival that wasrequirements, one or more of which may be combined to not supported by the subsequent 2006 study.5make up a product-specific REMS program.2 The require- A meta-analysis, published in 2008 by Bennett et al.,ments include: reinforced the elevated thromboembolic risk associated with ESA use compared with a placebo (7.5% vs. 4.9%, respectively).7 • a medication guide. The authors also found an increased mortality risk with • a communication plan to disseminate risk information to ESAs (hazard ratio [HR], 1.10; 95% confidence interval [CI], health care professionals (e.g., Dear Healthcare Profes- 1.01–1.20). sional letters). • elements to ensure safe use. Table 1 Elements to Ensure Safe Use • an implementation system to monitor and evaluate the program’s success. A REMS program to ensure safe use incorporates one or more of the following elements: Several elements to ensure safe use are outlined in the leg-islation (Table 1). Products can vary greatly in their REMS • Health care providers who prescribe the drug haverequirements. As of December 10, 2010, more than 150 drug specialized training or experience or are certified in aproducts had a REMS program.3 Of those drugs, almost all specific field.included a medication guide (Table 2). For other products, • Pharmacies, practitioners, or health care settings thatsuch as antidepressants as a class, a medication guide may be dispense the drug are certified in a specific field.required outside of a REMS program.4 • The drug is dispensed to patients only in certain health Many drugs also include a communication plan. A subset of care settings (e.g., hospitals). • The drug is dispensed to patients with evidence or otherDr. Reeves is an Oncology Clinical Specialist at St. Vincent Indi- documentation of safe-use conditions (e.g., laboratoryanapolis Hospital and an Assistant Professor of Pharmacy Practice results).at Butler University in Indianapolis, Ind. Dr. Quebe is Director of • Patients are subjected to certain monitoring requirements.Clinical Specialists and the Postgraduate Year 1 Residency • Patients are enrolled in a registry.Program at St. Vincent Indianapolis Hospital in Indianapolis. Data from FDA Amendments Act of 2007.2Dr. Patel is a Postgraduate Year 1 Pharmacy Resident at St. VincentIndianapolis Hospital in Indianapolis. Disclosure: The authors report that they have no financial or com-Approved for publication March 17, 2011. mercial relationships in regard to this article. Vol. 36 No. 7 • July 2011 • P&T® 423
  2. 2. REGULATORY COMPLIANCE: The ESA APPRISE Oncology Program A 2009 update to the 2006 meta-analysis5 revealed increased warn of the increased risks of thrombosis and tumor promotion.mortality with the use of ESAs (combined HR, 1.17; 95% CI, In 2007, the ODAC discussed four additional trials that1.06–1.3) and decreased survival (combined HR, 1.06; 95% CI, showed adverse outcomes: Epoetin Alfa in Advanced Non–1–1.12) during the active study period.8 There was no statisti- Small Cell Lung Cancer (EPO CAN-20),11 Amgen studies 2001-cally significant increase in mortality (combined HR, 1.10; 95% 010312 and 2000-0161,13 and the Danish Head and Neck CancerCI, 0.98–1.24) or decrease in overall survival (combined HR, Group (DAHANCA 10)14 (see Table 4). This review resulted1.04; 95% CI, 0.97–1.11) in the subgroup of patients receiving in the addition of a boxed warning to the labeling of ESAsconcomitant chemotherapy and ESAs. regarding an increased risk of death, more rapid tumor pro- In addition to the meta-analyses of studies investigating gression, and serious cardiovascular and thromboembolicESAs, the FDA Oncologic Drugs Advisory Committee (ODAC) events.met three times to discuss the findings and the future place of In 2008, the ODAC was convened to review the results of twoESAs in the management of patients with cancer. At the first additional trials: the Gynecologic Oncology Group (GOG-meeting in 2004, two trials with adverse findings were reviewed 191)15 and the Preoperative Epirubicin Paclitaxel Aranesp(Table 4, page 426): Evaluation of NeoRecormon on outcome (PREPARE16) study. Based on these trials and the earlierin Head And Neck Cancer in Europe (ENHANCE)9 and the literature showing adverse outcomes, the ODAC recom-Breast Cancer Erythropoietin Survival Trial (BEST).10 Based mended limiting the use of ESAs to patients receiving pallia-on these trials and previous data regarding thromboembolic tive treatment. The ODAC also recommended that the FDAevents, the FDA-approved labeling of ESAs was updated to require informed consent or a patient agreement before ESAs Table 2 Drug Products With REMS Programs—Medication Guide Only Antiepileptic drugs, selected Other agents Carbamazepine (Equetro) Bupropion (Aplenzin, Wellbutrin) Ethosuximide (Zarontin) Colchicine (Colcrys) Ethotoin (Peganone) Dabigatran (Pradaxa) Gabapentin (Neurontin) Diclofenac oral and topical solutions (Cambia, Pennsaid) Lacosamide (Vimpat) Doxepin (Silenor) Levetiracetam (Keppra) Fenofibric acid (Trilipix) Lamotrigine (Lamictal) Mefloquine (Lariam) Pregabalin (Lyrica) Methsuximide (Celontin) Primidone (Mysoline) Metoclopramide oral solution and disintegrating tablets Tiagabine (Gabitril) (Metozolv ODT) Topiramate (Topamax) Milnacipran (Savella) Zonisamide (Zonegran) Morphine oral solution Naltrexone (Vivitrol) Antiretrovirals, selected Olanzapine (Zyprexa) Abacavir (Ziagen) Olanzapine/fluoxetine (Symbyax) Abacavir/lamivudine (Epzicom) Omalizumab (Xolair) Lopinavir/ritonavir (Kaletra) Oral bowel prep kits Abacavir/lamivudine/zidovudine (Trizivir) Oxycodone oral solution Nevirapine (Viramune) Pancrelipase (Creon, Pancreaze, Zenpep) Didanosine (Videx,Videx EC) Pazopanib (Votrient) Telbivudine (Tyzeka) Propylthiouracil Saquinavir (Invirase) Quetiapine (Seroquel) Ramelteon (Rozerem) Fluoroquinolones, all Repository corticotropin (HP Acthar Gel) Ribavirin (Copegus, Rebetol) Interferon alfa and beta, all Rufinamide (Banzel) Sirolimus (Rapamune) Long-acting beta2-agonist combination products, selected Sitagliptin (Januvia, Janumet) Formoterol/budesonide (Symbicort) Sunitinib (Sutent) Salmeterol/fluticasone (Advair) Testosterone, topical (AndroGel, Axiron, Testim) Trazodone extended release (Oleptro) Thiazolidinediones, all Varenicline (Chantix) Zolpidem oral spray (ZolpiMist) Data from FDA, as of December 2010. Information for REMS is updated routinely on the FDA Web site.3424 P&T® • July 2011 • Vol. 36 No. 7
  3. 3. REGULATORY COMPLIANCE: The ESA APPRISE Oncology ProgramTable 3 REMS Program Requirements by Drug Product or Class Medication Communica- Elements of Implementa- Guide tion Plan Safe Use tion SystemAlvimopan (Entereg) X X XAlglucosidase alfa (Lumizyme) X X XAlosetron (Lotronex) X X XArmodafinil (Nuvigil) X XBotulinum toxin A (Botox, Dysport, Xeomin) and B (Myobloc) X XBuprenorphine transdermal (Butrans) X XBuprenorphine/naloxone sublingual film (Suboxone) X X XCollagenase Clostridium histolyticum (Xiaflex) X XDalfampridine (Ampyra) X XDenosumab (Prolia) X XDronedarone (Multaq) X XEcallantide (Kalbitor) X XEculizumab (Soliris) X XElectrolyte containing bowel prep tablets (OsmoPrep, Visicol) X XEltrombopag (Promacta) X X XEndothelin receptor antagonists (Letairis, Tracleer) X X XErythropoiesis-stimulating agents (Aranesp, Epogen, Procrit) X X X XEverolimus (Zortress) X XFingolimod (Gilenya) X XFormoterol/mometasone (Dulera) X XFentanyl buccal film (Onsolis) X X X XGlucagon-like peptides (Byetta,Victoza) X XHydromorphone extended release (Exalgo) X XIsotretinoin (Accutane, Amnesteem, Claravis) X X XLenalidomide (Revlimid) X X XModafinil (Provigil) X XMorphine/naltrexone (Embeda) X XNilotinib (Tasigna) X XOlanzapine extended release injection (Zyprexa Relprevv) X X X XOxycodone extended release X XPegloticase (Krystexxa) X XPrasugrel (Effient) X XQuinine (Qualaquin) X XRomiplostim (Nplate) X X X XSacrosidase (Sucraid) X X XSalmeterol (Serevent) X XTelavancin (Vibativ) X XTeriparatide (Forteo) X XTetrabenazine (Xenazine) X XThalidomide (Thalomid) X X XTocilizumab (Actemra) X XTolvaptan (Samsca) X XTumor necrosis factor antagonists: certolizumab (Cimzia), X X etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), golimumab (Simponi)Ustekinumab (Stelara) X XVigabatrin (Sabril) X X X X Data from FDA, as of December 2010. Information for REMS is updated routinely on the FDA Web site.3 Vol. 36 No. 7 • July 2011 • P&T® 425
  4. 4. REGULATORY COMPLIANCE: The ESA APPRISE Oncology ProgramTable 4 Summary of Trials of Erythropoiesis-Stimulating Agents (ESAs) Reviewed by the OncologicDrugs Advisory CommitteeTrial Study Design Selected ResultsReviewed in 2004ENHANCE9 • Patients with head and neck cancer receiving ESA use was associated with: radiotherapy • decreased locoregional progression-free survival • Randomized to receive an ESA or placebo (adjusted relative risk, 1.62; P = 0.0008) • Target Hb ≤ 14 g/dL for women, ≤ 15 g/dL for • decreased overall survival (relative risk, 1.39; men P = 0.02)BEST10 • Women with metastatic breast cancer receiving Study was stopped early; higher mortality rates in the ESA first-line chemotherapy group than in the placebo group: • Randomized to receive an ESA or placebo • 12-month overall survival rate 70% vs. 76% (P = 0.01) • Target Hb 12–14 g/dL • tumor response and time to progression were similar between groupsReviewed in 2007EPO CAN-2011 • Patients with non–small-cell lung cancer not Study was stopped early; higher mortality rates in the ESA receiving chemotherapy or receiving non– group than in controls: platinum-based chemotherapy regimens • Median survival, 63 days vs. 129 days (P = 0.04) • Randomized to receive an ESA or placebo • Target Hb 12–14 g/dLAmgen study • Patients with non-myeloid cancers not receiving ESA use was associated with:2001-010312 chemotherapy • increased cardiovascular and thromboembolic events • Randomized to receive an ESA or placebo (9.7% vs. 7.7%; P was not reported) • Target Hb 12–13 g/dL • decreased survival during treatment and long-term follow-up (HR for overall survival, 1.22; P = 0.022)Amgen study • Patients with lymphoma or myeloma receiving ESA use was associated with:2000-016113 chemotherapy • increased quality of life • Randomized to receive an ESA or placebo • decreased survival (HR for death, 1.37; P = 0.04) • Target Hb 13–14 g/dL for women, 13–15 g/dL for menDAHANCA 1014 • Patients with squamous cell carcinoma of the ESA use was associated with: head and neck receiving radiotherapy • decreased locoregional control (56% vs. 69%; P = 0.02) • Randomized to receive an ESA or placebo • decreased disease-free survival (48% vs. 63%; P = 0.004) • Target Hb ≤ 15.5 g/dL No statistically significant difference in overall survivalReviewed in 2008GOG-19115 • Women with cervical cancer receiving Study was stopped early; concerns about an increased rate chemotherapy and radiation of thromboembolic events with ESAs: • Randomized to receive an ESA or placebo • 19.2% vs. 7.7% • Target Hb 12–14 g/dL • fewer than 25% of planned patients enrolled ESA use was associated with a numerical, but not a statistically significant, decrease in: • progression-free survival (58% vs. 66%) • overall survival (60% vs. 74%)PREPARE16 • Women with breast cancer receiving neo- An unplanned interim analysis after a median follow-up adjuvant chemotherapy period of 3 years showed an association of ESA use with: • Randomized to receive an ESA or a transfusion • decreased overall survival (86% vs. 90%; • Target Hb 12.5–13 g/dL HR, 1.42; 95% CI, 0.93–2.18) • decreased progression-free survival (73% vs. 79%; HR, 1.33; 95% CI, 0.99–1.79) CI = confidence interval; Hb = hemoglobin; HR = hazard ratio. Trials: BEST = Breast Cancer Erythropoietin Survival Trial; DAHANCA = Danish Head and Neck Cancer Group; ENHANCE = Evaluation ofNeoRecormon on outcome in Head And Neck Cancer in Europe; EPO CAN-20 = Epoetin Alfa in Advanced Non–Small Cell Lung Cancer;GOG = Gynecologic Oncology Group; PREPARE = Preoperative Epirubicin Paclitaxel Aranesp. continued on page 431426 P&T® • July 2011 • Vol. 36 No. 7
  5. 5. REGULATORY COMPLIANCE: The ESA APPRISE Oncology Programcontinued from page 426could be administered. The FDA-approved labels were sub- ESAs, whereas other elements of ESA APPRISE are unique tosequently revised to state that ESAs were not recommended patients with cancer.)when the intent of chemotherapy was to cure and when a Some logistical considerations are associated with thisREMS program was initiated. process and must be addressed by each hospital, such as In response to published data, national guidelines have been which member of the health care team is responsible forupdated. The 2010 American Society of Clinical Oncology/ reviewing the information with the patient (nurse, pharmacist,American Society of Hematology guideline recommends ESAs or physician) and whether the medication guide must be usedas an option when hemoglobin levels are below 10 g/dL dur- to facilitate discussion. If the guide is used, the process bying chemotherapy.17 The guideline does not include a specific which it is stored and retrieved must also be addressed.hemoglobin target; instead, it recommends maintaining For instance, the medication guides are five pages long,hemoglobin at the lowest level required to avoid a transfusion. they are not supplied in a 1:1 ratio with the product, and theyNotably, the guideline differs from the FDA-approved labeling are subject to updates. At St. Vincent Indianapolis Hospital, theby stating that limiting the use of ESAs to palliative chemother- nurse reviews the guide with the patient. The guide is printedapy regimens is a clinical judgment and not expressly sup- by the pharmacy from the manufacturer’s Web site at the timeported by the literature. The Centers for Medicare & Medicaid of dispensing, It is then sent with the ESA to ensure that theServices (CMS) defined the appropriate setting for ESAs to most recent version is used, thereby eliminating the need toapply only to patients receiving chemotherapy in the palliative store paper copies. The medication guide is distributed withsetting with a hemoglobin level of less than 10 g/dL and fur- each drug administration to each patient so that the contentther recommend discontinuing ESAs within eight weeks of the provided and the method of dissemination are consistent.last chemotherapy dose.18 Communication PlanESA APPRISE and an Approach to Compliance The responsibility of the communication plan rests with the In February 2010, based on the ODAC’s recommendations manufacturer. The Dear Healthcare Provider letters and otherand the FDA’s subsequent action, Amgen and Centocor Ortho materials can be accessed at announced that the FDA had approved a REMS pro-gram called Assisting Providers and cancer Patients with Risk Elements to Ensure Safe Use20Information for the Safe use of ESAs (the ESA APPRISE On- Three of the elements to ensure safe use are incorporatedcology Program).19 This program incorporates a medication into the ESA APPRISE Oncology Program: (1) health careguide, a communication plan, elements to ensure safe use, and provider training and certification, (2) hospital certification,an implementation system.20 and (3) dispensing following the documentation of safe- use conditions. All prescribers who plan to order ESAs forMedication Guide cancer patients must receive training and must enroll in ESA The original REMS for ESAs included a requirement that a APPRISE. The manufacturer maintains an on-line list of en-medication guide be distributed to each patient when an ESA rolled prescribers through an independent third party. Thewas to be dispensed.20 There was no specific direction with hospital must appoint a designee to receive training and enrollregard to the practice setting (i.e., inpatient or outpatient) or in APPRISE on behalf of the institution. At our hospital, thethe frequency with which guides should be distributed (i.e., designee is the director of pharmacy.upon therapy initiation or with every drug administration). Training, which is available on the manufacturer’s Web site, In February 2011, the FDA issued a draft guidance ex- includes a review of the risks of using ESAs in cancer patients.plaining its approach to discretionary enforcement of the Enrollment includes an agreement to conform to the man-REMS regulations.21 Although not yet formally in effect as of dates of ESA APPRISE. The hospital designee is responsiblethis writing, the draft guidance specifies requirements for in- for establishing and overseeing a process that includes verifi-patient and outpatient sites and when medication guides must cation of prescriber enrollment in the program as well asbe distributed. For hospitalized patients, a guide is not manda- patient and prescriber discussions of risks and benefits beforetory unless the patient or patient’s agent requests it. Instead, ESAs are dispensed.providing patient information, including appropriate use, po- One of the elements of ESA APPRISE is a formal, docu-tential side effects, and follow-up by a health care professional mented discussion between a certified prescriber and thein the course of care, is considered sufficient to meet the reg- patient regarding the risks and benefits of ESA use in cancer.ulatory intent. In an outpatient setting, in which the ESA is Both parties sign an acknowledgment form. Outside the hos-dispensed to a health care professional to administer to the pital, these forms are faxed to a central repository and are alsopatient, the medication guide must be distributed upon re- maintained in the patient’s medical record. For in-hospital usequest, at the first time drug is dispensed, and when the guide’s of ESAs, forms are not submitted to a central repository; theycontent has been substantively changed. are provided to the hospital designee only to validate that the The FDA guidance does not affect the duty of the hospital discussion has occurred before an ESA has been inform a patient of the REMS program. Although distribu- Completion of the form does not constitute patient enrollmenttion of the actual medication guide is not mandated for each in any registry or program; it serves only as documentation ofpatient with each drug administration, a review of the infor- the required discussion between prescriber and patient.mation must still be included for each patient each time. We’ve noted many logistical problems involving the (Note: Distribution of the guide is required for all uses of acknowledgment form in our institution, which is a community Vol. 36 No. 7 • July 2011 • P&T® 431
  6. 6. REGULATORY COMPLIANCE: The ESA APPRISE Oncology Programhospital without an integrated electronic health record (EHR) duty of the prescriber to complete the acknowledgment formsystem. In the REMS program, a prescriber is required to with the patient. This task cannot be delegated to other mem-complete the form with the patient for each course of therapy, bers of the health care team. Verification also needs to occuralthough many times therapy is initiated in the outpatient set- with each admission, and completed forms must be stored andting and continued in the hospital. The hospital could choose retrieved by the pharmacist or must be provided again by theto require a copy of the acknowledgment form to verify com- office or physician with each admission.pletion. If so, the form must travel from the office to the hos- Our hospital has opted for a different approach and haspital, or it must be completed again in the hospital. The office determined that a specific medication order set for ESAs is themight be unable to provide a copy during off-hours, or the best approach in treating cancer patients (Figure 1). Includedphysician might be unavailable to complete it again. in the order set is a physician’s attestation that the medication According to the ESA APPRISE Oncology Program, it is the guide has been reviewed, the risks and benefits have been NOTE: Orders for erythropoiesis-stimulating agents IRON REPLACEMENT (ESAs) will not be honored unless all required infor- I Ferrous Sulfate 325 mg PO t.i.d. on an empty mation is provided. stomach I ______________________________ Hgb (g/dL): _________ (Date: ___/___/______) ERYTHROPOIESIS-STIMULATING AGENT *Hgb must be < 10 g/dL × I HOLD darbepoetin if Hgb > 10 g/dL Inpatient INDICATION: I Darbepoetin (Aranesp) 100 mcg subcutaneously I Chemotherapy-induced anemia once weekly * ESAs are indicated only in patients receiving concomitant chemotherapy. Therapy may be Outpatient continued for up to 8 weeks after the last dose I Darbepoetin (Aranesp) 500 mcg subcutaneously of chemotherapy. every three weeks * ESAs are not indicated in patients receiving I Darbepoetin (Aranesp) ________ mcg hormonal agents, therapeutic biologic products, (2.25 mcg/kg) subcutaneously weekly or radiotherapy unless they are also receiving concomitant myelosuppressive chemotherapy. Centers for Medicare & Medicaid Services (CMS) I Other (specify): ____________________________ Dose Adjustment Guidelines • If Hgb increase < 1 g/dL after 4 weeks and Hgb is *ESAs are not reasonable for AML, CML, or erythroid < 10 g/dL: increase dose by 25%. cancers; anemia of cancer not related to chemotherapy; • If Hgb increase > 1 g/dL over 2 weeks: hold until or prophylactic use. Hgb < 10 g/dL: decrease dose by 25%. LABS: I CBC prior to each dose ESA APPRISE Program I Tsat I Ferritin I Serum iron ***REQUIRED FOR ALL ONCOLOGY PATIENTS*** I Serum vitamin B12 (cobalamin) level By signing below I attest that: I Serum folate level • I have received training and I am enrolled in the ESA I ________________________________ APPRISE Oncology Program. I have been assigned an enrollment ID number. I ________________________________ • I have provided the Medication Guide to the patient and reviewed it with the patient prior to this course of therapy. • I counseled this patient on the risks/benefits of ESAs prior to this course of therapy. • I signed the ESA APPRISE Oncology Program Patient and Healthcare Professional Acknowledgment form and witnessed the patient sign the same form. I have retained the archival copy of this form. Signature:__________________________ Date: ___/___/______ Date ________Time ____________ Signature________________________MDFigure 1 Sample ESA Oncology Order Set. AML, CML = acute and chronic forms of leukemia; CBC = complete blood count;Hgb = hemoglobin; PO = orally; t.i.d. = three times daily; Tsat = transferrin saturation.432 P&T® • July 2011 • Vol. 36 No. 7
  7. 7. REGULATORY COMPLIANCE: The ESA APPRISE Oncology Programdiscussed, and the prescriber and patient have signed the therapy: A survival study. J Clin Oncol 2005;23:5960–5972.acknowledgment form. Following confirmation that the pre- 11. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind,scriber is registered with the ESA APPRISE Oncology Pro- placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25:1027–gram, this order set serves as our hospital’s documentation of 1032.compliance. The patient acknowledgment form, in addition to 12. Smith RE, Aapro MS, Ludwig H, et al. Darbepoetin alfa for thethe medication order set, may be submitted to the pharmacy; treatment of anemia in patients with active cancer not receivinghowever, this is not required, because the physician’s attesta- chemotherapy or radiotherapy: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncoltion serves as a surrogate. 2008;26:1040–1050. 13. Hedenus M, Adriansson M, San Miguel J, et al. Efficacy andImplementation safety of darbepoetin alfa in anaemic patients with lympho- The manufacturer is responsible for confirming compliance proliferative malignancies: A randomized, double-blind, placebo-with ESA APPRISE. This is achieved through a series of ran- controlled study. Br J Haematol 2003;122:394–403. 14. Overgaard J, Hoff C, Sand Hansen H, et al. Randomized study ofdom on-site audits of enrolled hospitals. Those hospitals that the importance of novel er ythropoiesis stimulating proteinare not enrolled or that are not in compliance may not have (Aranesp) for the effect of radiotherapy in patients with primaryaccess to ESAs.20 squamous cell carcinoma of the head and neck (HNSCC): The Danish Head and Neck Cancer Group DAHANCA 10 ran-Conclusion domized trial. Eur J Cancer Suppl 2007;5:7. 15. Thomas G, Ali S, Hoebers FJP, et al. Phase III trial to evaluate the REMS programs represent a new facet of drug safety regu- efficacy of maintaining hemoglobin levels above 120 g/dl with ery-lation. With a growing number of programs and a wide variety thropoietin vs. above 100 g/dl without erythropoietin in anemicof requirements within the programs, hospitals may be chal- patients receiving concurrent radiation and cisplatin for cervicallenged to meet the criteria for compliance. The ESA APPRISE cancer: A Gynecologic Oncology Group Study. Gynecol Oncol 2008;108:317–325.Oncology Program represents a difficult challenge, in that 16. FDA. Background information for the Oncologic Drugs AdvisoryESAs may be high-use agents, and the elements to ensure safe Committee meeting, March 13, 2008. Available at: www.fda.use present logistical considerations for hospital pharmacy gov/ohrms/DOCKETS/ac/08/briefing/2008-4345b2-05-AMGEN.pdf.departments. Accessed December 30, 2010. 17. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clin- ical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adultReferences patients with cancer. Blood 2010;116:4045–4059. 1. Identification of drug and biological products deemed to have risk 18. Centers for Medicare & Medicaid Services (CMS). Decision evaluation and mitigation strategies for purposes of the Food and memo for erythropoiesis-stimulating agents (ESAs) for non-renal Drug Administration Amendments Act of 2007. Fed Register disease indications (CAG 00383N). Available at: https://www. 2008;73(60):16313–16314. 2. FDA. Full text, FDA Amendments Act of 2007. Available at: www. asp&id=203&. Accessed December 20, 2010. 19. Amgen and Centocor Ortho Biotech Products Finalize ESA Risk andCosmeticActFDCAct/SignificantAmendmentstotheFDCAct Evaluation and Mitigation Strategy (REMS) With FDA. February /FoodandDrugAdministrationAmendmentsActof2007/FullText 16, 2010. Available at: ofFDAAALaw/default.htm. Accessed December 21, 2010. jsp?release ID=1391301. Accessed December 22, 2010. 3. FDA. Approved Risk Evaluation and Mitigation Strategies. 20. ESA APPRISE Oncology Program. Amgen. Available at: https:// Available at: DrugSafetyInformationforPatientsandProviders/ucm111350.htm. Accessed December 22, 2010. Accessed December 10, 2010. 21. Guidance for Industry. Medication Guides—Distribution Require- 4. Drug products with medication guides. Pharm Lett Prescriber ments and Inclusion in Risk Evaluation and Mitigation Strategies Lett 2006;22(220331). (REMS). Draft Guidance, February 2011. Available at: www. 5. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human ery- y thropoietins and cancer patients: Updated meta-analysis of 57 Information/Guidances/UCM244570.pdf. Accessed March 16, studies including 9353 patients. J Natl Cancer Inst 2006;98:708– 2011. I 714. 6. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: Results of a comprehensive meta-analysis. J Natl Cancer Inst 2005;97:489–498. 7. Bennett CL, Siver SM, Bjulbegovic B, et al. Venous thrombo- embolism and mortality associated with recombinant erythro- poietin and darbepoetin administration for the treatment of cancer- associated anemia. JAMA 2008;299:914–924. 8. Bohlius J, Schmidlin, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: A meta-analysis of randomized trials. Lancet 2009;373: 1532–1542. 9. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomized, double-blind, placebo-controlled trial. Lancet 2003; 362:1255–1260.10. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first line chemo- Vol. 36 No. 7 • July 2011 • P&T® 433