Letters
showing excellent agreement between the raters. Given the lack of other tools and research in the area of clinical pharmacy service evaluation, this assessment tool is a preliminary step in designing a method for evaluation. Preliminary evidence suggests that this tool may provide affiliated institutions a reliable means to evaluate faculty members, thereby strengthening relationships with colleges of pharmacy and documenting the faculty member’s overall performance. 1. Ray MD, Boucher BA. Strengthening relationships between pharmacy faculty members and clinical training sites. Am J Health-Syst Pharm. 2010; 67:1558-62. 2. Burke JM, Miller WA, Spencer AP et al. Clinical pharmacist competencies. Pharmacotherapy. 2008; 28:806-15.
3. American Society of Health-System Pharmacists. ASHP statement on professionalism. Am J Health-Syst Pharm. 2008; 65:172-4.
Joe D. Strain, Pharm.D., Associate Professor of Pharmacy Practice Pharmacy Department South Dakota State University 353 Fairmont Boulevard Rapid City, SD 57702 [email protected] Debra K. Farver, Pharm.D., Professor of Pharmacy Practice South Dakota State University Yankton, SD
yopathy and rhabdomyolysis resulting from the coadministration of simvastatin and amiodarone have previously been described.1,2 To minimize this risk, FDA has limited the maximum dosage of simvastatin to 20 mg daily when coadministered with amiodarone.2 However, doses of simvastatin 40 and 80 mg daily are still commonly coprescribed with amiodarone in practice.3,4 Computerized provider order entry may offer a solution to this problem by providing alerts to prescribers regarding drug–drug interactions (DDIs) at order entry.5 The original DDI alert for the interaction between amiodarone and simvastatin at our study site contained 299 words, and providers had to scroll past extraneous background information to view the available management recommendations. A more-efficient dose-specific alert was developed and implemented on July 5, 2011. The revised DDI alert contained 14 words and provided recommendations about drug management. This alert was a hard stop, so providers could not pro-
1878
Olayinka O. Shiyanbola, Ph.D., Assistant Professor of Pharmacy Practice South Dakota State University Sioux Falls, SD The assistance of Jeffrey C. Delafuente, M.S., FCCP, FASCP, is acknowledged. The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp120462
Jodi R. Heins, Pharm.D., Assistant Department Head and Professor of Pharmacy Practice South Dakota State University Sioux Falls, SD
Effect of simvastatin–amiodarone drug interaction alert on appropriate prescribing
M
Jane R. Mort, Pharm.D., Associate Dean for Academic Programs South Dakota State University Brookings, SD
ceed past the alert without changing the order. The electronic records of 40 consecutive patients who were admitted to a 60-bed cardiology service for a twomonth intervention period (August 28 to November 5, 2011) were compared with those of 43 consecutive patients admitted to the same units during a twomonth baseline period (March 1 to April 30, 2011). There was a four-month gap between study periods to allow for staff education about the revised alert. Electronic records were eligible for evaluation if the patient had concomitant orders for amiodarone and any statin. The primary endpoint was the percentage of appropriate simvastatin orders entered for patients also receiving amiodarone. An appropriate order was defined as an order for simvastatin of ≤20 mg/day for the original alert and ≤10 mg/day for the revised alert. The dosage limits for simvastatin were different for the original and the revised alerts because, in June 2011, FDA changed the maximum recommended dosage of simvastatin when
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
coprescribed with amiodarone to 10 mg daily.6 Although FDA subsequently changed the maximum recommended dosage of simvastatin back to 20 mg daily when coprescribed with amiodarone in October 2011, 10 mg daily was the FDArecommended dosage during our intervention period. The rates of musclerelated adverse effects, including muscle pain, myopathy, and rhabdomyolysis, were also evaluated. Student’s t test was used to compare continuous variables. Categorical variables were analyzed using Fisher’s exact test. The a priori level of significance was 0.05. Baseline characteristics were similar between groups, except for ventricular arrhythmia, which was more common in the control group (58% versus 18%, p < 0.001). Simvastatin orders were appropriate for all 10 patients in the intervention group for whom simvastatin and amiodarone were coprescribed, compared with 9 (56%) of 16 patients in the control group (p = 0.02). Among the 44% of inappropriate simvastatin orders in the control group, 43% were subsequently changed to an appropriate order during the patients’ hospitalization. One hundred percent of orders in the intervention group for any statin coad-
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
O
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
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
1879
showing excellent agreement between the raters. Given the lack of other tools and research in the area of clinical pharmacy service evaluation, this assessment tool is a preliminary step in designing a method for evaluation. Preliminary evidence suggests that this tool may provide affiliated institutions a reliable means to evaluate faculty members, thereby strengthening relationships with colleges of pharmacy and documenting the faculty member’s overall performance. 1. Ray MD, Boucher BA. Strengthening relationships between pharmacy faculty members and clinical training sites. Am J Health-Syst Pharm. 2010; 67:1558-62. 2. Burke JM, Miller WA, Spencer AP et al. Clinical pharmacist competencies. Pharmacotherapy. 2008; 28:806-15.
3. American Society of Health-System Pharmacists. ASHP statement on professionalism. Am J Health-Syst Pharm. 2008; 65:172-4.
Joe D. Strain, Pharm.D., Associate Professor of Pharmacy Practice Pharmacy Department South Dakota State University 353 Fairmont Boulevard Rapid City, SD 57702 [email protected] Debra K. Farver, Pharm.D., Professor of Pharmacy Practice South Dakota State University Yankton, SD
yopathy and rhabdomyolysis resulting from the coadministration of simvastatin and amiodarone have previously been described.1,2 To minimize this risk, FDA has limited the maximum dosage of simvastatin to 20 mg daily when coadministered with amiodarone.2 However, doses of simvastatin 40 and 80 mg daily are still commonly coprescribed with amiodarone in practice.3,4 Computerized provider order entry may offer a solution to this problem by providing alerts to prescribers regarding drug–drug interactions (DDIs) at order entry.5 The original DDI alert for the interaction between amiodarone and simvastatin at our study site contained 299 words, and providers had to scroll past extraneous background information to view the available management recommendations. A more-efficient dose-specific alert was developed and implemented on July 5, 2011. The revised DDI alert contained 14 words and provided recommendations about drug management. This alert was a hard stop, so providers could not pro-
1878
Olayinka O. Shiyanbola, Ph.D., Assistant Professor of Pharmacy Practice South Dakota State University Sioux Falls, SD The assistance of Jeffrey C. Delafuente, M.S., FCCP, FASCP, is acknowledged. The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp120462
Jodi R. Heins, Pharm.D., Assistant Department Head and Professor of Pharmacy Practice South Dakota State University Sioux Falls, SD
Effect of simvastatin–amiodarone drug interaction alert on appropriate prescribing
M
Jane R. Mort, Pharm.D., Associate Dean for Academic Programs South Dakota State University Brookings, SD
ceed past the alert without changing the order. The electronic records of 40 consecutive patients who were admitted to a 60-bed cardiology service for a twomonth intervention period (August 28 to November 5, 2011) were compared with those of 43 consecutive patients admitted to the same units during a twomonth baseline period (March 1 to April 30, 2011). There was a four-month gap between study periods to allow for staff education about the revised alert. Electronic records were eligible for evaluation if the patient had concomitant orders for amiodarone and any statin. The primary endpoint was the percentage of appropriate simvastatin orders entered for patients also receiving amiodarone. An appropriate order was defined as an order for simvastatin of ≤20 mg/day for the original alert and ≤10 mg/day for the revised alert. The dosage limits for simvastatin were different for the original and the revised alerts because, in June 2011, FDA changed the maximum recommended dosage of simvastatin when
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
coprescribed with amiodarone to 10 mg daily.6 Although FDA subsequently changed the maximum recommended dosage of simvastatin back to 20 mg daily when coprescribed with amiodarone in October 2011, 10 mg daily was the FDArecommended dosage during our intervention period. The rates of musclerelated adverse effects, including muscle pain, myopathy, and rhabdomyolysis, were also evaluated. Student’s t test was used to compare continuous variables. Categorical variables were analyzed using Fisher’s exact test. The a priori level of significance was 0.05. Baseline characteristics were similar between groups, except for ventricular arrhythmia, which was more common in the control group (58% versus 18%, p < 0.001). Simvastatin orders were appropriate for all 10 patients in the intervention group for whom simvastatin and amiodarone were coprescribed, compared with 9 (56%) of 16 patients in the control group (p = 0.02). Among the 44% of inappropriate simvastatin orders in the control group, 43% were subsequently changed to an appropriate order during the patients’ hospitalization. One hundred percent of orders in the intervention group for any statin coad-
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
O
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
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
1879
