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WHO Information Vol. 30, No. 1, 2016

Safety of medicines

The WHO Collaborating Centre for International Drug Monitoring

Detecting and addressing medicines-related problems is critically important for patient safety. As the manufacture and supply of medicines becomes more globalized, so too should the approaches to monitoring the safety of vaccines and medicines. WHO, through its Programme for International Drug Monitoring, works with the Uppsala Monitoring Centre (UMC) to maintain the world’s single global repository of data on adverse drug reactions and to promote good pharmacovigilance practices in Member States.

Background decisions and safety signals for medicinal Pharmacovigilance is the science products at a global level. and activities relating to the detection, assessment, understanding and WHO Programme for International prevention of adverse effects or any Drug Monitoring other drug-related problem (1). Although An important part of WHO’s medicines all medicines are rigorously tested in safety work is the Programme for clinical safety and efficacy trials before International Drug Monitoring (PIDM). The they are made publicly available, most WHO PIDM members submit Individual of the safety data on medicines only Case Safety Reports (ICSRs) into a global becomes known once the products are database. on the market. Continued monitoring in The ICSRs submitted by member real world settings, where medicines are countries are managed by the WHO used in conjunction with other products, Collaborating Centre for International among different patient populations and Drug Monitoring, known as the Uppsala in patients with multiple illnesses, is Monitoring Centre (UMC)1. With over therefore critically important. one hundred staff and consultants, WHO promotes medicines safety UMC carries out a wide range of in Member States in several ways. activities to support and promote The organization develops normative patient safety through effective global guidance with a focus on low- and middle- pharmacovigilance practice. The centre income countries, supports countries in maintains relationships with hundreds implementing best pharmacovigilance of individuals, institutions, professional practices, and communicates regulatory societies, research units, government

1 www.who-umc.org

This article is based on the Annual Report 2015 of the Uppsala Monitoring Centre (UMC) (2). We thank Paula Alvarado and Lembit Rägo for their useful input.

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Figure 1. Participation in the WHO Programme for International Drug Monitoring (PIDM)

Number of WHO PIDM member countries 120 122 12000 111 104 10000 91 81 70 75 8000 60 53 6000 41 46 32 4000 22 24 14 16 19 ICSRs in VigiBase™ 10 2000

0 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

departments and commercial operations. In 2015, aggregated safety data from UMC receives a sustained flow of VigiBase became accessible to the public guidance through the WHO Advisory through the launch of VigiAccess™ 2. Committee on the Safety of Medicinal Products (ACSoMP) and WHO-appointed Research UMC Board members. With VigiBase as the sole global database of safety information, the detection and A global database dissemination of signals of suspected drug The core repository of ICSRs submitted safety concerns is a major focus of UMC’s globally is the VigiBase™ database, which work. A total of 42 signals were detected, is developed and maintained by the UMC assessed and published in 2015. on behalf of WHO. Identifying safety signals is rather like In December 2015 there were 122 WHO finding needles in haystacks. The UMC’s PIDM member countries and a cumulative research team is continuously seeking total of over 11 million ICSRs submitted to new and better ways of recognizing VigiBase (Figure 1), including more than medicinal problems early in order to one million reports from low- and middle- protect patients. Some examples include: income countries. From 2017, VigiBase • detecting syndromes, when more than will receive ICSRs transferred by the one ADR is reported and there is a European Medicines Agency (EMA) on a need to group reports with similar ADR daily basis (see also page 57). profiles; UMC has developed a range of data • finding risks in specific populations management and analysis tools in support (paediatrics, vaccines, geographical of VigiBase, notably the web-based regions); ICSR management system VigiFlow™ • highlighting case series with sufficient – provided free of charge to WHO PIDM information for assessment; members as a limited-access version • detecting signals in electronic health enabling electronic ICSRs reporting – and records; the search and analysis tool VigiLyze™. 2 www.vigiaccess.org

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• developing software to analyze free-text to leverage mobile-phone reporting and narratives in case reports; find ways to analyze social media for • detecting substandard ; and pharmacovigilance purposes. • exploring the potential of social media In 2009–2013 UMC coordinated the as a source of patient risk information. Monitoring Medicines project, a multi- Members of the UMC’s research team regional pharmacovigilance and public contribute to professional meetings and health effort funded by the European research conferences and have won Commission (3). This project was international awards for their work. developed by WHO and brought together UMC also contributes to external diverse parties to develop methods, tools collaborative projects. Examples and guidelines for pharmacovigilance include the PROTECT project aiming to and resulted in significant synergies. Its strengthen the benefit-risk monitoring outputs illustrate how pharmacovigilance of medicines in Europe by developing activities can serve to detect, assess, and validating new signal detection understand and prevent not only adverse methods, the SALUS project aiming to reactions to medicines, but also threats develop tools and protocols for mining to patient safety caused by other drug- and analyzing real-time patient data related problems such as product quality from heterogeneous electronic health deficiencies or inappropriate use of records, and WEB-RADR, which aims medicines (Table 1).

Table 1. The Monitoring Medicines project: addressing medicines-related safety issues Stated objectives Outputs 1. Support and strengthen consumer WHO handbook (4) reporting of suspected adverse drug Online reporting system (used in six pilot countries, reactions (ADRs) offered free of charge to all VigiFlow users) 2. Expand the role and scope of national WHO handbook (5) pharmacovigilance centres to identify, analyse and prevent errors 3. Promote better and broader use of existing Methodology for detecting drug dependence in pharmacovigilance data for patient safety spontaneous adverse drug reaction databases (6) Methodology for detecting substandard or counterfeit medicines (7) 4. Develop additional pharmacovigilance Publication on WHO strategy for collecting safety data in methods to complement data from public health programmes (8) spontaneous reporting systems Cohort event monitoring (CEM) Web-based data management tool CemFlow (used in Belarus, Kenya, Nigeria, Tanzania and Zimbabwe) Targeted spontaneous reporting (TSR) WHO handbook on pharmacovigilance of medicines used for tuberculosis (9) Clinical use of pharmacovigilance data Web-based database and risk assessment tool in anti- retroviral therapy, available at www.hivpv.org

Source: Adapted from: (3). More information about the Monitoring Medicines project available at: www.monitoringmedicines.org.

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Terminology and coding tools In 2015 UMC organized or participated The data collected in VigiBase are in pharmacovigilance training courses in also the source of the content for the Asia, Africa, South America and Europe. WHODrug™ Dictionary portfolio. This Two major events were the 17th annual UMC resource aims at optimizing the pharmacovigilance training course global analysis and reporting of medical held in Uppsala with participants from product information during the whole life 28 countries, and the first Asia-Pacific cycle of a drug. WHODrug is mandated Pharmacovigilance training course in in Japan and recommended in the United Mysore, India, organized in collaboration States for concomitant in with JSS University. clinical trials. It is regularly updated with In addition, UMS held webinars on a new releases and components to support range of topics in five languages and its use in specific contexts. The 2015 launched a YouTube channel providing releases include an Enhanced version access to over 150 training sessions. produced in collaboration with IMS Health, the Cross Reference Tool Japan and the Advocacy Cross Reference ATC 5. In 2015 UMC launched its first public A mapping bridge has been developed campaign, Take&Tell™ 3, encouraging between the WHO Adverse Reaction patients to tell their health professionals Terminology (WHO-ART) and MedDRA, about adverse effects. This innovative the standard terminology of the and unique campaign raised much International Council for Harmonization interest around the world and was (ICH). For the future UMC is seeking to taken on board by a number of national collaborate with ICH towards one global pharmacovigilance centres and other terminology solution for both regulatory major organizations. It thus achieved its and pharmacovigilance purposes. aims to raise global awareness of the importance of pharmacovigilance and to Support activities change the way people view the process of taking medicines. Training UMC carries out training activities in Technical support member countries on a wide range UMC provides individual technical of topics including signal detection, support in response to hundreds of – the use of data management tools, often complex – enquiries and search communications skills and safety requests every year. More than 170 reporting processes. Its platform of search requests from external and internal partners includes the WHO Collaborating stakeholders were received in 2015. Centres in Ghana, Morocco and the Netherlands, the International Society of Information base Pharmacovigilance (ISoP), Jagadguru The UMC regularly produces a range of Sri Shivarathreeswara (JSS) University guidelines, manuals and support materials in Mysore, India, and the Asia-Pacific on specific topics such as adverse drug Economic Cooperation (APEC) among reaction (ADR) reporting forms and data others. management tools, and makes them

3 www.takeandtell.org/

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available in the Publications section of its wise therapeutic decisions in their use of web site. Its quarterly newsletter “Uppsala medicines. reports” celebrated its 70th edition in July 2015. UMC also maintains a collection of References links to resources available elsewhere, 1 WHO. The importance of such as pharmacovigilance guidelines pharmacovigilance: safety monitoring of produced by member countries and the medicinal products. Geneva: WHO Press; websites of their regulatory authorities. 2002. 2 Uppsala Monitoring Centre. Annual Report 2015. Uppsala: 2015. Conclusion The steady growth of membership in 3 Pal SN, Olsson S, Brown EG. The Monitoring Medicines Project: A WHO PIDM, the high attendance at UMC multinational pharmacovigilance and public training events, the increasing uptake of health project. Drug Safety. 2015;38(4): its core tools and the improved quality 319–328. of reporting by a number of members 4 WHO. Safety monitoring of medicinal show that the Programme is reaching a products: reporting system for the general wider audience of patients and health public. Geneva: WHO Press; 2012. professionals. Many low- and middle- 5 WHO. Reporting and learning systems income countries have become active for medication errors: the role of contributors to the WHO PIDM. And at pharmacovigilance centres. Geneva, WHO Press; 2014. the 2015 annual meeting of WHO PIDM 6 Caster O, Edwards IR, Norén GN, Lindquist member countries, India proposed to M. Earlier discovery of ’s make its Commission dependence potential might have the first WHO collaborating centre for been possible. Eur J Clin Pharmacol. pharmacovigilance in the region - a 2011;67(3):319–20. promising development, particularly as 7 Juhlin K, Andér M, Norén N et al. Using many low-cost generic medicines supplied VigiBase to identify substandard medicines: internationally originate in India. Detection Capacity and key prerequisites. Safer medicines, safer use of medicines Drug Safety, 2015, DOI 10.1007/s40264- 015-0271-2; 2015, 38(4):373-382. and safer patients are high priorities for 8 Pal SN, Duncombe C, Falzon D, Olsson S. the world. The results achieved under the WHO strategy for collecting safety data in WHO PIDM are difficult to quantify, but public health programmes: complementing clearly they have contributed to enhancing spontaneous reporting systems. Drug pharmacovigilance practices and building Safety. 2013;36:75–81. a global safety culture. If this work is 9 WHO. A practical handbook on the kept up, it can bring the world closer to pharmacovigilance of medicines used in UMC’s vision of a place where where all the treatment of tuberculosis: enhancing the safety of the TB patient. Geneva: WHO patients and health professionals make Press; 2012. æ

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Look-alike sound-alike drug name confusion: emtansine

Look-alike sound-alike drug names may be responsible for as many as one in four error reports received by surveillance programs. Not only brand names but also International Nonproprietary Names (INNs) may be subject to look-alike sound-alike confusion, including those for complex products manufactured with new technologies. This article looks at reports of confusion between trastuzumab and , action taken, and possible future measures that could mitigate the risk of confusion and protect patient safety.

Introduction direction to the on Drug name confusion has been well the processes to follow when determining documented in recent years as a the potential for proposed names to be contributing factor to the burden of health confused with those of other products on care-related harm to patients around the the Canadian market. Similarly, the FDA’s world. In particular, look-alike sound- process for name review was developed alike drug names have been identified from initiatives that aim to minimize the as a significant risk for the occurrence potential for medication errors. (3) These of medication errors. Some estimates documents and processes address drug suggest that look-alike sound-alike name brand names under the authority of the confusion is responsible for as many regulator in granting approval for the as one quarter of error reports received marketing of health products. by surveillance programs such as the International Nonproprietary Names Institute for Safe Medication Practices (INN) may also be subject to look-alike (ISMP) Medication Error Reporting sound-alike confusion. Unlike brand Program in the United States. (1) names, these names are selected by the Recognition of the potential for error WHO’s INN Programme. Many of the drug caused by similar drug name pairs has name pairs on ISMP’s list of confusable prompted regulatory authorities, patient names are INNs. (4) In addition, the safety organisations, the pharmaceutical complexity of biological products and industry and health professionals to the application of technologies such develop strategies that seek to lower as nanotechnology and pegylation has the risk of error while acknowledging led to the use of drug names that pose challenges in the provision of health challenges for error-free communication care. Health Canada recently revised its across all stages of the medication use Guidance Document on the Review of process. Drug Brand Names (2) to provide greater

WHO Programme on International Nonproprietary Names (INN). Working Doc. 15.381, September 2015. Authors: Sally Pepper, Sarel Malan, Gilles Mignot, Raffaella Balocco Mattavelli

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Trastuzumab and trastuzumab health facilities. Differences in dose and emtansine treatment schedule (conjugate used at In 2013 regulators including Medsafe, ±50 % of the antibody dose) make the the FDA, and Health Canada issued correct use of these products critical. The safety communications (5, 6, 7) alerting Lists of Recommended and Proposed health professionals to the potential for International Nonproprietary Names medication errors based on look-alike published by the INN Programme indicate sound-alike confusion between two that there are other monoclonal antibodies nonproprietary names1, trastuzumab (78) which may be available in the future both (40) and trastuzumab emtansine (103) with and without conjugates, such as (65). The communications directed health indusatumab (112)(74) / indusatumab professionals to use the respective brand vedotin (112)(74) and vorsetuzumab (107) names of Herceptin® and Kadcyla® (69) / (107)(69). throughout the medication use process Antibody-drug conjugates have also been in order to reduce the risk of name developed in which the same antibody is confusion. conjugated with different cytotoxic agents Trastuzumab emtansine (103)(65) (e.g. cantuzumab (105)(65) represents the first example of an and (105)(66)). antibody-active drug conjugate for The number of look-alike and sound- which the portion – alike INNs for monoclonal antibodies will trastuzumab – was previously marketed naturally increase, with a corresponding as a separate compound. The two INNs greater risk of name confusion. are both in use concurrently within The examples in Table 1 illustrate that confusion between the antibody and 1 Numbers in brackets refer to the numbers of Recommended and Proposed INN Lists the antibody-drug conjugate as well as available at: http://www.who.int/medicines/ between antibody-drug conjugates with publications/druginformation/innlists/en/

Table 1. Sample list of antibody-active drug conjugates INNs Active moieties* trastuzumab emtansine (103)(65) Emtansine vorsetuzumab mafodotin (107)(69) Mafodotin (111)(73) (103)(65) Mertansine (105)(65) cantuzumab ravtansine (105)(66) Ravtansine (105)(67) anetumab ravtansine (109)(71) coltuximab ravtansine (109)(71) (103)(65) Vedotin (109)(71) (110)(71) (108)(70) (110)(72)

* See reference (8)

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either the same antibody or the same As a result of these medication errors, drug/toxin is possible. Errors relating to the FDA took the step of modifying the antibody-drug conjugates (cantuzumab approved nonproprietary name of the mertansine (105)(65) vs cantuzumab conjugated compound to ado-trastuzumab ravtansine (105)(66)) could theoretically emtansine. The effectiveness of the be even more dangerous than confusion addition of the prefix in preventing name between the antibody and the antibody- confusion errors is difficult to determine drug conjugate where toxicity or adverse at this date. Reports published shortly effects are mainly related to the incorrect after the approval indicated that there dose or lack of effect. were inconsistencies in the terminology Antibody-active drug conjugates are used in U.S. drug information references named in accordance with the naming as well as in health information systems, policy of the INN Programme in which with some publications displaying the a separate, second word identifies the prefix ‘ado’ and others omitting it. It was conjugate. (9) Changing the order of postulated that health professionals may the words so that the conjugate appears have encountered difficulties in accessing first would not mitigate the risk of name key information or placing orders for the confusion as some drugs/toxins are drug. (11) Unilateral use of this strategy conjugated to more than one antibody. In may also make cross-referencing of data the case of trastuzumab emtansine (103) or information retrieval by other regulatory (65), regulators and healthcare providers authorities or organizations difficult. For have proposed strategies to address the example, some Canadian databases possibility of confusion. These include such as those used by poison control the addition of a prefix (ado-trastuzumab centres may rely on content from U.S.- emtansine) as well as specific prescribing, based sources, and delays in retrieving dispensing, labelling, systems and storage information may occur if users do not requirements. enter the ‘ado’ prefix as part of their search criteria. The continued use of the FDA experience – does the addition ‘ado’ prefix may pose a challenge in light of a prefix prevent errors? of the possibility of new conjugates as well During clinical trials prior to market as new monoclonal antibodies. authorization in the United States, four patients inadvertently received Roche/Genentech Global Safety trastuzumab emtansine at 6 mg/kg Database instead of trastuzumab. It was reported At the request of the INN Programme, that all four patients developed Grade 2 Roche/Genentech performed a search thrombocytopenia and increased liver of their Global Safety Database for transaminases. In one case a Holter post-market reports of medication errors monitoring 18 days after the error showed between the two substances. The search asymptomatic ventricular extrasystoles. looked for reports of (ado)-trastuzumab The following day, the patient died. The emtansine entered in the database until cardiologist did not believe that the 21 February 2015 under the MedDRA extrasystoles contributed to death. No High Level Group Term (HLGT) autopsy was performed. (10) “Medication Error”. Although there was a lack of detail in the data provided, three

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cases reported in the U.S. are suggestive The error was caught when the label of product confusion. A mix-up between generated by the computer was being trastuzumab and ado-trastuzumab checked for accuracy. The reporter emtansine cannot be excluded. indicated that limitations in systems had prevented the consistent use of the brand EMA data name as per the Health Canada safety According to the assessment report for communication. marketing authorization from the EMA,”six The third report outlines a sequence cases of medication error occurred in of events that led to a patient receiving the clinical trials. Of these 4 were due trastuzumab instead of trastuzumab to a confusion between trastuzumab emtansine. The prescription for emtansine and trastuzumab. The trastuzumab emtansine was correctly medication error occurred with a product entered into the pharmacy software labeled for clinical trials, which had no and verified by the pharmacist. During tradename or specific distinguishing compounding the technician inadvertently features to differentiate the two products.“ mixed the order using vials of trastuzumab Clinical consequences from these errors and then labelled the product as are not provided in the report. (12) trastuzumab emtansine. At the time of the The post-market data from Roche/ incident, labels generated by the computer Genentech indicates that a total of 12 used only the nonproprietary name and medication errors involving trastuzumab did not include the brand name. The emtansine were reported until 21 February pharmacist did not catch the error and the 2015 in the following countries of the drug was then given to the patient labelled European Union: Germany (7), Greece as trastuzumab emtansine although it (2), United Kingdom (2) and Denmark (1). contained trastuzumab. No further details regarding the role of Later a technician observed extra name confusion were provided. stock of trastuzumab emtansine in the fridge, and the error was detected. The Health Canada data reporter stated that the same situation had As regards Canadian data, three cases occurred a week or so prior, but had been were reported to Health Canada until intercepted by the pharmacist before the March 31, 2015. The first report was patient received the drug. received as a communication prior to The patient did not suffer any the market authorization in Canada of adverse effects from the error and was trastuzumab emtansine under the brand rescheduled to receive trastuzumab name Kadcyla® in October 2013. The emtansine the following week, eventually communication identifies the potential resuming the originally planned schedule for selection errors during ordering, of administration on a three-week cycle. computer order entry, compounding and The report revealed that the following programming IV pumps. changes were implemented as a result of The second report received describes a the error and the near-miss: near-miss incident in which trastuzumab • The order of the name in the pharmacy emtansine (Kadcyla®) was selected at software was switched so that the brand order entry in the pharmacy software name appears first (e.g. Kadcyla® – instead of trastuzumab (Herceptin®). trastuzumab emtansine)

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• Labels affixed to the IV bags now stage of the medication use process. include the brand name in addition to Challenges such as software limitations the INN. and diversity of processes will need to be • The two medications are now stored addressed in recognition of the continued separately. development of antibody-drug conjugates • A high-alert2 colour-coded label has and the increased complexity of look-alike been added. sound-alike name candidates. The use of Additional risk mitigation strategies have brand names in addition to nonproprietary been proposed to support the safe use of names for these antibody-drug conjugates trastuzumab and trastuzumab emtansine during prescribing and dispensing as including the following: (13) well as clearly distinguishable packaging • Recommended dosing and dose limits and labelling would be key to preventing should be programmed into software at medication errors. Promotion of the INN the point of order entry. as a standard for drug nomenclature • Automated alerts and warning labels is also important to ensure that health should remind practitioners that the professionals understand its role and medications are not interchangeable. application. Other strategies such as • Use of the brand names in addition to the addition of a prefix or a suffix (e.g. a nonproprietary names should occur 4‑letter biological qualifier) require further at each stage of the medication use evidence of their effectiveness as patient process. safety measures. The market authorization holder has also provided training materials and other References resources to health facilities to help 1 Hoffman JM, Proulx SM. Medication Errors minimize the risk for name confusion. Caused by Confusion of Drug Names. Drug Safety 2003;26(7):445-52. Conclusion 2 Health Canada. Guidance Document for The influence of under-reporting on the Industry - Review of Drug Brand Names. Pub. 140304, 2 July 2014. voluntary reporting of medication errors and adverse effects is such that the rate 3 FDA. Best Practices in Developing Proprietary Names for Drugs. Draft of occurrence of these events cannot Guidance. May 2014. be effectively determined. The true 4 Institute for Safe Medication Practices incidence of errors between trastuzumab (ISMP). ISMP’s List of Confused Drug and trastuzumab emtansine is therefore Names. 2015. not known, although the reported cases 5 Medsafe. Preventing Medication Errors: highlight the potential for serious harm Kadcyla and Herceptin. Prescriber Update. from medication errors resulting from December 2013; 34(4): 43. name confusion. 6 U.S. FDA. Kadcyla (ado-trastuzumab For the future, healthcare providers emtansine): Drug Safety Communication - should continue implementation of a Potential Medication Errors Resulting from Name Confusion. 6 May 2013. system-wide set of standard risk mitigation strategies that acknowledge risks at each 7 Health Canada. Kadcyla (trastuzumab emtansine) and Herceptin (trastuzumab) - Potential Risk for Medication Error Due 2 High-alert medications are drugs that bear a to Name Confusion. Dear Healthcare heightened risk of causing significant patient Professional Letter. 9 October 2013. harm when they are used in error.

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8 WHO. International Nonproprietary Names 11 National Alert Network (NAN). Confusion (INN) for pharmaceutical substances. regarding the generic name of the HER2- Names for radicals, groups & others. targeted drug KADCYLA (ado-trastuzumab Comprehensive list. Geneva: WHO, 2015. emtansine). 17 April 2013. 9 WHO. The Use of Common Stems in the 12 EMA Committee for Medicinal Products for Selection of International Nonproprietary Human Use (CHMP). Assessment report. Names (INN) for Pharmaceutical Kadcyla. 19 September 2013. Substances. ANNEX 1: INNs for 13 Roche. Kadcyla®. Trastuzumab emtansine. monoclonal antibodies. Geneva: WHO, EU Healthcare Professional Information. 2003. Prevention of medication errors. June 2015. 10 Center for Drug Evaluation and Research. æ Application Number: 125427orig1s000. Other Review(s). 31 January 2013.

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