R E V I E W S & A N A LY S E S An Analysis of Reported Adverse Drug Reactions Michael O’Connor, PharmD, MS INTRODUCTION Patient Safety Analyst Matthew Grissinger, RPh, FISMP, FASCP There are various published definitions for adverse drug reactions (ADRs) currently Manager, Medication Safety Analysis being used in practice and published in the literature. The World Health Organization Pennsylvania Patient Safety Authority defines ADRs as “any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, ABSTRACT or for the modification of physiological function.”1 Past research has shown that both the The American Society of Health-System Pharmacists (ASHP) expands upon this defini- incidence and severity of adverse drug tion by stating that an ADR is “any unexpected, unintended, undesired, or excessive reactions (ADRs) are significant. The response to a drug that requires discontinuing the drug (therapeutic or diagnostic), American Society of Health-System requires changing the drug therapy, requires modifying the dose (except for minor dos- Pharmacists (ASHP) has published age adjustments), necessitates admission to a hospital, prolongs stay in a health care guidelines on ADR monitoring and facility, necessitates supportive treatment, significantly complicates diagnosis, negatively reporting. As a part of these guidelines affects prognosis, or results in temporary or permanent harm, disability, or death.”2 for pharmacists, ASHP states that any There are two major types of ADRs, type A and type B. Type A reactions are related to ADR program should include “evaluat- the pharmacological action of the drug and are typically predictable. Type B reactions ing, documenting, and reporting ADRs are not related to the pharmacological action of the drug, are typically unpredictable, as well as intervening and providing and are frequently classified as either immune-mediated or idiosyncratic reactions.3 educational feedback to prescribers, other health care professionals, and Past research has shown that both the incidence and severity of ADRs are significant.3-5 patients.” Over a 12-month period, A study published in 19984 sought to describe the overall incidence of ADRs and Pennsylvania hospitals reported serious ADRs occurring in US hospitals by evaluating previously published literature. 4,875 reports through the Pennsylvania The overall incidence of ADRs for hospitalized patients was 15.1%. A 2005 study Patient Safety Authority’s Pennsylvania completed in the United Kingdom5 evaluated the incidence of ADRs on medical and Patient Safety Reporting System describ- surgical wards. Over a six-month time period, 14.7% of hospitalized patients experi- ing ADRs. Nearly 30% (n = 1,365) of enced at least one ADR. Additionally, ADRs directly increased the length of stay for these reports described ADRs to contrast 147 patients during this same six-month time period. In order to address the significant agents, which are considered high-alert impact that ADRs may have on patients, ASHP published guidelines on ADR monitor- medications by the Institute for Safe ing and reporting in 2009.2 As a part of these guidelines for pharmacists, ASHP states Medication Practices. Other high-alert that any ADR program should include “evaluating, documenting, and reporting ADRs agents that were frequently reported as well as intervening and providing educational feedback to prescribers, other health include opioids, taxane derivatives, care professionals, and patients.” platinum analogs, warfarin, and insu- Analyses of ADRs reported by Pennsylvania healthcare facilities to the Pennsylvania lin. While many of the ADRs reported Patient Safety Authority have identified the most common agents associated with to the Authority could not have been ADRs in Pennsylvania. While many of the reported events appear to have been unpre- prevented, there are strategies that can ventable, there are strategies that can be implemented to reduce the risk and severity be utilized to reduce the incidence and of patient harm for several of the most common agents involved in ADRs reported to severity for a portion of these ADRs. the Authority. These strategies may include appropri- ate premedication regimens, providing METHODS clear instructions for the administration of medications with complicated infu- Authority analysts queried the Authority’s Pennsylvania Patient Safety Reporting Sys- sion rate titrations, ensuring thorough tem database for reports of ADRs submitted over a 12-month period, from November patient medication and allergy histories 2012 through October 2013. Pennsylvania hospitals reported 4,875 events describing are completed, and improving the qual- ADRs during this time. Analysts manually reviewed the reported ADRs to determine ity of ADR reports within healthcare the medication(s) involved in the reported event as well as other contributing factors. organizations. (Pa Patient Saf Advis When the medication name field was left blank but the name of the suspected medica- 2014 Jun;11[2]:61-8.) tion was provided in the event description, the medication name field was adjusted. The analysts determined, when possible, if an ADR could have been prevented. Corresponding Author Analysts made note of ADRs involving high-alert medications, based on ISMP’s List of Matthew Grissinger High-Alert Medications.6 Vol. 11, No. 2—June 2014 Pennsylvania Patient Safety Advisory Page 61 ©2014 Pennsylvania Patient Safety Authority R E V I E W S & A N A LY S E S ANALYSIS Table. Predominant Medications in Adverse Drug Reaction Events Reported to the Pennsylvania Patient Safety Authority, November 2012 through October 2013 (N = 4,875) The Table displays the medications, NO. OF % OF TOTAL or medication classes, most frequently MEDICATION OR MEDICATION CLASS EVENTS EVENTS involved in the reported ADRs. Nearly 30% (n = 1,365) of the ADRs reported to Contrast* 1,365 28.0 the Authority were for contrast agents. A Opioids* 416 8.5 discussion of the most frequently reported Fluoroquinolones 300 6.1 ADRs, as well as those that may be pre- Vancomycin 250 5.1 ventable, follows. RiTUXimab* 235 4.8 Taxane derivatives* 219 4.5 Contrast Platinum analogs* 199 4.1 The majority of contrast-related reports (n = 851, 62.3%) described reactions that Cephalosporins 136 2.8 are consistent with product labeling for Chlorhexidine 64 1.3 contrast agents. These reactions included Intravenous immune globulin 62 1.3 headache, nausea, vomiting, itching, rash, Warfarin* 62 1.3 and sensation of heat. More severe reac- Insulin* 58 1.2 tions included throat tightness, swelling, shortness of breath, and anaphylaxis. Unknown 281 5.8 There were 484 instances (35.5%) of more * A high-alert medication severe reactions reported to the Authority. For 30 (2.2%) of the reports, the type of reaction could not be determined due to One trend that emerged through analysis Dermatologic reactions were the most a lack of information. The Figure displays of the opioid-related ADRs was the use of frequently reported ADRs for fluoro- the specific products involved in the ADRs naloxone. In 136 (32.7%) of the reported quinolones (ciprofloxacin, levofloxacin, reported to the Authority by trade name. ADRs with the causative agent being one and moxifloxacin), accounting for or more opioids, naloxone was admin- 268 (89.3%) of the reports. In 130 (9.5%) of the reported contrast- istered to the patient due to the level of There were four instances of documented related reactions, the patient had a sedation. Examples of reported ADRs cardiac rhythm abnormalities as detected documented history of an allergy to a that involved the administration of nalox- on electrocardiogram (prolonged QT contrast agent. In these cases in which an one include the following: interval or ventricular tachycardia). In allergy was present prior to administration of contrast, the use of a premedication Patient on fentaNYL patch, post-op these instances, no other medications protocol was documented in 106 (81.5%) from bowel resection, was found to known to cause these changes were of these cases. be less responsive than last night per included in the event description or as a [registered nurse]. The patient was suspected medication. An event reported Opioids giving one-word or short-sentence to the Authority involving prolongation of answers to questions when stimulated. the QT interval is as follows: There were a total of 416 reports (8.5%) Naloxone was given with an Patient was admitted to the medical- for ADRs with opioids, including reactions appropriate response. surgical unit with acute bronchitis to the following medications: butorphanol, codeine, fentaNYL, hydrocodone- Patient was admitted for severe and dyspnea. Patient started on moxi- acetaminophen, HYDROmorphone, pain and received three doses of floxacin 400 mg IV [intravenous] meperidine, morphine, nalbuphine, HYDROmorphone 2 mg [over a daily and received one dose in the oxyCODONE, oxyCODONE- six-hour period]. Patient was found to evening and a second dose the next acetaminophen, and tapentadol. The be hypoxic and drowsy and received morning. Repeat electrocardiograms on event descriptions revealed a variety of 0.04 mg of naloxone with relief. subsequent days showed a prolonged reactions, ranging from generalized itching QT interval from baseline. Moxifloxa- and rash to shortness of breath, excess Fluoroquinolones cin stopped after the second dose. sedation, and respiratory depression. Fluoroquinolones were cited in The results of a recently published case- 300 (6.1%) of the reported ADRs. control study indicated that there is an Page 62 Pennsylvania Patient Safety Advisory Vol. 11, No. 2—June 2014 ©2014 Pennsylvania Patient Safety Authority Figure. Products Involved in Contrast-Related Adverse Drug Reaction Events Reported to the Pennsylvania Patient Safety Authority, November 2012 through October 2013 (N = 1,365) NO. OF EVENT REPORTS 400 354 350 302 300 247 250 200 156 150 100 53 52 50 48 50 30 29 17 8 7 6 2 2 1 1 0 e® ce ® t® t® e® ist ® ity ® in ® t® r® w® e™ n y™ ™ ™ ™ k™ ow vis vis vis va ue an in vu nc vie ira af ar qu av fin an ur kn la ne tra Eo aq sc Iso Ha gr im tro ad pt De pa az tiH Ab Un ni ag Ul tro sip O pt o ph G as ni m ul Pr M O as Vi m O G m M G O Ly MS14244 CONTRAST PRODUCT increased risk of hepatotoxicity associ- Examples of these event reports are polyarteritis nodosa, and Wegener granu- ated with exposure to fluoroquinolones.7 as follows: lomatosis. RiTUXimab was involved in There was one possible case of hepato- [There was a] likely nephrotoxic 235 (4.8%) of the reported ADRs. toxicity due to ciprofloxacin reported to accumulation of vancomycin after The types of reactions reported for the Authority. In this report, there were following the protocol. A patient riTUXimab were consistent with those no other medications listed as a possible received a 2 g load then 1.5 g IV that are reported in the prescribing cause of hepatotoxicity, but there were not every 12 hours. The vancomycin level information for the product.8 Infusion enough details provided in the report to after four days was 100, and serum reactions consisted of itching, chills, definitively state that ciprofloxacin was creatinine went from 0.7 to 1.8. rigors, hives, nausea, vomiting, and dia- the causative agent. phoresis. The prescribing information Patient had been on vancomycin [for for riTUXimab contains a boxed warning 10 days before a vancomycin trough Vancomycin stating that severe and fatal infusion reac- was drawn]. The patient’s serum tions may occur with riTUXimab. Serious Overall, 250 (5.1%) of the ADR events creatinine began to climb and went involved vancomycin. Infusion reactions infusion reactions reported included from 0.9 to 1.4. On [the 10th day of hypotension, chest pain, angioedema, (e.g., rash, itching, redness of the skin) therapy], the trough was drawn and accounted for 208 (83.2%) of the hypoxia, and anaphylactic reactions. These the [vancomycin] level was 56. reactions occurred in 94 (40.0%) of the vancomycin-related ADRs reported to the Authority. There were several reported riTUXimab-related ADR reports submit- RiTUXimab ted to the Authority. ADRs in which the patient’s renal function worsened during the course of RiTUXimab is a monoclonal antibody Based on the prescribing information, a vancomycin therapy (n = 14, 5.6%). that is approved by the US Food and Drug premedication regimen consisting of an Administration to treat non-Hodgkin antihistamine and acetaminophen should lymphoma, chronic lymphocytic leuke- be initiated prior to the infusion.8 There mia, rheumatoid arthritis, microscopic were examples for which the administration Vol. 11, No. 2—June 2014 Pennsylvania Patient Safety Advisory Page 63 ©2014 Pennsylvania Patient Safety Authority R E V I E W S & A N A LY S E S of premedication, as recommended in that there is data to support the use of organs arrived to the infusion center the prescribing information, was docu- premedications to prevent and minimize for chemotherapy. During oxaliplatin mented in the event description; however, hypersensitivity reactions.9,10 There were infusion, the patient developed facial other reports lacked this information. examples of cases for which premedica- flushing. The flushing became severe. Examples of these event reports are tions were listed in the event description Drug [oxaliplatin] stopped and methyl- as follows: and cases for which there was no mention PREDNISolone sodium succinate Patient having first riTUXimab of the administration of these premedica- 125 mg IVP, diphenhydrAMINE infusion. Infusion started at tions. Reports for each of these scenarios 25 mg IVP, and levalbuterol treat- 50 mL/hr increments. When rate are included as follows: ment given. Symptoms resolved. increased to 150 mL/hr, the patient [The patient] had less than ¼ of his Patient rechallenged at slower rate started to complain of feeling cold ordered PACLitaxel dose for this date without any further issues. and then developed chills. Infusion when [the patient] had complaints of The majority of hypersensitivity reactions stopped. Normal saline running. back pain. [The patient] was given that occur with these agents develop after Physician and pharmacist were NSS [normal saline solution] and frequent treatment. Multiple studies called. MethylPREDNISolone hydrocortisone. The patient had been have shown that the risk of hypersensitiv- sodium succinate 100 mg IVP [IV pretreated with dexamethasone and ity reactions increases with subsequent push], meperidine 25 mg IVP, and diphenhydrAMINE and still reacted. courses of therapy with these agents.11,12 diphenhydrAMINE 25 mg IVP CARBOplatin was able to be started were all given. Rigors stopped after as planned and was completed. The Cephalosporins approximately 10 minutes. Infusion patient was able to tolerate it with no Cephalosporins were involved in restarted at 50 mL/hr after approxi- issues and was discharged after it was 136 (2.8%) of the ADR events. The mately one hour. completed. majority of the reactions seen with Patient here for first R-CHOP DOCEtaxel had been infusing for cephalosporins (n = 102, 75.0%) were der- [riTUXimab, cyclophosphamide, about an hour when the patient matologic in nature (e.g., rash, red skin, DOXOrubicin, vinCRIStine, predni- began feeling flush. Infusion was itching) and hives. Previous studies have SONE], premedicated. RiTUXimab stopped and emergency medications shown that there is a small percentage of started. Patient complained of “itchy provided. The physician was made patients who will experience a reaction to throat.” RiTUXimab was stopped, aware and evaluated [the patient]. a cephalosporin if there is a documented and additional diphenhydrAMINE Once symptoms subsided, the infu- history of penicillin allergy.13,14 There 25 mg and methylPREDNISolone sion was resumed and tolerated were eight instances in which the patient sodium succinate 100 mg given IVP. without any further difficulty. No had a documented penicillin allergy. The [Patient] returned to baseline and harm to patient. reactions for these patients were hives riTUXimab restarted [two hours (five cases), redness of the skin (one case), later]. [Infusion] completed with no Platinum Analogs shortness of breath (one case), and swell- further problems. Analysts identified that platinum analogs ing of the tongue (one case). were implicated in 199 (4.1%) of the Taxane Derivatives reported ADRs. Platinum analogs are Chlorhexidine Taxane derivatives are used to treat a currently used to treat a variety of types Chlorhexidine is a topical product that is variety of cancers. Overall, taxane deriva- of cancer. The reactions reported to the used as a part of infection prevention prac- tives were cited in 219 (4.5%) of the ADR Authority for this group of medications tices in many hospitals and health systems. events. The ADRs for PACLitaxel and (CARBOplatin, CISplatin, oxaliplatin) All of the reports (n = 64) submitted to DOCEtaxel were consistent with previ- were consistent with those reported in the Authority for chlorhexidine described ously published reactions. The majority of previous studies. These consisted of rash, dermatologic reactions (e.g., redness, itch- the reports described mild reactions (e.g., itching, hives, flushing, and shortness of ing, rash). rash, flushing, pruritus, fever), but several breath. An example of a reaction to oxali- severe reactions (e.g., hypotension, angio- platin is as follows: Intravenous Immune Globulin edema, bronchospasm) were also reported. Outpatient with a diagnosis of Analysts identified 62 (1.3%) ADR events When analyzing reactions for these metastatic colon adenocarcinoma with that involved intravenous immune globu- medications, it is important to note metastases to lung and reproductive lin (IVIG). The events reported to the Page 64 Pennsylvania Patient Safety Advisory Vol. 11, No. 2—June 2014 ©2014 Pennsylvania Patient Safety Authority Authority described ADRs that consisted provided in the reports (e.g., insulin For several of the aforementioned events, of itching, flushing, chills, fever, nausea, product, dose, time of dose admin- there are mitigation strategies that can be and diaphoresis. While the majority of istration) to determine causality or utilized to reduce the incidence and sever- the reports described these mild infu- contributing factors for these reports. ity of patient harm. In many of the ADRs sion reactions, there were several that An example of this type of event report reported to the Authority, there was not described more severe reactions following is as follows: enough information included to deter- infusion of an IVIG product. An example Patient on insulin drip with titra- mine the specific medication involved in of a severe infusion reaction is as follows: tion accuchecks being done every the ADR, the type of reaction, or if the Patient in for immune globulin hour. [Most recent] accucheck was event may have been preventable. infusion. Premedications given and 60. Patient was nonverbal with no Potential risk reduction strategies include infusion started at 25 mL/hr, with physical symptoms noted. Physician the following: max rate calculated at 150 mL/hr. aware, patient given ½ amp of D50 Rate increased to 50 mL/hr per proto- [Dextrose 50%]. Contrast col [with] vital signs stable. Evaluated —— The American College of Radiol- patient prior to next rate increase, Unknown ogy (ACR)16 offers several elective and noted change in respiratory rate. There were a total of 281 (5.8%) ADR premedication regimens to be given Patient reported difficulty breathing reports in which the suspected medica- prior to contrast for patients with a and chest tightness. Infusion stopped tion, or medication class, could not be documented allergy: and the doctor evaluated the patient. determined. In these events, multiple PredniSONE 50 mg by Patient nebulizer activated and emer- medications from different classes were mouth at 13 hours, 7 hours, gency medications given per physician. listed as possible causative agents. and 1 hour before contrast Oxygen increased to 15 L/minute. media injection, plus diphen- Patient received diphenhydrAMINE RISK REDUCTION STRATEGIES hydrAMINE 50 mg IV, 25 mg IV, hydrocortisone sodium intramuscularly, or by mouth When evaluating events involving medica- succinate 100 mg IV, and methyl- 1 hour before contrast medium. tions, it is important for organizations PREDNISolone sodium succinate MethylPREDNISolone 32 mg to focus on those that may be prevented 100 mg IV. Vital signs improved, and by mouth 12 hours and 2 hours or minimized. There are several ques- the patient [was transferred] to hospi- before contrast media injection. tions that can be used to help determine tal in stable condition. An antihistamine (e.g., diphen- whether or not an ADR could have been prevented.15 A listing of such questions hydrAMINE) may also be added Warfarin can be found in “Criteria for Determining to this regimen. All of the ADR reports (n = 62) submitted Preventability of an ADR.” to the Authority for warfarin revealed an elevated international normalized ratio (INR). There were not enough details CRITERIA FOR DETERMINING PREVENTABILITY OF AN ADR (e.g., dose, duration of therapy) provided Answering “yes” to one or more of the following suggests that at an adverse drug in the event descriptions to determine reaction (ADR) is preventable: causality or contributing factors for these ——  Was the medication involved inappropriate for the patient’s clinical condition? reports. An example of a reported ADR for warfarin is as follows: ——  Was the dose, route, or frequency of administration of the medication inappro- priate for the patient’s age, weight, or disease state? Vitamin K administered to patient ——  Was required therapeutic drug monitoring or another necessary laboratory test due to elevated INR levels (repeat not performed? levels drawn x1). Patient on ——  Was there a history of allergy or previous reactions to the medication? Coumadin 1 mg to 7.5 mg. ——  Was a drug interaction involved in the ADR? Insulin ——  Was a toxic serum drug concentration (or laboratory monitoring test) documented? All of the ADR reports (n = 58) submit- ——  Was poor adherence involved in the ADR? ted to the Authority for insulin therapy Source: Schumock GT, Thornton JP Focusing on the preventability of adverse drug reactions. Hosp . described patients with low blood glucose Pharm 1992 Jun;27(6):538. values. There were not enough details Vol. 11, No. 2—June 2014 Pennsylvania Patient Safety Advisory Page 65 ©2014 Pennsylvania Patient Safety Authority R E V I E W S & A N A LY S E S —— When time does not allow for either RiTUXimab proper premedication regimens are of the regimens listed above, ACR —— Ensuring that protocols are in place included. Studies have shown that offers the following for patients with for riTUXimab infusions that address the incidence and severity of hyper- a documented allergy to contrast:16 premedication, management of infu- sensitivity reactions can be reduced MethylPREDNISolone sodium sion reactions, and infusion rates. by administering corticosteroids and succinate 40 mg or hydrocorti- —— Premedicating patients before each antihistamines prior to treatment sone sodium succinate 200 mg riTUXimab infusion with an antihis- with taxane derivatives.9,10 IV every 4 hours until contrast tamine and acetaminophen.8 study is required, plus diphen- Platinum Analogs —— For the first riTUXimab infusion, hydrAMINE 50 mg IV 1 hour initiating the infusion at a rate of —— Ensuring that appropriate treatment prior to contrast injection. 50 mg/hr and then increasing the for hypersensitivity reactions for Omit steroids entirely and give infusion rate by 50 mg/hr incre- CARBOplatin, CISplatin, and oxali- diphenhydrAMINE 50 mg IV. ments every 30 minutes (in the platin is included in protocols for absence of an infusion reaction), to a these agents. Consider establishing IV steroids have not been shown maximum of 400 mg/hr.8 clear guidelines for the treatment to be effective in preventing of these hypersensitivity reactions ADRs with contrast when —— For subsequent riTUXimab infusions, (e.g., corticosteroids, antihistamines). administered less than 4 to initiating the infusion at a rate of 6 hours before contrast injection. 100 mg/hr and then increasing the Intravenous Immune Globulin —— While the ADRs reported to rate by 100 mg/hr increments every —— Ensuring that instructions for the the Authority did not reveal any 30 minutes (in the absence of an infusion rates are clearly defined for incidences of contrast-induced infusion reaction), to a maximum staff, as dosing and infusion rates vary nephropathy (CIN), this is a of 400 mg/hr.8 among the different IVIG products concern for patients with certain risk Taxane Derivatives currently on the market. Titration factors.16 See “Risk Factors for the schedules also vary, many of which Development of Contrast-Induced —— Reviewing protocols for PACLitaxel are product specific and included Nephropathy” for a list of risk factors and DOCEtaxel to ensure that in the product-specific prescribing identified by ACR. Developing and reviewing institutional guidelines for the identification and management RISK FACTORS FOR THE DEVELOPMENT OF CONTRAST- of patients at risk for CIN can pre- INDUCED NEPHROPATHY vent or mitigate patient harm. The American College of Radiology suggests that the presence of any of the risk fac- tors listed below may warrant preadministration serum creatinine screening in patients Vancomycin ordered to receive intravascular iodinated contrast agents. Developing tools to assess —— Reviewing institutional guidelines patients for these risk factors can help avoid or identify contrast-induced nephropathy for the administration and therapeu- in order to mitigate patient harm. tic monitoring of vancomycin. ——  Age greater than 60 years —— Ensuring that vancomycin infusions ——  History of renal disease, including the following: are administered over a period of at * Dialysis least one hour to minimize infusion- related reactions. For larger doses * Kidney transplant (e.g., 2 g), the infusion time should * Single kidney be extended to 1.5 to 2 hours.17 * Renal cancer —— Utilizing the published report “Ther- * Renal surgery apeutic Monitoring of Vancomycin in ——  History of hypertension requiring medical therapy Adult Patients” to guide the dosing ——  History of diabetes mellitus and monitoring of vancomycin.17 ——  Use of metFORMIN or metFORMIN-containing medications Source: American College of Radiology. ACR manual on contrast media, version 9 [online]. 2013 [cited 2014 May 6]. http://www.acr.org/quality-safety/resources/contrast-manual Page 66 Pennsylvania Patient Safety Advisory Vol. 11, No. 2—June 2014 ©2014 Pennsylvania Patient Safety Authority information. It is important that these recommendations can also Information about the these are clearly defined for nurses improve the ability of an organiza- response to therapy dechallenge and other healthcare practitioners. tion to utilize its internal ADR data. or rechallenge —— The characteristics of a good case Medication Reconciliation report include the following:18 CONCLUSION —— Reviewing policies and procedures for Description of the event, includ- Although not all ADRs can be prevented, collecting and documenting patient ing the time to onset of signs it is still important for organizations to medications and allergy histories. or symptoms evaluate the medications, or medication —— Ensuring that medication allergies, Suspected and concomitant classes, suspected to be involved with including the type of reaction, are product therapy details, includ- ADRs. In order for organizations to see documented in the patient’s ing over-the-counter medications tangible benefits from ADR reporting medical record. programs, it is important to continually Patient characteristics (e.g., age, review reported ADRs; educate pre- race, sex), baseline condition ADR Reporting Quality scribers, caregivers, and patients about prior to the initiation of therapy, —— In order to improve the ability of suspected ADRs; identify and monitor use of concomitant medications, hospitals and health systems to drugs most likely to cause an ADR; and comorbid conditions, and pres- utilize reported ADRs and ensure implement strategies to minimize the ence of other risk factors that appropriate mitigation strategies incidence and severity of ADRs. By con- Clinical course of the event and tinually assessing the types of ADRs being are used, there are recommenda- patient outcomes (e.g., hospital- reported, reviewing the mitigation strate- tions provided by the US Food and ization, death) gies utilized for medications involved in Drug Administration to improve the quality of reported events for phar- Relevant therapeutic measures these reports, and updating protocols as macovigilance practices.18 If used, and laboratory data, if appropriate necessary, practitioners can likely reduce the incidence and severity of ADRs. NOTES 1. Requirements for adverse reaction reporting. 8. Genentech, Inc. Rituxan® (rituximab) studies. J Allergy Clin Immuno 1989 Geneva (Switzerland): World Health prescribing information [online]. 2013 Feb;83(2 Pt 1):381-5. Organization; 1975. Sep [cited 2014 Apr 21]. http://www. 15. Schumock GT, Thornton JP. Focusing on 2. ASHP guidelines on adverse drug reaction gene.com/download/pdf/rituxan_ the preventability of adverse drug reac- monitoring and reporting. Am J Health- prescribing.pdf tions. Hosp Pharm 1992 Jun;27(6):538. Syst Pharm 1995 Feb 15;52(4):417-9. 9. Trudeau ME, Eisenhauer EA, Higgins 16. American College of Radiology. ACR 3. Edwards IR, Aronson JK. Adverse BP, et al. Docetaxel in patients with meta- manual on contrast media, version 9 drug reactions: definitions, diagnosis, static breast cancer: a phase II study of the [online]. 2013 [cited 2014 May 6]. http:// and management. Lancet 2000 Oct National Cancer Institute of www.acr.org/quality-safety/resources/ 7;356(9237):1255-9. Canada-Clinical Trials Group. J Clin contrast-manual 4. Lazarou J, Pomeranz BH, Corey PN. Oncol 1996;14(2):422-8. 17. Rybak M, Lomaestro B, Rotschafer JC, et Incidence of adverse drug reactions in 10. Verweij J, Clavel M, Chevalier B. Pacli- al. Therapeutic monitoring of vancomycin hospitalized patients. JAMA 1998 Apr taxel (Taxol) and docetaxel (Taxotere): in adult patients: a consensus review of 15;279(15):1200-5. not simply two of a kind. Ann Oncol 1994 the American Society of Health-System 5. Davies EC, Green CF, Taylor S, et al. Jul;5(6):495-505. Pharmacists, the Infectious Diseases Adverse drug reactions in hospital 11. Markman M, Kennedy A, Webster K, et Society of America, and the Society of in-patients: a prospective analysis of al. Clinical features of hypersensitivity Infectious Diseases Pharmacists. Am J 3695 patient-episodes. PLoS ONE reactions to carboplatin. J Clin Oncol 1999 Health Syst Pharm 2009 Jan 1;66(1):82-98. 2009;4(2):e4439. Apr;17(4):1141-5. 18. US Food and Drug Administra- 6. Institute for Safe Medication Practices. 12. Weiss RB. Hypersensitivity reactions. tion. Guidance for industry: good ISMP’s list of high-alert medications Semin Oncol 1992 Oct;19(5):458-77. pharmacovigilance practices and phar- [online]. 2012 [cited 2014 Apr 21]. 13. Apter AJ, Kinman JL, Bilker WB, et al. macoepidemiologic assessment [online]. http://www.ismp.org/Tools/institutional Is there cross-reactivity between penicil- 2005 Mar [cited 2014 Jan 27]. http:// highAlert.asp lins and cephalosporins? Am J Med 2006 www.fda.gov/downloads/regulatory 7. Alshammari TM, Larrat EP, Morrill HJ, et Apr;119(4):354.e11-9. information/guidances/ucm126834.pdf al. Risk of hepatotoxicity associated with 14. Blanca M, Fernandez J, Miranda A, et al. fluoroquinolones: a national case-control Cross-reactivity between penicillins and safety study. Am J Health Syst Pharm 2014 cephalosporins: clinical and immunologic Jan 1;71(1):37-43. Vol. 11, No. 2—June 2014 Pennsylvania Patient Safety Advisory Page 67 ©2014 Pennsylvania Patient Safety Authority R E V I E W S & A N A LY S E S LEARNING OBJECTIVES SELF-ASSESSMENT QUESTIONS —— Identify the medications most The following questions about this article may be useful for internal education and frequently involved in adverse assessment. You may use the following examples or come up with your own questions. drug reaction (ADR) events submit- 1. Which of the following medications, or medication classes, was most frequently ted to the Pennsylvania Patient reported to the Authority as an ADR? Safety Authority. a.Heparin —— Recognize ADRs that may be pre- b.Opioids vented or mitigated. c.Warfarin —— Identify risk reduction strategies that d. Contrast can be implemented as a part of an e. Vancomycin ADR monitoring program. 2. Which of the following is not a question that may help practitioners and organiza- tions determine the preventability of ADRs? a. Was required therapeutic drug monitoring or another necessary laboratory test not performed? b. Was a drug interaction involved in the ADR? c. Was poor adherence involved in the ADR? d. Was a nonformulary medication involved in the ADR? e. Was the medication involved inappropriate for the patient’s clinical condition? 3. For which of the following medications, or medication classes, should the infusion time be extended for larger doses to reduce the risk of adverse effects? a. Platinum analogs b. RiTUXimab c. Vancomycin d. Insulin e. Cephalosporins 4. Which of the following is not a risk factor for the development of contrast-induced nephropathy? a. History of diabetes mellitus b. History of liver disease c. Age greater than 60 years d. Use of metFORMIN or metFORMIN-containing medications e. History of hypertension requiring medical therapy Questions 5 refers to the following case: A patient presented for a planned, outpatient computed tomography scan of the abdomen, with contrast. Shortly after administration of the contrast agent, the patient began complaining of severe itching on both arms and legs. Hives were noted upon physical examination. The imaging procedure was temporarily stopped, and the patient was treated for an allergic reaction. After the reaction was noticed, a note was discovered in the patient’s medical record that described a previ- ous reaction (redness of the skin, hives) to a contrast agent. 5. Which of the following risk reduction strategies may have prevented this reaction? a. Conducting a thorough patient medication and allergy history b. Continuing with the imaging procedure as planned c. Administering 0.9% sodium chloride prior to the imaging procedure d. Considering an alternative contrast agent e. Administering intravenous steroids immediately prior to the imaging procedure Page 68 Pennsylvania Patient Safety Advisory Vol. 11, No. 2—June 2014 ©2014 Pennsylvania Patient Safety Authority PENNSYLVANIA PATIENT SAFETY ADVISORY This article is reprinted from the Pennsylvania Patient Safety Advisory, Vol. 11, No. 2—June 2014. The Advisory is a publication of the Pennsylvania Patient Safety Authority, produced by ECRI Institute and ISMP under contract to the Authority. Copyright 2014 by the Pennsylvania Patient Safety Authority. This publication may be reprinted and distributed without restriction, provided it is printed or distributed in its entirety and without alteration. Individual articles may be reprinted in their entirety and without alteration provided the source is clearly attributed. This publication is disseminated via e-mail. To subscribe, go to http://visitor.constantcontact.com/ d.jsp?m=1103390819542&p=oi. To see other articles or issues of the Advisory, visit our website at http://www.patientsafetyauthority.org. Click on “Patient Safety Advisories” in the left-hand menu bar. THE PENNSYLVANIA PATIENT SAFETY AUTHORITY AND ITS CONTRACTORS The Pennsylvania Patient Safety Authority is an independent state agency created by Act 13 of 2002, the Medical Care Availability and Reduction of Error (Mcare) Act. Consistent with Act 13, ECRI Institute, as contractor for the Authority, is issuing this publication to advise medical facilities of immediate changes that can be instituted to reduce Serious Events and Incidents. For more information about the Pennsylvania Patient Safety Authority, see the Authority’s An Independent Agency of the Commonwealth of Pennsylvania website at http://www.patientsafetyauthority.org. ECRI Institute, a nonprofit organization, dedicates itself to bringing the discipline of applied scientific research in healthcare to uncover the best approaches to improving patient care. As pioneers in this science for more than 40 years, ECRI Institute marries experience and indepen- dence with the objectivity of evidence-based research. More than 5,000 healthcare organizations worldwide rely on ECRI Institute’s expertise in patient safety improvement, risk and quality management, and healthcare processes, devices, procedures and drug technology. The Institute for Safe Medication Practices (ISMP) is an independent, nonprofit organization dedicated solely to medication error prevention and safe medication use. ISMP provides recommendations for the safe use of medications to the healthcare community including healthcare professionals, government agencies, accrediting organizations, and consumers. ISMP’s efforts are built on a nonpunitive approach and systems-based solutions. 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