Letters

ministered with amiodarone were appropriate, compared with 84% of orders in the control group (p = 0.01). There were no reports of muscle pain, myopathy, or rhabdomyolysis in either group. Our study found that the use of an efficient DDI alert with a hard stop resulted in 100% compliance. Because the revised alert used a hard stop, we were unable to determine if the more-concise wording of the revised alert alone could have improved prescribing. The patients in our study did not experience any muscle-related adverse effects. This is not surprising, given that myopathy and rhabdomyolysis rarely result from statin use, and rhabdomyolysis is more common with longer periods of amiodarone and statin coadministration.1,2,7 Our study had several limitations. First, due to our small sample size, the power to detect differences in event rates was limited, particularly for rare events. Second, only patients admitted to the cardiology service were enrolled, which comprised only 8% of the hospital census. Third, there was a lack of consistent pharmacist presence during daily physician rounds on this service. Fourth, we did not examine the potential effect of the revised hard-stop alert on delays in treatment.8 The use of a hard-stop alert may be reasonable for addressing many other serious DDIs; however, caution is advised to ensure such alerts do not result in delays in important treatments. 1. Armitage J, Bowman L, Wallendszus K et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010; 376:1658-69. 2. Food and Drug Administration. Interaction between amiodarone (marketed as Cordarone and Pacerone) and simvastatin (marketed as Zocor and generics) or simvastatin combination products (marketed as Vytorin and Simcor): amiodarone potentiates the risk for simvastatinassociated rhabdomyolysis. www.fda.gov/ downloads/Drugs/DrugSafety/Drug S a f e t y Ne w s l e t t e r / u c m 1 0 9 1 7 8 . p d f (accessed 2013 Aug 26). 3. Karimi S, Hough A, Beckey C et al. Results of a safety initiative for patients on concomitant amiodarone and simvastatin therapy in a Veterans Affairs medical center. J Manag Care Pharm. 2010; 16:472-81.

4. Borders-Hemphill V. Concurrent use of statins and amiodarone. Consult Pharm. 2009; 24:372-9. 5. Bates DW. CPOE and clinical decision support in hospitals: getting the benefits. Arch Intern Med. 2010; 170:1578-83. 6. Beckman MG, Hooper WC, Critchley SE et al. Venous thromboembolism: a public health concern. Am J Prev Med. 2010; 38:S495-501. 7. De Lemos JA, Blazing MA, Wiviott SD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004; 292:1307-16. 8. Strom BL, Schinnar R, Aberra F et al. Unintended effects of a computerized physician order entry nearly hard-stop alert to prevent a drug interaction: a randomized controlled-trial. Arch Intern Med. 2010; 170:1578-83.

Rathasen Prom, Pharm.D., Cardiology Clinical Pharmacy Specialist Department of Pharmacy Mission Hospitals 509 Biltmore Avenue Asheville, NC 28801 [email protected]

Craig A. Umscheid, M.D., MSCE, FACP, Assistant Professor of Medicine and Epidemiology and Director, Center for Evidence-Based Practice University of Pennsylvania Philadelphia, PA Nishaminy Kasbekar, B.S., Pharm.D., FASHP, Director of Pharmacy Department of Pharmacy PENN Presbyterian Medical Center Philadelphia, PA Sarah A. Spinler, Pharm.D., FCCP, FAHA, FASHP, AACC, BCPS (AQ-Cardiology), Professor of Clinical Pharmacy Department of Pharmacy Practice and Pharmacy Administration Philadelphia College of Pharmacy University of the Sciences Philadelphia, PA

Dr. Spinler has received consulting fees from Bristol-Myers Squibb. The remaining authors have declared no potential conflicts of interest. DOI 10.2146/ajhp120553

Workshop on the challenges in substitution of nonbiological complex drugs

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ver recent years, nonbiological complex drugs (NBCDs) such as iron carbohydrate complexes for i.v. use, heterogeneous polypeptide mixtures as immunomodulators, and liposomes have been approved by established regulatory rules.1 However, approval and handling of follow-on products comprise an unexpected challenge to regulators, prescribing physicians, and dispensing pharmacists. Biosimilar pathways designed for biologicals cannot be applied to nonbiologicals by definition, and the abridged pathway for generics of small molecules is not appropriate. As clinical cases are emerging, questioning the therapeutic equivalence of NBCD follow-on products, regulatory experts from industry and academia and other authorities at the 2012 International Pharmaceutical Federation Congress discussed how to adjust the regulatory environment.

NBCDs consist of mixtures of closely related structures. Possible slight modifications in structure and their clinical meaning are not understood. Therefore, a full characterization by analytic means is not sufficient. As a consequence, proof of identity, a prerequisite of generic approval, is precluded. Furthermore, the biologic activity of an NBCD often depends on target tissue disposition and the release of active substructures rather than classical pharmacokinetics of the drug substance. In addition, it is possible that both disposition and release are modulated by underlying diseases. Thus, a basic comparison of pharmacokinetics in healthy volunteers, the second pillar of proving a generic’s therapeutic equivalence, seems insufficient for an NBCD follow-on candidate. Accordingly, the experts at the NBCD workshop concluded that the generic

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pathway is not applicable for the approval of NBCD follow-on products. Therapeutic equivalence should be evaluated by a “biosimilarlike” approach including nonclinical and clinical tests. The challenge of substitution with NBCD follow-on compounds has been exemplified with comparative clinical and nonclinical data of the originator product iron sucrose (Venofer, American Regent, Shirley, NY), a well-established i.v. iron complex used to treat iron deficiency and anemia, and different follow-on preparations (iron sucrose similars). 2-6 The first clinical evidence showing that iron sucrose similar products are not therapeutically equivalent to the originator product was found in stable, hemodialysis-dependent patients with chronic kidney disease.3 After being switched from the iron sucrose originator to an iron sucrose similar product, patients’ hemoglobin levels decreased rapidly, and anemia medication dosages needed to be increased. Since then, further reports showed a higher risk of adverse reactions to an iron sucrose similar product compared with the originator,4 even in patients who previously tolerated the originator.5 Nonclinical comparisons of originator iron sucrose and different iron sucrose similar products showed significant off-target iron disposition from the similar products as well as associated induction of oxidative stress and inflammation markers that may explain the different tolerability profiles.6 Notably, in two of the abovementioned reports,3,5 iron sucrose preparations were substituted by the pharmacist without informing the prescribing physician. Since substitution is common practice with approved generics, reports citing clinical differences between different iron sucrose preparations confirm the need for comparative clinical tests to prove therapeutic equivalence and safety comparability of follow-on NBCDs with reference products before granting market approval. Driven by the evidence about differences between originator and follow-on products, the European Medicines Agency and the Food and Drug Administra-

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tion independently drafted guidance on iron nanoparticles.7,8 Overall, a better understanding of NBCDs and the clinical implications of interchange and substitution is warranted. Substitution of NBCDs without involvement of the prescribing physicians is discouraged. 1. Schellekens H, Klinger E, Mühlebach S et al. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011; 59:176-83. 2. Borchard G, Flühmann B, Mühlebach S. Nanoparticle iron medicinal products— requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol. 2012; 64:324-8. 3. Rottembourg J, Kadri A, Leonard E et al. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant. 2011; 26:3262-7. 4. Lee ES, Park BR, Kim JS et al. Comparison of adverse event profile of intravenous iron sucrose and iron sucrose similar in postpartum and gynecologic operative patients. Curr Med Res Opin. 2013; 29:141-7. 5. Stein J, Dignass A, Chow KU. Clinical case reports raise doubts about the therapeutic equivalence of an iron sucrose similar preparation compared with iron sucrose originator. Curr Med Res Opin. 2012; 28:241-3. 6. Toblli JE, Cao G, Oliveri L et al. Differences between original intravenous iron sucrose and iron sucrose similar preparations. Drug Res. 2009; 59:176-90. 7. European Medicines Agency. Reflection paper on non-clinical studies for generic nanoparticle iron medicinal product applications. www.ema.europa.eu/docs/ en_GB/document_library/Scientific_ guideline/2011/04/WC500105048.pdf (accessed 2012 Aug 17). 8. Food and Drug Administration. Draft guidance on iron sucrose (Mar 2012). w w w. f d a . g o v / d ow n l o a d s / D r u g s /

GuidanceComplianceRegulator y Information/Guidances/UCM297630.pdf (accessed 2013 May 20).

Vinod P. Shah, Ph.D., Pharmaceutical Consultant North Potomac, MD Arnold G. Vulto, Ph.D., Professor of Hospital Pharmacy and Practical Therapeutics and Deputy Head, Hospital Pharmacy Erasmus University Medical Center Rotterdam, Netherlands Stefan Mühlebach, Ph.D., Scientific Director Vifor Pharma Ltd. Flughofstrasse 61 P.O. Box CH-8152 Glattbrugg, Switzerland [email protected]

Dr. Shah is Steering Committee Member of the Non-Biological Complex Drugs Working Group, Regulatory Sciences Special Interest Group of the International Pharmaceutical Federation. Dr. Mühlebach is Chair and Steering Committee Member of the Non-Biological Complex Drugs Working Group. Medical writing support by SFL Regulatory Affairs and Scientific Communication, Basel, Switzerland (funded by Vifor Pharma). Dr. Mühlebach is an employee of Vifor Pharma Ltd. The authors have declared no other potential conflicts of interest. DOI 10.2146/ajhp130141

An interdisciplinary approach to determine schistosomiasis prevalence and administer praziquantel to school-age children in Tanzania

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our students at the James L. Winkle College of Pharmacy, accompanied by a faculty member, traveled to Tanzania on an elective ambulatory care advanced pharmacy practice experience rotation to learn, provide care, and implement

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

a schistosomiasis project in the village of Burere. We were part of a Village Life Outreach Project team that also included a U.S.-trained physician, an internal medicine resident, two nursing students, a nursing faculty member, and translators.

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Workshop on the challenges in substitution of nonbiological complex drugs.

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