Introductory Guide forStandardised MedDRA
Queries (SMQs) Version 20.0

March 2017
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Acknowledgements

Acknowledgements®

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TABLE OF CONTENTS
1.

INTRODUCTION ......................................................................................3
1.1

DEFINITION OF A STANDARDISED MedDRA QUERY .........................3

1.2

BACKGROUND .......................................................................................3

1.3

DEVELOPMENT OF SMQS .....................................................................4

1.4

DESIGN CONCEPTS FOR SMQ CONTENT ...........................................4

1.5

NOTES ON SMQ IMPLEMENTATION AND THE EXPECTATIONOF QUERY RESULT ...............................................................................7

2.

INDIVIDUAL SMQS .................................................................................9
2.1

ACCIDENTS AND INJURIES (SMQ) .....................................................10

2.2

ACUTE CENTRAL RESPIRATORY DEPRESSION (SMQ) ................... 13

2.3

ACUTE PANCREATITIS (SMQ) ............................................................16

2.4

ACUTE RENAL FAILURE (SMQ) ..........................................................18

2.5

AGRANULOCYTOSIS (SMQ)................................................................20

2.6

ANAPHYLACTIC REACTION (SMQ) ....................................................22

2.7

ANGIOEDEMA (SMQ) ...........................................................................24

2.8

ANTICHOLINERGIC SYNDROME (SMQ) ............................................. 26

2.9

ARTHRITIS (SMQ) .................................................................................28

2.10

ASTHMA/BRONCHOSPASM (SMQ).....................................................31

2.11

BILIARY DISORDERS (SMQ) ...............................................................33

2.12

BREAST NEOPLASMS, MALIGNANT AND UNSPECIFIED (SMQ) ..... 37

2.13

CARDIAC ARRHYTHMIAS (SMQ) ........................................................39

2.14

CARDIAC FAILURE (SMQ) ...................................................................42

2.15

CARDIOMYOPATHY (SMQ)..................................................................44

2.16

CENTRAL NERVOUS SYSTEM VASCULAR DISORDERS (SMQ) ...... 47

2.17

CHRONIC KIDNEY DISEASE (SMQ) ....................................................51

2.18

CONJUNCTIVAL DISORDERS (SMQ) ..................................................56

2.19

CONVULSIONS (SMQ)..........................................................................58

2.20

CORNEAL DISORDERS (SMQ) ............................................................60

2.21

DEMENTIA (SMQ) .................................................................................62

2.22

DEMYELINATION (SMQ) ......................................................................65

2.23

DEPRESSION AND SUICIDE/SELF-INJURY (SMQ) ............................ 68

2.24

DRUG ABUSE, DEPENDENCE AND WITHDRAWAL (SMQ) ............... 71

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2.25

DRUG REACTION WITH EOSINOPHILIA AND SYSTEMICSYMPTOMS SYNDROME (SMQ) ..........................................................75

2.26

DYSLIPIDAEMIA (SMQ) ........................................................................81

2.27

EMBOLIC AND THROMBOTIC EVENTS (SMQ)................................... 83

2.28

EOSINOPHILIC PNEUMONIA (SMQ)....................................................87

2.29

EXTRAPYRAMIDAL SYNDROME (SMQ) ............................................. 90

2.30

EXTRAVASATION EVENTS (INJECTIONS, INFUSIONS AND
IMPLANTS) (SMQ) ................................................................................93

2.31

FERTILITY DISORDERS (SMQ) ............................................................95

2.32

GASTROINTESTINAL NONSPECIFIC INFLAMMATION AND
DYSFUNCTIONAL CONDITIONS (SMQ) .............................................. 97

2.33

GASTROINTESTINAL PERFORATION, ULCERATION,HAEMORRHAGE OR OBSTRUCTION (SMQ) .................................... 100

2.34

GENERALISED CONVULSIVE SEIZURES FOLLOWINGIMMUNISATION (SMQ) ....................................................................... 103

2.35

GLAUCOMA (SMQ) .............................................................................106

2.36

GUILLAIN-BARRE SYNDROME (SMQ) .............................................. 109

2.37

HAEMATOPOIETIC CYTOPENIAS (SMQ).......................................... 113

2.38

HAEMODYNAMIC OEDEMA, EFFUSIONS AND FLUIDOVERLOAD (SMQ) .............................................................................116

2.39

HAEMOLYTIC DISORDERS (SMQ) .................................................... 119

2.40

HAEMORRHAGES (SMQ) ................................................................... 121

2.41

HEARING AND VESTIBULAR DISORDERS (SMQ) ........................... 123

2.42

HEPATIC DISORDERS (SMQ) ............................................................ 126

2.43

HOSTILITY/AGGRESSION (SMQ) ...................................................... 132

2.44

HYPERGLYCAEMIA/NEW ONSET DIABETES MELLITUS (SMQ) .... 134

2.45

HYPERSENSITIVITY (SMQ) ................................................................ 138

2.46

HYPERTENSION (SMQ)...................................................................... 140

2.47

HYPOGLYCAEMIA (SMQ) .................................................................. 143

2.48

HYPONATRAEMIA/SIADH (SMQ) ...................................................... 146

2.49

HYPOTONIC-HYPORESPONSIVE EPISODE (SMQ) .......................... 149

2.50

INTERSTITIAL LUNG DISEASE (SMQ) .............................................. 152

2.51

ISCHAEMIC COLITIS (SMQ) ............................................................... 154

2.52

ISCHAEMIC HEART DISEASE (SMQ) ................................................ 156

2.53

LACK OF EFFICACY/EFFECT (SMQ) ................................................ 158

2.54

LACRIMAL DISORDERS (SMQ) ......................................................... 160

2.55

LACTIC ACIDOSIS (SMQ)................................................................... 162

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2.56

LENS DISORDERS (SMQ) .................................................................. 164

2.57

LIPODYSTROPHY (SMQ) ................................................................... 167

2.58

MALIGNANCIES (SMQ) ...................................................................... 170

2.59

MALIGNANT LYMPHOMAS (SMQ) .................................................... 174

2.60

MEDICATION ERRORS (SMQ) ........................................................... 176

2.61

MYELODYSPLASTIC SYNDROME (SMQ) ......................................... 179

2.62

NEUROLEPTIC MALIGNANT SYNDROME (SMQ) ............................. 182

2.63

NONINFECTIOUS DIARRHOEA (SMQ) .............................................. 185

2.64

NONINFECTIOUS ENCEPHALITIS (SMQ) ......................................... 187

2.65

NONINFECTIOUS ENCEPHALOPATHY/DELIRIUM (SMQ) ............... 190

2.66

NONINFECTIOUS MENINGITIS (SMQ) ............................................... 194

2.67

OCULAR INFECTIONS (SMQ) ............................................................ 197

2.68

OCULAR MOTILITY DISORDERS (SMQ) ........................................... 199

2.69

OPTIC NERVE DISORDERS (SMQ).................................................... 201

2.70

OROPHARYNGEAL DISORDERS (SMQ) ........................................... 203

2.71

OSTEONECROSIS (SMQ) ................................................................... 206

2.72

OSTEOPOROSIS/OSTEOPENIA (SMQ) ............................................. 209

2.73

OVARIAN NEOPLASMS, MALIGNANT AND UNSPECIFIED (SMQ) . 212

2.74

PERIORBITAL AND EYELID DISORDERS (SMQ) ............................. 214

2.75

PERIPHERAL NEUROPATHY (SMQ) ................................................. 216

2.76

PREGNANCY AND NEONATAL TOPICS (SMQ) ................................ 218

2.77

PREMALIGNANT DISORDERS (SMQ) ............................................... 223

2.78

PROSTATE NEOPLASMS, MALIGNANT AND UNSPECIFIED(SMQ) ..................................................................................................227

2.79

PROTEINURIA (SMQ) ......................................................................... 229

2.80

PSEUDOMEMBRANOUS COLITIS (SMQ).......................................... 232

2.81

PSYCHOSIS AND PSYCHOTIC DISORDERS (SMQ) ......................... 234

2.82

PULMONARY HYPERTENSION (SMQ) .............................................. 237

2.83

RENOVASCULAR DISORDERS (SMQ) .............................................. 240

2.84

RESPIRATORY FAILURE (SMQ) ........................................................ 242

2.85

RETINAL DISORDERS (SMQ) ............................................................ 245

2.86

RETROPERITONEAL FIBROSIS (SMQ) ............................................. 247

2.87

RHABDOMYOLYSIS/MYOPATHY (SMQ) ........................................... 249

2.88

SCLERAL DISORDERS (SMQ) ........................................................... 251

2.89

SEVERE CUTANEOUS ADVERSE REACTIONS (SMQ) .................... 255

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2.90

SHOCK (SMQ) .....................................................................................258

2.91

SKIN NEOPLASMS, MALIGNANT AND UNSPECIFIED (SMQ) ......... 262

2.92

SYSTEMIC LUPUS ERYTHEMATOSUS (SMQ).................................. 264

2.93

TASTE AND SMELL DISORDERS (SMQ) .......................................... 268

2.94

TENDINOPATHIES AND LIGAMENT DISORDERS (SMQ) ................ 270

2.95

THROMBOPHLEBITIS (SMQ) ............................................................. 273

2.96

THYROID DYSFUNCTION (SMQ) ....................................................... 275

2.97

TORSADE DE POINTES/QT PROLONGATION (SMQ) ...................... 278

2.98

TUBULOINTERSTITIAL DISEASES (SMQ) ........................................ 280

2.99

TUMOUR LYSIS SYNDROME (SMQ) ................................................. 283

2.100 UTERINE AND FALLOPIAN TUBE NEOPLASMS, MALIGNANT
AND UNSPECIFIED (SMQ) ................................................................. 285
2.101 VASCULITIS (SMQ).............................................................................287
APPENDIX I – LIST OF ABBREVIATIONS USED IN THIS DOCUMENT ................... 290
APPENDIX II – CIOMS SMQ WORKING GROUP MEMBERSHIP (AS OF 6 JULY2016)..................................................................................................291
APPENDIX III – COMPREHENSIVE LISTING OF ACTIVE SMQS AND SUB-SMQS 294

LIST OF FIGURES
Figure 1-1. Narrow Search vs. Broad Search .................................................................5
Figure 2-1. Hierarchy Structure of Biliary disorders (SMQ) ........................................... 35
Figure 2-2. Hierarchy Structure of Breast neoplasms, malignant and unspecified(SMQ).......................................................................................................38
Figure 2-3. Hierarchy Structure of Cardiac arrhythmias (SMQ) ..................................... 40
Figure 2-4. Hierarchy Structure of Central nervous system vascular disorders(SMQ).......................................................................................................48
Figure 2-5. Hierarchy Structure of Depression and suicide/self-injury (SMQ)................ 69
Figure 2-6. Hierarchy Structure of Drug abuse, dependence and withdrawal (SMQ) .... 73
Figure 2-7. Hierarchy Structure of Embolic and thrombotic events (SMQ) .................... 84
Figure 2-8. Hierarchy Structure of Extrapyramidal syndrome (SMQ) ............................ 91
Figure 2-9. Hierarchy Structure of Gastrointestinal nonspecific inflammation anddysfunctional conditions (SMQ) ................................................................98
Figure 2-10. Hierarchy Structure of Gastrointestinal perforation, ulceration,
haemorrhage or obstruction (SMQ) ........................................................ 102
Figure 2-11. Hierarchy Structure of Haematopoietic cytopenias (SMQ) ...................... 115
Figure 2-12. Hierarchy Structure of Haemorrhages (SMQ) ......................................... 122
Figure 2-13. Hierarchy Structure of Hearing and vestibular disorders (SMQ).............. 124
Figure 2-14. Hierarchy Structure of Hepatic disorders (SMQ) ..................................... 130
Figure 2-15. Hierarchy Structure of Ischaemic heart disease (SMQ) .......................... 157
Figure 2-16. Hierarchy Structure of Malignancies (SMQ) ............................................ 173
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Figure 2-17. Hierarchy Structure of Oropharyngeal disorders (SMQ).......................... 205
Figure 2-18. Hierarchy Structure of Ovarian neoplasm, malignant and unspecified(SMQ).....................................................................................................213
Figure 2-19. Hierarchy Structure of Pregnancy and neonatal topics (SMQ) ................ 222
Figure 2-20. Hierarchy Structure of Premalignant disorders (SMQ) ............................ 225
Figure 2-21. Hierarchy Structure of Prostate neoplasms, malignant and unspecified(SMQ).....................................................................................................228
Figure 2-22. Hierarchy Structure of Shock (SMQ) ...................................................... 260
Figure 2-23. Hierarchy Structure of Skin neoplasms, malignant and unspecified(SMQ).....................................................................................................263
Figure 2-24. Hierarchy Structure of Thyroid dysfunction (SMQ) .................................. 276
Figure 2-25. Hierarchy Structure of Uterine and fallopian tube neoplasms,
malignant and unspecified (SMQ)........................................................... 286

LIST OF TABLES
Table 2-1. Link Table between CIOMS WG Document and SMQ Introductory Guide
for Central nervous system vascular disorders (SMQ) .............................. 50
Table 2-2. Link Table between CIOMS WG Document and SMQ Introductory Guide
for Embolic and thrombotic events (SMQ) ................................................ 85
Table 2-3. Modifications of sub-SMQ names under Haematopoietic cytopenias(SMQ) in V. 14.0.....................................................................................114
Table 2-4. Topics of Hepatic disorders (SMQ) ............................................................. 126
Table 2-5. Modifications of sub-SMQ names under Hepatic disorders (SMQ) in V.
12.1 ........................................................................................................129
Table 2-6. Algorithmic levels of diagnostic certainty for Hypotonic-hyporesponsive
episodes .................................................................................................150
Table 2-7. Terms not included in sub-SMQ Malignancy related therapeutic anddiagnostic procedures (SMQ) ................................................................. 172
Table 2-8. Link Table between CIOMS WG Document and SMQ Introductory Guide
for Shock (SMQ).....................................................................................261
Table 2-9. Categories of Systemic lupus erythematosus (SMQ) .................................. 266

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Introduction

Notice to Readers
The Introductory Guide for Standardised MedDRA Queries (SMQs), prepared in
English, is intended only for use with the English version of MedDRA and its versionspecific SMQs. It is included with each MedDRA release, and is also accessible on the
MedDRA website under Support Documentation. In addition to the English version,
editions of the Introductory Guide for Standardised MedDRA Queries (SMQs) havebeen developed in other languages and are included with the respective MedDRA
version release translations.
Please note that SMQs do not cover all medical topics or safety issues. Also, thecontent of an SMQ may change subsequent to implementation, because all SMQs are
subject to ongoing refinement with the successive versions of MedDRA.
If any modifications are made to term content or structure of an SMQ by a subscriber oruser, it can no longer be called an “SMQ” but it should instead be referred to as a“modified MedDRA query based on an SMQ”. Under no circumstances should aquery constructed for the specific need of an organization be called an “SMQ” by
its originator. This is to ensure that there is no confusion with the ICH-endorsed SMQs
applied by other MedDRA users. Any alternate name for the organization-constructedquery is acceptable as long as it could not be potentially confused with an ICHendorsed SMQ.
Throughout this Introductory Guide for Standardised MedDRA Queries, there areoccasional references to "Phase II testing." Earlier in the development of SMQs, there
was a period of time when the queries were provided to MedDRA subscribers for preproduction testing and feedback; this was called "Phase II." As of July 2006, Phase II
has been eliminated.
This document includes a number of web site citations and hyperlinks in the lists ofreferences for individual SMQs, and in other sections. Note that some web sites may
no longer be active, or may have changed, but they remain included in their originalformat for historical purposes.
Substantive changes to Introductory Guide for Standardised MedDRA Queries Version
include the addition of four new level 4 sub-SMQs to Malignancies (SMQ) in Section
2.58:
Haematological malignant tumours (SMQ)
Non-haematological malignant tumours (SMQ)
Haematological tumours of unspecified malignancy (SMQ)
Non-haematological tumours of unspecified malignancy (SMQ)
These additional sub-SMQs were added to Malignancies (SMQ) to further enhance
specificity options for case identification: Haematological malignant tumours (SMQ) and
Non-haematological malignant tumours (SMQ) were added as sub-SMQs of Malignant
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tumours (SMQ); Haematological tumours of unspecified malignancy (SMQ) and Nonhaematological tumours of unspecified malignancy (SMQ) were added as sub-SMQs of
Tumours of unspecified malignancy (SMQ).

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Introduction

1.

INTRODUCTION

1.1

Definition of a Standardised MedDRA Query

Standardised MedDRA Queries (SMQs) are groupings of MedDRA terms, ordinarily at
the Preferred Term (PT) level that relate to a defined medical condition or area ofinterest. SMQs are intended to aid in the identification and retrieval of potentiallyrelevant individual case safety reports. The included terms may relate to signs,
symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic
test data, etc. The only Lowest Level Terms (LLTs) represented in an SMQ are thosethat link to a PT used in the SMQ; all others are excluded.
1.2

Background

SMQs arose out of a recognized need of the MedDRA user community for standard
tools to assist in the identification and retrieval of safety data. The original MedDRA
Special Search Categories (SSCs) were intended for a similar purpose, but after several
years of MedDRA use, the biopharmaceutical community (regulators and industry)
concluded that these tools did not adequately address the need. In response, the
MedDRA Maintenance and Support Services Organization (MSSO), in early 2002,
began to develop MedDRA Analytical Groupings (MAGs). MAGs were defined ascollections of terms from any level of the MedDRA hierarchy (except, in general, LLTs)
and from any, several, or all MedDRA SOCs that relate to the medical condition or areaof interest defined by the name of the MAG, including signs, symptoms, physicalfindings, laboratory and other physiologic test data, and associated social
circumstances related to the medical condition or area of interest.
At the same time that MAGs were being developed at the MSSO, an independent
initiative by the Council for International Organizations of Medical Sciences (CIOMS)
was started to address the need for special queries/groupings using MedDRA-coded
data; their groupings were called Standardised Search Queries (SSQs). It was clearthat the concepts of MAGs and SSQs were quite similar to one another and were bothintended to fulfill the perceived need for a retrieval tool to accompany MedDRA. Thus,
CIOMS and the MSSO agreed that it was in the user community’s best interest for the
CIOMS Working Group and the MSSO to combine their efforts in developing this tool.
To recognize the joint effort, the former “MAG” and “SSQ” designations were dropped,
and an agreement on a name for these new standard groupings was reached. Since
May 2003, the joint efforts of the CIOMS Working Group and MSSO have been
designated Standardised MedDRA Queries (SMQs). In November 2003, the ICH
MedDRA Management Board endorsed the cooperative effort, and the ICH process was
adopted for the development of SMQs.
The CIOMS Working Group is composed of senior scientists from several drug
regulatory authorities, international pharmaceutical companies, the MSSO, theJapanese Maintenance Organization (JMO), the World Health Organization, and otherinstitutions.
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1.3

Development of SMQs

A focus of the early phase of SMQ development was to identify which areas of interest
were candidates for development. Close to 100 possible topics were initially identified.
The CIOMS Working Group continually reviews this list and prioritizes topics fordevelopment. Subteams work on each candidate SMQ prior to review and approval by
the entire CIOMS Working Group.
The definitions, inclusion and exclusion criteria, hierarchy (if applicable), and algorithm(if applicable) for each SMQ are included in this Introductory Guide. Much of thisinformation was derived from the anonymized SMQ CIOMS Working Group detailed
documentation and can be found at https://www.meddra.org/software-packages. The
general methodological approach to the development and use of SMQs was publishedin a document published by CIOMS Development and Rational Use of Standardised
MedDRA Queries (SMQs): Retrieving Adverse Drug Reactions with MedDRA. The
reader is referred to the CIOMS Web site for further information: http://www.cioms.ch/.
1.4

Design Concepts for SMQ Content

SMQs may have a mixture of very specific terms and less specific terms that areconsistent with a description of the overall clinical syndrome associated with a particularadverse event and drug exposure. Some SMQs are a straightforward collection ofterms; others have been designed to accommodate combinations of terms from morethan one group (see 1.4.2 Algorithm, below). To address these varied aspects, SMQs
may have certain specific design features:
1.4.1 Narrow and Broad Scope
This approach accommodates those instances in which a user may need to identify
cases that are highly likely to represent the condition of interest (a “narrow” scope) andthose instances in which a user seeks to identify all possible cases, including some thatmay prove to be of little or no interest on closer inspection (a “broad” scope). Thus, a“narrow” search yields “specificity” while the “broad” search yields “sensitivity.” A“broad” search includes both the “narrow” terms and the additional “broad” terms, often
of a less-specific nature.

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Narrow
SearchNarrow Scope
Terms

Broad
SearchBroad Scope
Terms

Figure 1-1. Narrow Search vs. Broad Search

1.4.2

Algorithm

In addition to narrow and broad searches, for some SMQs an algorithmic search
approach is available. This is a combination of search terms from various subcategories of the broad search terms to further refine the identification of cases ofinterest compared to the broad search category. Algorithmic search methodology yields
greater sensitivity compared to the narrow search and greater specificity compared tothe broad search. A typical example is Acute pancreatitis (SMQ) where the broad
search terms are grouped into two categories: Category B is a list of laboratory values
and Category C is a list of signs and symptoms. The algorithm for Acute pancreatitis(SMQ) defines a case of interest as a record coded with either at least one term of
Category A (narrow scope), or coded with a combination of at least one term of
Category B AND one term of Category C.
Use of an algorithm is not required in order to be able to retrieve cases of interest using
a particular SMQ. Application of the algorithm may be most helpful when it is expectedthat a large number of cases will be retrieved by broad scope terms; the algorithm may
reduce the need for manual sorting for cases of interest.
1.4.3

Category

For those SMQs that are algorithmic, the broad search terms are divided into various
categories so that a defined combination of terms may be applied. In algorithmic
SMQs, narrow search terms are always Category A, and broad search terms are always
Categories B, C, D, etc. For example, in Acute pancreatitis (SMQ), the broad searchterms are grouped into two categories: Category B is a list of laboratory values and
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Category C is a list of signs and symptoms. The algorithm for Acute pancreatitis (SMQ)
defines a case of interest as a record coded with one of the Category A (narrow scope)terms OR a record coded with one of the Category B AND one of the Category C terms.
1.4.4

Weight

SMQ term weight may also be used with an algorithm. A term weight indicates therelevancy of each category within the algorithm. For example, terms in Systemic lupus
erythematosus (SMQ) are grouped into 9 categories with Category A being the narrow
scope terms and Categories B through I being the broad scope terms. Each broad
scope Category is assigned a weight from 1 to 3. Based on the algorithm for Systemic
lupus erythematosus (SMQ), a case of interest is a record coded with one of theCategory A (narrow scope) terms OR a record with various broad search categories
terms with a sum of the category weights greater than 6.
1.4.5 Hierarchy
Some SMQs are a series of queries related to one another in a hierarchical relationshipsimilar to the hierarchical structure of MedDRA itself. These consist of one or more
subordinate SMQs that could be combined to create a superordinate, more inclusive
SMQ. In some hierarchical SMQs, there are no separate “narrow” and “broad”
categories within the subordinate SMQs (sub-SMQs). A specific term may be included
in more than one of the sub-SMQs in a hierarchical SMQ provided that the term is of thesame scope – narrow or broad – in each sub-SMQ.
The hierarchy provides flexibility for the user. For example, a user may wish to apply
the entire scope of the SMQ topic (e.g., the entire Hepatic disorders (SMQ) including all
sub-SMQs) to retrieve all cases related to hepatic disorders in a database. A user may
also elect to apply a single sub-SMQ of Hepatic disorders (SMQ) (e.g., Pregnancyrelated hepatic disorders (SMQ)) or combinations of more than one sub-SMQ in thehierarchy based on the user’s need.
1.4.6 PT/LLTIn SMQ_Content file, PTs (level 4) are not duplicated at the LLT level (level 5). Users
can conduct a search with only PTs if the data are stored at the PT level. Users canalso conduct a search with both PTs and LLTs if the data are stored at the LLT level
because in MedDRA, all PTs are duplicated at the LLT level.
1.4.7 Term Status
Each SMQ – including its sub-ordinate PTs/LLTs – has an assigned status. The status
can be either “active” or “inactive.”
An active SMQ is the one that is currently maintained by the MSSO. An inactive SMQ
is no longer maintained although it is included in and distributed with the SMQ ASCII
files for at least one release. An SMQ may be made inactive if it has been found to not
be useful to users, becomes outdated, or is found to be otherwise problematic.

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PTs and LLTs that have been made inactive remain in their SMQ and are neverdeleted. An “inactive” status could be assigned for the following circumstances:•

A PT that is included in error or is no longer part of the SMQ (e.g., due to achange of an SMQ’s inclusion or exclusion criteria)•

An LLT that is moved to a PT that is not part of the SMQ
When applying an SMQ for data retrieval, inactive LLTs and PTs should be
removed from the search.

1.5

Notes on SMQ Implementation and the Expectation of Query Result

The various design features described in sections 1.4.1 – 1.4.5 have impacts on the
SMQ implementation and ultimate query results. The following sections explain optionsof SMQ implementation and usage.
1.5.1 Performing Searches without Using SMQ Special Features
The special features (narrow vs. broad searches, algorithmic search, and hierarchies)
are intended to improve the quality of query result by increasing the specificity andreducing the noise level. It should be noted that they are optional, which means thatusers could use an SMQ as a list of MedDRA terms without any special features.
1.5.2 Performing Searches Using SMQ Special Features
1.5.2.1

Narrow and Broad

Based on the specificity, the user may perform:•

A narrow search for specificity of case retrieval: only narrow terms are appliedin the queryOR•

A broad search for sensitivity of case retrieval: both narrow and broad terms
are applied in the query

Although most SMQs have both narrow and broad scope terms, some SMQs have only
narrow terms or only broad terms, which impact the SMQ programming outputs asfollows:•

SMQs with both narrow and broad terms: The results for narrow search andbroad search are different. Broad search results include those cases
retrieved by narrow terms and additional ones retrieved by broad terms.

•

SMQs with only narrow terms: The retrieved cases from narrow search andbroad search are the same because there are no additional broad terms in
the SMQ.

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1.5.2.2

SMQs with only broad terms: The narrow search returns null result (or zerocase) because there are no narrow terms. Only broad search retrieves
cases.
Algorithm Search Option

An algorithmic SMQ is designed to reduce the “noise” level among broad terms. Not all
SMQs have an algorithm. For those SMQs that do have an algorithm, each algorithm isunique and needs to be implemented individually. For detailed information, see the“Algorithm” section under a particular algorithmic SMQ.
1.5.2.3

Hierarchy Search Option

In most hierarchical SMQs, the sub-SMQs as well as the superordinate SMQ are
independent search queries. User may take any of the sub-SMQ or the superordinate
SMQ and obtain all relevant MedDRA terms related to that sub-topic or super-topic.
However, a few hierarchical SMQs have unique features related to the sub-SMQs in theway that narrow and broad searches are utilized. These unique SMQs are listed below:•

Biliary disorders (SMQ)•

Cardiac arrhythmias (SMQ)•

Embolic and thrombotic events (SMQ)•

Hepatic disorders (SMQ)

For detailed information on how these unique hierarchical SMQs should be
implemented or used, please refer to the particular session of that SMQ.

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2.

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2.1

Accidents and injuries (SMQ)(Production Release September 2007)
2.1.1•

Definition
Accidents and injuries have been associated with use of medications
Particularly older psychotropic medications

Especially patients with pre-existing high risk levels and/or continuing
mental problems

In a study of falls in elderly, use of certain drugs (benzodiazepines,
phenothiazines, and antidepressants) was an independent risk factorStudy on risk of accidental injury and benzodiazepines also confirmed anincreased risk, especially in patients who had recently filled theirprescription•“Accident” defined as “an unplanned or unintended but sometimes predictable
event leading to injury, e.g., in traffic, industry, or a domestic setting, or such an
event developing in the course of a disease.”•

In medicine, the term “injury” can have a very broad meaning.


•

2.1.2
•

For the purpose of this SMQ, a more narrow definition is used, i.e., “toinjure” is “to wound, hurt or harm”

Focus of this SMQ is not on “metabolic” injury (toxicity, etc.), but on personal
injury or accident to the individual as a result of altered perception,
consciousness, attention, behavior, etc. (see NOTE below)
Inclusion/Exclusion Criteria
Included: Terms that relate to definition, i.e., terms for accident, injury, burns, trauma,fall, fracture, wound, crush, contusion, etc.
 PT Wound but not terms for complications of wound such as PT Woundinfection•

PT Snake bite and other animal and human “bite” terms (except arthropod bitesand stings)•

Relevant “foreign body” terms (e.g., PT Foreign body in eye) but not “sensationof foreign body” terms such as PT Foreign body sensation in eyes•

Procedure terms that could only relate to trauma, e.g., PT Limb reattachment
surgery•

Excluded:

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 Terms that refer to risk factors for accident or injury (e.g., PT Sudden onset ofsleep)
 Terms related to poisoning/toxicities and radiation associated accidents andinjuries (e.g., PT Pulmonary radiation injury)
 Terms for device and procedural complications
 Terms for repetitive motion injuries (e.g., PT Iliotibial band syndrome) Terms for tissue trophic consequences of injury (e.g., PT Myositis ossificans,
PT Eschar) Terms for arthropod, bites and stings
 Terms for birth trauma (e.g., PT Perinatal brain damage); this includes thematernal complication of laceration of cervix
 Terms for self-injury (e.g., PT Intentional self-injury)
 Terms for medication errors, iatrogenic injuries, and overdoses (e.g., PT Drugprescribing error, PT Iatrogenic injury)
 Terms for victims of crimes and abuse (e.g., PT Victim of child abuse)
 “Removal of foreign body” terms (e.g., PT Removal of foreign body fromexternal ear)
NOTE: Several specific terms pertaining to hemorrhage and hematoma were originally
included in this SMQ because they were found to be useful in the identification of cases
relevant to Accidents and injuries (SMQ). However, these conditions may result frommultiple etiologies, including, but not limited to injury. In addition to the selected
hemorrhage terms in this SMQ, this note is included to remind the user that
Haemorrhages (SMQ) may also be useful in identifying potential reports of accidents
and injuries
NOTE: Currently, many MedDRA PTs (e.g., PT Gallbladder injury) have dual links togroupings in SOC Injury, poisoning and procedural complications and groupings in“disorder” SOCs, implying that the terms can represent either metabolic or traumatic
injury. This needs to be borne in mind when reviewing cases retrieved by this SMQ.
NOTE: Users should consider including cases coded to LLT Loss of teeth due toaccident, extraction, or local periodontal disease; to LLT Injury asphyxiation; and to LLT
Accidental needle stick – these terms are not currently linked to an included PT in thisSMQ but may retrieve cases of interest.
2.1.3 Notes on Implementation and/or Expectation of Query Results
Accidents and injuries (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.

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2.1.4 List of References for Accidents and injuries (SMQ)•

Wadsworth, EJK, Moss, SC, Simpson, SA, and Smith, AP. Psychotropic
medication use and accidents, injuries and cognitive failures. Hum
Psychopharmacol Clin Exp 2005; 20: 391-400.

•

Tinetti, ME, Speechley, M, and Ginter, SF. Risk factors for falls among elderly
persons living in the community. N Engl J Med 1988; 319(26): 1701-1707.

•

Oster, G, Huse, DM, Adams, SF, Imbimbo, J, and Russell, MW. Benzodiazepine
tranquilizers and the risk of accidental injury. Am J Public Health 1990; 80: 14671470.

•

Stedman’s Medical Dictionary, 27th edition, 2000.

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2.2

Acute central respiratory depression (SMQ)(Production Release September 2007)

NOTE: The original CIOMS WG documentation sometimes refers to this SMQ as“Central respiratory depression”; it was subsequently renamed to Acute central
respiratory depression (SMQ).
2.2.1 Definition•

Acute central respiratory depression is a form of respiratory failure•

Respiratory failure is defined as impairment of gas exchange between ambient
air and circulating blood Problems in intrapulmonary gas exchange lead to hypoxemia
 Problems in the movement of gases cause hypercapnia•

Depression of the respiratory center with resulting respiratory acidosis may
occur:
 Acutely with general anesthetics, sedatives, and head trauma
 Chronically with sedatives, alcohol, intracranial tumors, and syndromes of
sleep-disordered breathing, including the primary alveolar and obesityhypoventilation syndromes•

Acute hypoxemia may cause cardiac arrhythmia and coma. Alteration of
consciousness is typical, confusion is common•

Acute hypercapnia may cause: Subtle personality changes and headache through to marked confusion andnarcosis
 Cerebral vasodilatation and increased CSF pressure Acidemia which, when severe, contributes to pulmonary arteriolar
vasoconstriction, systemic vascular dilatation, reduced myocardial
contractility, hyperkalemia, hypotension, and cardiac irritability•

Central respiratory depression mainly occurs in neonates of prematurity or insleep apnea
 Apnea of prematurity may be caused by CNS immaturity (central) or airway
obstruction
 Central sleep apnea (CSA) has two categories:o Hypercapnia with decreased ventilatory drive or a decreased ability tobreathe. Causes include central lesions, such as brain stem infarctions,encephalitis, Arnold-Chiari malformation.
o Eucapnia or hypocapnia with increased ventilatory drive but sleep-induced
apnea and periodic breathing. Cheyne-Stokes breathing is a discrete

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pattern of this form of CSA. Causes include heart failure, high altitude,
pain, anxiety. (Cheyne-Stokes respiration is also seen in opiate associatedrespiratory depression).
2.2.2 Inclusion/Exclusion Criteria•

Included: Relevant investigation terms containing the word “abnormal”, such as thoseunder HLT Blood gas and acid base analyses, included in broad search
 Broad “umbrella” terms such as PT Respiratory failure included in narrowsearch Other potential umbrella terms such as PT Respiratory acidosis included inbroad search Terms indicating neonatal events (e.g., PT Neonatal respiratory depression) Signs and symptoms like PT Respiratory arrest, PT Cardio-respiratory arrest
included in broad search although pre-production testing indicated that thesetwo PTs might create “noise”•

Excluded: PTs containing the word “normal” (e.g., PT Blood gases normal)
 Terms without a qualifier (e.g., PT PO2, PT Carbon dioxide) PTs that indicate an etiology rather than that potentially drug-induced, e.g.,
PT Cardiac asthma or PT Pickwickian syndrome PT Anxiety due to high “noise” level Non-specific symptoms related to respiratory acidosis/failure such as
peripheral arterial vasodilatation, central vasoconstriction and pulmonaryedema Known causes of respiratory depression due to high “noise” level

NOTE: The terms in Acute central respiratory depression (SMQ) were updated in
Version 18.0 on the basis of new testing results. The original testing of Acute central
respiratory depression (SMQ) was performed with MedDRA 10.1. During a subsequent
initiative to broaden the scope of this SMQ to include terms for both chronic and noncentral causes, re-testing was performed using the PTs from the existing Acute central
respiratory depression (SMQ) and a set of new PT proposals for the broader
Respiratory failure (SMQ) which was in development. Upon review of the test results,
this initiative was not pursued, because it was determined that the specificity of the
SMQ would have been diminished, and excessive “noise” complicated retrieval ofcases specific to centrally acting drugs potentially associated with acute central
respiratory depression. Consequently, Respiratory failure (SMQ) was developed as anadditional stand-alone SMQ. As a result of this testing, 28 term modifications to Acute
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central respiratory depression (SMQ) were included in the MedDRA Version 18.0
release. For detailed information, please refer to the original documentation for Acutecentral respiratory depression (SMQ), to which the most recent re-test results havebeen added.
2.2.3 Notes on Implementation and/or Expectation of Query Results
Acute central respiratory depression (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.2.4 List of References for Acute central respiratory depression (SMQ)•

The Merck Manual accessed online on 12 January 2006.
http://www.merck.com/mmpe/sec06/ch065/ch065c.html?qt=acute%20respiratory&alt=sh•Harrison’s Principles of Internal Medicine, accessed online on 12 January 2006.

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2.3

Acute pancreatitis (SMQ)(Production Release November 2005)
2.3.1 Definition•

Drug-induced pancreatitis is usually an acute condition. If clinically suspected, itshould always be confirmed by biochemical investigations•

Definition of acute pancreatitis: An inflammatory disease of the pancreas characterized by upper abdominal
pain and vomiting; in severe cases – abdominal guarding, rigidity, reboundtenderness and diminution or loss of bowel sounds
 Almost always accompanied by increased pancreatic enzymes – amylase
and lipase – in the blood and urine Other signs/findings are icterus, increased alkaline phosphatase and/or
bilirubin, ileus, ascites, hyperglycemia, hypocalcemia and leukocytosis
 Cullen’s sign is sometimes associated with severe necrotizing pancreatitis•

Severe attacks may lead to shock with renal and pulmonary insufficiency, which
may be fatal

2.3.2 Inclusion/Exclusion Criteria•

Included: PTs with the word “pancreatitis” (other than those indicative of chronic
conditions) PTs indicative of pancreatic dysfunction (such as pancreatorenal syndrome) PT Cullen’s sign
 Terms for laboratory values (abnormal/increased values) and signs andsymptoms relevant for pancreatitis per definition
 Terms for typical complications, e.g. PT Pancreatic pseudocyst•

Excluded: Terms for chronic pancreatitis
 Terms representing forms of pancreatitis not considered drug-related (e.g. PT
Pancreatitis mumps, PT Cytomegalovirus pancreatitis)

2.3.3 Algorithm
To apply the algorithm for this SMQ, a report is considered a relevant case for further
review if:•

it includes a term from Category A

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OR•

it includes at least one term from Category B (the list of laboratory values) and at
least one term from Category C (the list of signs and symptoms)

2.3.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Acute pancreatitis (SMQ) is an algorithmic
SMQ. The algorithm is a combination of broad search terms among various categories
to further refine the identification of cases of interest. The algorithm can be
implemented in a post-retrieval process as noted below:•

First, retrieve relevant cases by applying the SMQ query as a narrow and broad
searches (see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination to screen thecases retrieved above. For small data sets of retrieved cases, the algorithm may
be applied on manual review of cases. The algorithm for Acute pancreatitis(SMQ) is A or (B and C). Cases filtered by the algorithm can be listed for output.

2.3.5 List of References for Acute pancreatitis (SMQ)•

Anonymous. Pancreatitis. Reporting Adverse Drug Reactions: Definitions ofTerms and Criteria for Their Use. Bankowski Z, Bruppacher R, Crusius I et al(Eds). Council for International Organizations of Medical Sciences: Geneva,
1999, pp 53-54.

•

Berardi RR and Montgomery PA. Pancreatitis. Pharmacotherapy: A
Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert RL, Yee GC et al (Eds).
McGraw-Hill: New York, NY. 1999. pp 701-715.

•

Greenberger NJ, Toskes PP, and Isselbacher KJ. Acute and chronicpancreatitis. Harrison’s Principles of Internal Medicine (14th Ed). Fauci AS,
Braunwald E, Isselbacher KJ et al (Eds). McGraw-Hill: New York, NY. 1998. pp
1741-1752.

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2.4

Acute renal failure (SMQ)(Production Release April 2005)
2.4.1 Definition
Acute renal failure (ARF) is a syndrome characterized by:•

A relatively rapid decline in renal function that leads to the accumulation of water,
crystalloid solutes, and nitrogenous metabolites in the body.

•

Other clinical features include: increase in serum creatinine and urea nitrogenlevels (azotemia) greater than 0.5 and 10 mg per deciliter, respectively; oliguria;
and changes in the rate of urine flow.

ARF may present with a de novo onset in individuals whose baseline renal function waswithin normal limits. Additionally, ARF may consist of acute exacerbation of pre-existing
chronic renal insufficiency.
2.4.2 Inclusion/Exclusion Criteria•

Included: Narrow scope: diagnoses and symptoms that are unique or directly lead toacute renal failure are included. For example, PT Acute kidney injury(diagnosis) and PT Anuria (symptom).
 Broad scope: These terms have the potential of identifying positive cases.
o Test results that are closely related to acute renal failure, such as PT
Blood urea increased (test result).
o Key pathological changes of ARF, such as acute tubular necrosis

o Prominent drug-induced etiologies of ARF, such as interstitial nephritis
 Some commonly reported reactions identified in drug-induced acute renal
failure, such as terms for acute tubular necrosis, pre-renal failure, vascularnephropathy, and tubular obstruction.
 Renal dialysis PTs from SOC Surgical and medical procedures, e.g., dialysis,
hemodialysis, and peritoneal dialysis•

Excluded: Normal and unspecified investigational terms (e.g., PT Blood creatinine),
except for PT Fractional excretion of sodium (please refer to note below)
 PTs referring to chronic renal failure (e.g., PT Chronic kidney disease) Electrolyte imbalances (i.e., terms for hyperkalemia, hyponatremia, and blood
potassium increased): case evaluations in Phase I testing revealed that theseelectrolyte imbalances were not specific enough for ARF to identify
representative cases.

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 Terms representing prerenal etiologies (e.g., PT Renal vein occlusion, PT
Cardiac failure, PT Hepatic cirrhosis, etc.) or terms suggestive of a non-druginduced renal failure (e.g., PT Glomerulonephritis acute, etc.)
 PT Nephritic syndrome because it is commonly caused by infection or othernon-drug related events.
 This SMQ is focused on the acute phase, i.e., sudden, reversible failure ofkidney function. Terms for prolonged reactions are excluded, such as focal
glomerulosclerosis, which occurs when scar tissue forms in some of theglomeruli of the kidney; proliferative glomerulonephritis, and rapidly
progressive glomerulonephritis that include conditions in which progressive
loss of kidney function occurs over weeks to months.
NOTE: In Version 18.0, in accordance with recent International Society of Nephrology
classifications and terminology, LLT Acute kidney injury was swapped with PT Renal
failure acute, resulting in new PT Acute kidney injury; and LLT Chronic kidney disease
was switched with PT Renal failure chronic, resulting in new PT Chronic kidney disease.
NOTE: In Version 18.0, PT Fractional excretion of sodium was added as a broad scope
term to Acute renal failure (SMQ), as an exception to the exclusion criterion “Normal
and unspecified investigational terms.” Fractional excretion of sodium assessment isuseful in the evaluation of acute renal failure to determine whether renal failure is due topre-renal, post-renal, or intrinsic renal pathology. PT Fractional excretion of sodium isthus of potential relevance for inclusion in this SMQ for the identification of cases ofacute renal failure.
2.4.3 Notes on Implementation and/or Expectation of Query Results
Acute renal failure (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.4.4 List of References for Acute renal failure (SMQ)•

The Merck Manual, 17th Edition.

•

Cecil Textbook of Medicine, 19th Edition.

•

Harrison’s Principles of Internal Medicine, 13th Edition.

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2.5

Agranulocytosis (SMQ)(Production Release November 2005)
2.5.1 Definition•

Agranulocytosis can occur as a reaction to a wide variety of toxic agents(including drugs)•

Life-threatening due to increased susceptibility to infection•

Overall annual incidence less than 1:100,000 in the general population•

Severe neutropenia (< 0.5 x 109/l of circulating granulocytes) associated with thesudden onset of signs and symptoms of bacterial infection such as: Fever, malaise and prostration
 Oropharyngeal or anorectal lesions

2.5.2 Inclusion/Exclusion Criteria•

Included: All MedDRA terms with the word “agranulocytosis”
 Terms representing serious disorders affecting white blood cells
 “Combination” terms of white blood cell disorders and infections/fever (e.g.,
PT Febrile neutropenia)
 All sepsis terms related to bacterial infections except PT Anthrax sepsis (seeexclusion criteria below). This including those sepsis conditions that are mostfrequent although not solely caused by bacteria infection, such as PT
Abdominal sepsis.
 Terms representing typical mucosal and tonsillar lesions•

Excluded: Non-specific terms representing general signs and symptoms ofagranulocytosis (e.g., arthralgia, fever, chills, swelling of cervical lymph
nodes, malaise, and prostration)
 PT Anthrax sepsis: it is not associated with agranulocytosis. A patient could
have anthrax sepsis without a deficit of neutrophils.

NOTE: If possible, full blood counts and repeated white blood cell counts should bereported, sought for in follow up, and coded. Concerning database queries with broad
search terms, additionally coded data on hematological values help to find relevantcases more easily. In case laboratory values are not coded in a database, individual
review is then needed to decide upon relevance in the context of agranulocytosis.
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2.5.3 Notes on Implementation and/or Expectation of Query Results
Agranulocytosis (SMQ) has features of narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
2.5.4 List of References for Agranulocytosis (SMQ)•

Reporting Adverse Drug Reactions, Definitions and Criteria for Their Use,CIOMS, Geneva, 1999.

•

Harrison’s Principles of Internal Medicine, 15th edition, Eugene Braunwald [etal.], McGraw-Hill, 2001.

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2.6

Anaphylactic reaction (SMQ)(Production Release November 2005)
2.6.1 Definition•

An acute systemic reaction characterized by pruritus, generalized flush, urticaria,
respiratory distress and vascular collapse•

Occurs in a previously sensitized person upon re-exposure to the sensitizing
antigen•

Other signs and symptoms: agitation, palpitation, parasthesias, wheezing,angioedema, coughing, sneezing and difficulty breathing due to laryngeal spasm
or bronchospasm
 Less frequent clinical presentations: seizures, vomiting, abdominal cramps
and incontinence

2.6.2 Inclusion/Exclusion Criteria•

Included: Any terms, at the PT level, representing events which may be noted during
anaphylaxis
 In a spreadsheet format, the testing pharmaceutical company’s list and thetesting regulator’s list were positioned alongside the MedDRA SSC list foranaphylaxis, and this three-column table was then systematically reviewed
top-down. Unanimous agreement for/against inclusion of each term wasachieved by the group•

Excluded: Terms for signs and symptoms that do not fall within the three defined
categories (Upper Airway/Respiratory, Angioedema/Urticaria/Pruritus/Flush,
and Cardiovascular/Hypotension) in the broad search are excluded.

NOTE: There are two SMQs related to anaphylaxis: Anaphylactic reaction (SMQ) andAnaphylactic/anaphylactoid shock conditions (SMQ). The two SMQs have different
focuses. Anaphylactic/anaphylactoid shock (SMQ) is specific for more severe
anaphylactic manifestations, i.e. those that result in shock, and not less severe ones
such as rash. Anaphylactic reaction (SMQ) widens the search beyond shock conditions
by including such terms as PT Type I hypersensitivity.
2.6.3 Algorithm
The SMQ Anaphylactic reaction consists of three parts:•

A narrow search containing PTs that represent core anaphylactic reaction terms

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A broad search that contains additional terms that are added to those includedin the narrow search. These additional terms are signs and symptoms possibly
indicative of anaphylactic reaction;•

An algorithmic approach which combines a number of anaphylactic reaction
symptoms in order to increase specificity. A case must include either: A narrow term or a term from Category A;
 A term from Category B - (Upper Airway/Respiratory) AND a term from
Category C - (Angioedema/Urticaria/Pruritus/Flush);
 A term from Category D - (Cardiovascular/Hypotension) AND [a term from
Category B - (Upper Airway/Respiratory) OR a term from Category C (Angioedema/Urticaria/ Pruritus/Flush)]

2.6.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Anaphylactic reaction (SMQ) is an algorithmic
SMQ. The algorithm is a combination of broad search terms among various categories
to further refine the identification of cases of interest. The algorithm can be
implemented in a post-retrieval process as noted below:•

First, retrieve relevant cases by applying the SMQ query as a narrow/broad SMQ(see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination to screen thecases retrieved above. For small data sets of retrieved cases, the algorithm may
be applied on manual review of cases. The algorithm for Anaphylactic reaction(SMQ) is A or (B and C) or (D and (B or C)). Cases filtered by the algorithm canbe listed for output.

2.6.5 List of References for Anaphylactic reaction (SMQ)•

The Merck Manual. 15th edition. Merck, Sharp & Dohme Research Laboratories.
(1987): 306-7.

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2.7

Angioedema (SMQ)(Production Release November 2005)
2.7.1•

Definition
Urticaria (CIOMS definition): Many possible causes (e.g., insect stings, food and drugs)
 Characterized by multiple transient wheals, usually with itching; individual
lesions may come and go but are of short duration•

Angioedema (also called Quincke’s oedema or angioneurotic oedema): Similar to urticaria but involving the deeper dermal, submucosal andsubcutaneous tissues
 Sometimes associated with severe respiratory distress due to edema of theupper airway
 Edema results from dilatation and increased permeability of the capillaries•

Urticaria and angioedema may appear separately or together as cutaneous
manifestations of localized nonpitting edema
 Similar process may occur at mucosal surfaces of the upper respiratory or
gastrointestinal tract Angioedema of the upper respiratory tract may be life-threatening due tolaryngeal obstruction•

Urticaria and/or angioedema are classified as: IgE-dependent, e.g., specific antigen sensitivity to pollens, food, drugs, etc.
fungi, molds, Hymenoptera venom, etc.
 Complement-mediated (hereditary type 1 and 2; acquired type 1 and 2,
necrotizing vasculitis, serum sickness, etc.)
 Non-immunologic (opiates, antibiotics, radiocontrast media, aspirin, azo dyes,etc.) Idiopathic

2.7.2
•

Inclusion/Exclusion Criteria
Included: Terms containing the words “angioedema” or “angioneurotic oedema”
 All PTs linked to HLT Angioedemas. This includes PT Hereditaryangioedema which -- although initially considered for exclusion -- is listed as anarrow search term for optional use.

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 PTs indicating similar conditions, edema, or swelling affecting the face, upper
respiratory tract, and other parts of the body, including the gastrointestinaltract All PTs containing the word “urticaria” that link to HLT Urticarias (such as PT
Urticaria, PT Urticaria chronic, PT Idiopathic urticaria, etc.) and which do notindicate a relationship to the application site (such as PT Application site
urticaria) or a non-drug related cause (such as PT Solar urticaria)
 PT Allergic oedema•

Excluded: Terms indicating a relation to an injection/infusion/application of a drug suchas infusion site swelling, infusion site edema, etc.
 Urticaria pigmentosa, as this condition is cutaneous mastocytosis
 Nausea and vomiting (non-specific symptoms that would create too much“noise” relative to signal)

2.7.3

Notes on Implementation and/or Expectation of Query Results

Angioedema (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.7.4

List of References for Angioedema (SMQ)•

Bankowski Z, Bruppacher R, Crusius I et al. Reporting adverse drug reactions,definition of terms and criteria for their use. Council for International
Organizations of Medical Sciences (CIOMS) 1999 pp 12 -13.

•

Dorland’s Illustrated Medical Dictionary, 28th Edition 1994 p78.

•

Braunwald E, Fauci A and Kasper D. Harrison’s Principles of Internal Medicine,
15th Edition, 2001 p 341 and pp 1917-1918.

•

Beers M and Berkow R. The Merck Manual of diagnosis and therapy, 17thedition, dated 1999 pp 1054-56.

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2.8

Anticholinergic syndrome (SMQ)(Production Release September 2006)
2.8.1

Definition•

Anticholinergic syndrome is a confusional state with characteristic features
related to dysfunction of the autonomic parasympathetic (cholinergic) nervous
system.

•The presence of fixed and dilated pupils is essential.

•

Anticholinergic compounds (muscarinic receptor antagonists) inhibit the actionsof acetylcholine at receptors on neurons, ganglions, autonomic effector sites
innervated by postganglionic cholinergic nerves and also at sites lacking
cholinergic innervation.

•

Clinical picture described as “hot as a hare, blind as a bat, dry as a bone, red asa beet and mad as a hatter”.

•

Symptoms classified into systemic and CNS manifestations.
 Systemic (peripheral) symptoms: blurred vision, photophobia, nonreactive
mydriasis, loss of accommodation response, flushed and dry skin, dry mouth,tachycardia, hypertension and fever. Gastrointestinal and urinary motility are
frequently reduced.
 Central Anticholinergic Syndrome is an acute psychosis-like picture
characterized by delirium, agitation, disorientation, and visual hallucinations.
Ataxia, choreoathetosis, myoclonus and seizures may also occur without
peripheral symptoms.

2.8.2
•

Inclusion/Exclusion Criteria
Included PTs related to anticholinergic syndrome and its major manifestations as
described above This SMQ is focused on the acute anticholinergic syndrome•

Excluded No specific terms excluded

2.8.3

Algorithm

The categories are defined as following:•

Category A (narrow scope): Cases encoding to PT Anticholinergic syndrome•

Category B (broad scope): Nervous system-related PTs•

Category C (broad scope): Psychiatric-related PTs

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Category D (broad scope): Other relevant anticholinergic syndrome-related PTs

The algorithmic approach is as follows: Cases to be selected for further review would
include any cases reporting the PT listed for Category A or any case reporting somecombination of at least one PT from each of the three groups of PTs listed as
Categories B, C, and D.
Note: Some reporters included only terms from the SOC Psychiatric disorders; otherreporters included only non-CNS related terms. If it is considered important to identify
these cases, then a non-algorithmic approach should be taken for the broad search;however, this approach may identify a large number of irrelevant cases.
The CIOMS WG for SMQs reviewed phase II feedback on this SMQ at their May 2006
meeting. A MedDRA subscriber had commented that PT Hypertension is not includedin this SMQ. The leader of the development team for this SMQ indicated that inclusionof PT Hypertension had been considered, but that it was felt to be non-specific andlikely to lead to retrieval of many non-relevant cases. In addition, the team reviewed allcases in a regulatory database for a strong positive control test product for this SMQ
and found only a single case that reported hypertension.
2.8.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Anticholinergic syndrome (SMQ) is analgorithmic SMQ. The algorithm is a combination of broad search terms among various
categories to further refine the identification of cases of interest. The algorithm can be
implemented in a post-retrieval process as noted below:•

First, retrieve relevant cases by applying the SMQ query as a narrow and broad
searches (see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination to screen thecases retrieved above. For small data sets of retrieved cases, the algorithm may
be applied on manual review of cases. The algorithm for Anticholinergic
syndrome (SMQ) is A or (B and C and D). Cases filtered by the algorithm can belisted for output.

2.8.5 List of References for Anticholinergic syndrome (SMQ)•

Bankowski Z, Bruppacher R, Crusius I et al. Reporting adverse drug reactions,definition of 1. Terms and criteria for their use. Council for International
Organizations of Medical Sciences (CIOMS), 1999. Pages 24-25.

•

Heller Brown J, Taylor P. Muscarinic receptor agonists and antagonists. In:
Hardman JG, Limbird LE, Molinoff PB, Ruddon RW eds. Goodman and Gilman:
The Pharmacological Basis of Therapeutics. New York, NY: McGraw Hill;
1996:141-160.

•

Watemberg NM et al. Central Anticholinergic Syndrome on Therapeutic Doses of
Cyproheptadine. Pediatrics. 103(1):158-60, Jan 1999.

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2.9

Arthritis (SMQ)(Production Release September 2013)
2.9.1 Definition•

SMQ Arthritis is intended to identify potential cases of arthritis and worsened
arthritis that may be drug related•

Arthritis = inflammation of one or more joints, resulting in: Redness
 Warmth Pain Swelling Stiffness
 Limited movement•

Numerous types of arthritis exist, including: Osteoarthritis (degenerative joint disease) Infective arthritis
 Rheumatoid arthritis
 Psoriatic arthritis
 Related autoimmune diseases•

Pain caused by intra-articular disorders may be secondary to: Inflammatory arthritis (e.g., infection, RA, crystal deposition)
 Noninflammatory process (e.g., osteoarthritis)•

Inflammatory arthritis may involve: Peripheral joints only (e.g., hands, knees, feet); or Both peripheral and axial joints (e.g., sacroiliac, apophyseal, discovertebral,costovertebral)•

Peripheral oligoarticular and polyarticular arthritis have specific likely causessuch as: Juvenile idiopathic arthritis
 Lyme disease arthritis•

Acute polyarticular arthritis:
 Most often due to infection (usually viral), or flare of a rheumatic disease•

Chronic polyarticular arthritis:
 In adults:
o Most often due to rheumatoid arthritis (inflammatory), or osteoarthritis(noninflammatory)

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 In children:o Most often due to juvenile idiopathic arthritis
•

2.9.2
•

In many patients, arthritis is often transient, resolving without diagnosis, or may
not fulfill criteria for a defined rheumatic disease
Inclusion/Exclusion criteria
Included: Terms for various forms of arthritis including infective, reactive and rheumatic
disorders Terms for signs and symptoms of joint inflammations, e.g., PT Joint stiffness
 Terms for relevant investigations and procedural that help to identify and treat
arthritis and common complications
 Terms for systemic autoimmune diseases for which joint inflammation is partof the concept, e.g., PT SLE arthritis
 Terms for diseases that can mimic arthritis because of similar characteristics,
e.g., PT Plica syndrome Terms for genetic syndromes affecting joints e.g., PT Pyogenic sterile arthritis
pyoderma gangrenosum and acne syndrome•

Excluded: Terms for non-drug etiologies that are not always associated with arthritis,
e.g., PT Diabetic arthropathy, PT Behcet's syndrome Terms for organ abnormalities of rheumatoid diseases in which the arthritic
component is not the focus. e.g., PT Rheumatoid lun Causative terms, e.g., PT Femoroacetabular impingement
 Terms for non-specific and broad concepts that contribute to “noise” in data
output, e.g., PT Pain in extremity, PT Bone scan abnormal

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2.9.3
•

List of References for Arthritis (SMQ)
Polyarticular joint pain. The Merck Manual for Health Professionals,
http://www.merckmanuals.com/professional/musculoskeletal_and_connective_tis
sue_disorders/symptoms_of_joint_disorders/polyarticular_joint_pain.html

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2.10

Asthma/bronchospasm (SMQ)(Production Release November 2005)
2.10.1 Definition•

Asthma: A chronic inflammatory disorder of the airways in which mast cells,
eosinophils and T lymphocytes play a role
 The inflammation causes an increased airway responsiveness to a variety ofstimuli leading to bronchospasm/bronchoconstriction
 Clinically characterized by recurrent, generally short-lived episodes(especially at night or in early morning) of wheezing, breathlessness, chest
tightness, and cough Characteristic of these episodes is variable airflow limitation; this may resolve
or partly reversed either spontaneously or with treatment•

Bronchospasm/bronchoconstriction:
 Airflow limitation due to contraction of bronchial smooth muscle; an
improvement in airflow in response to bronchodilators is essential for the
diagnosis
 Bronchospasm, along with airway inflammation, is a contributing factor to
airway limitation in asthmatics
 “Aggravated bronchospasm/bronchoconstriction” and “paradoxicalbronchospasm” are terms used when there is an unexpected episode of
bronchospasm/bronchoconstriction with inhalation aerosol treatment of lungdisorders; its causes can be either the inhalation procedure or irritation due tothe aerosol (active or inactive ingredients)

2.10.2 Inclusion/Exclusion Criteria•

Included: Terms describing various forms of asthma/bronchospasm (excluding PT
Cardiac asthma) Terms representing the various signs and symptoms, mainly of a respiratory
nature Supporting investigations terms such as PT Charcot-Leyden crystals;
additional investigation terms representative of pulmonary function test
abnormalities (e.g., PT Forced expiratory volume decreased)

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Excluded: Related infectious disorders (e.g., PT Bronchopulmonary aspergillosis
allergic)
 Treatment and/or prophylaxis-related terms (e.g., PT Asthma prophylaxis)
 Various respiratory signs and symptoms considered too non-specific to add
value in case identification (e.g., PT Dyspnoea, PT Chest discomfort, PT
Rhonchi, PT Respiratory distress, and PT Total lung capacity increased)

2.10.3 Notes on Implementation and/or Expectation of Query Results
Asthma/bronchospasm (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.10.4 List of References for Asthma/bronchospasm (SMQ)•CIOMS publication, “Reporting Adverse Drug Reactions: Definitions of Terms
and Criteria for their Use”, pp 89 – 90, 1999.

•

The Merck Manual, Seventeenth Edition, pp 556 – 568, 1999.

•“Harrison’s Principles of Internal Medicine”, 14th edition, pp 1419 – 1426, 1998.

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2.11

Biliary disorders (SMQ)(Production Release September 2007)
2.11.1 Definition•

SMQ developed to detect all types of disorders related to the biliary tract(treatment-associated or as medical history)•

Concerns all types of gallbladder and bile duct disorders.

•

Includes neoplasms and congenital disorders related to biliary tract

2.11.2 Inclusion/Exclusion Criteria•

Included: SMQ Biliary disorders covers all types of conditions related to biliary disorders
including:o Neoplasmso Congenital disorderso Investigationso Signs and symptoms of biliary disorders
 Sub-SMQ Functional, inflammatory and gallstone related biliary disorders
o All functional, inflammatory and gallstone related biliary disorders
 Sub-SMQ Biliary system related investigations, signs and symptoms
o Investigationso Signs and symptoms
 Sub-SMQ Gallbladder related disorderso Specific disorders of the gallbladder Sub-SMQ Biliary tract disorderso Specific disorders of the bile duct Sub-SMQ Infectious biliary disorders
o Infections of the biliary tracto Inflammatory conditions which are possibly the result of infection
 Sub-SMQ Gallstone related disorders
o Conditions related to gallstones
 Sub-SMQ Biliary neoplasms
o Biliary neoplasms (benign and malignant)
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 Sub-SMQ Biliary neoplasms malignant and unspecified
o Malignant biliary neoplasms

o Biliary neoplasms unspecified as benign or malignant
 Sub-SMQ Biliary neoplasms benign (incl cysts and polyps)o Benign biliary neoplasms
 SMQ Congenital biliary disorders
o Congenital disorders of biliary system•

Excluded: Non-specific laboratory test results (e.g., PT Hepatic enzyme increased, PT
Gamma-glutamyltransferase abnormal, PT Gamma-glutamyltransferase
increased) LLT Pancreatitis due to gallstones is excluded because it is linked to PT
Pancreatitis which is not included in the SMQ (see NOTE below)
 Sub-SMQ Functional, inflammatory and gallstone related biliary disorders
o Neoplasmso Congenital disorders
NOTE: In MedDRA v16.0, Level 3 SMQ Bile duct related disorders was renamed to
SMQ Biliary tract disorders because some of the included “biliary” terms are not bileduct-specific. Also, Level 3 SMQ Site unspecified biliary disorders was merged under
the renamed SMQ Biliary tract disorders (please refer to the v16.0 Version Report for alisting of the impacted terms); therefore, SMQ Site unspecified biliary disorders nolonger exists
NOTE: If the user requires a complete search of all biliary tract and liver-related
investigation terms, use of SMQ Liver related investigations, signs and symptoms (subsearch SMQ of SMQ Hepatic disorders) together with SMQ Biliary system related
investigations, signs and symptoms is recommended.
NOTE: LLT Pancreatitis due to gallstones links to PT Pancreatitis which is not included
in SMQ Biliary disorders. Inclusion of this LLT in a search may, however, be consideredby the user.
NOTE: Sub-search SMQ Biliary system related investigations, signs and symptoms iscalled SMQ Bile system related investigations, signs and symptoms in the CIOMS WG
original documentation.
NOTE: In Version 14.0, two new sub-SMQs have been added to existing sub-SMQ
Biliary neoplasms malignant and unspecified to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.

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NOTE: In Version 12.1, sub-SMQ Biliary neoplasms benign was renamed sub-SMQ
Biliary neoplasms benign (incl cysts and polyps)
NOTE: In Version 12.1, sub-SMQ Biliary system related investigations, signs andsymptoms was modified in scope to include both broad and narrow search terms, fromformerly narrow terms only.
NOTE: In Version 12.1, sub-search SMQ Biliary system related investigations, signs
and symptoms was modified to have both broad and narrow scope terms, fromformerly having narrow terms only. Other than the hierarchy structure, theimplementation for this sub-search SMQ is similar to the non-hierarchical SMQs withnarrow and broad search terms (see section 1.5.2.1).

2.11.3 Hierarchy Structure
Biliary disorders(20000118)

Functional, inflammatoryand gallstone related
biliary disorders(20000119)
Biliary system
relatedinvestigations,signs andsymptoms(20000123)

Gallbladder
relateddisorders(20000124)

Gallstone
relateddisorders(20000127)

Biliary
neoplasms(20000121)

Infectious biliary
disorders(20000120)

Biliary tract
disorders(20000125)

Biliary
neoplasms
malignant andunspecified(20000128)

Biliary malignant
tumours (SMQ)(20000196)

Congenital
biliary disorders(20000122)

Biliary
neoplasms
benign (inclcysts andpolyps)(20000129)

Biliary tumours of unspecified
malignancy (SMQ)(20000197)

Figure 2-1. Hierarchy Structure of Biliary disorders (SMQ)

2.11.4 Notes on Implementation and/or Expectation of Query Results
Biliary disorders (SMQ) is a hierarchical SMQ with only narrow search terms for elevenof the twelve sub-SMQs (Sub-SMQ Biliary system related investigations, signs andsymptoms includes both broad and narrow terms). Therefore, for eleven of the subSMQs, narrow search and broad search return the same result for superordinate andsubordinate SMQs. Other than the hierarchy structure, the implementation is similar to
the non-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1).
The superordinate SMQ can be applied by combining the terms in the subordinate
SMQs.
Because terms for investigations, signs and symptoms are grouped in sub-SMQ Biliary
system related investigations, signs and symptoms (SMQ), subordinate SMQs of Biliary
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disorders (SMQ) are not independent queries. For example, to find relevant cases of“gallstone related disorders”, those retrieved by sub-SMQ Gallstone related disorders(SMQ) may not be sufficient. Cases retrieved by terms for relevant signs andsymptoms, such as PT Jaundice, and those for laboratory result terms, such as bilirubin
test terms (located in sub-SMQ Biliary system related investigations, signs andsymptoms (SMQ)) may need to be included to get a complete set of relevant cases.
Therefore, some level of manual intervention is required when applying subordinate
SMQs. Medical judgment may need to be applied.
2.11.5 List of References for Biliary disorders (SMQ)•

Harrison’s Principles of Internal Medicine 16th ed, Mc Graw Hill, 2005, pp
1880-1891.

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2.12

Breast neoplasms, malignant and unspecified (SMQ)(Production Release September 2008)

2.12.1 Definition•

Developed to detect all malignant and unspecified tumors related to breast•

Covers all malignant and unspecified neoplasms related to breast and in
addition: Malignancy related conditions
 Malignancy related therapeutic and diagnostic procedures Tumor markers specific for this organ

2.12.2 Inclusion/Exclusion Criteria•

Included: Terms for malignant or unspecified neoplasms with a clear reference tobreast Terms for conditions related to malignant or unspecified neoplasms ofbreast, including:o Procedureso Investigationso Tumor markers

o Signs and symptoms pointing to such disorders
 Male versions of breast neoplasm terms
 PT Phyllodes tumour , (denotes a rare, predominantly benign tumor which
can be malignant)•Excluded: Terms for malignant or unspecified neoplasms without a clear reference tobreast Terms for unspecified site malignancy related therapeutic and diagnostic
procedures and tumor markers
 Terms for metastases to breast PT Metastases to reproductive organ PT Breast operation as it is not a malignancy specific therapeutic
procedure. (This term may, however, be added if a very broad search is
required).

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NOTE: In Version 14.0, two new sub-SMQs have been added to Breast neoplasms,
malignant and unspecified (SMQ) to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.
NOTE: For searches of non-specific malignancy related conditions and malignancy
related therapeutic and diagnostic procedures, it is recommended to use the respective
lower level sub-SMQ of SMQ Malignancies.
NOTE: PT Breast operation is excluded from this SMQ but may be added if a verybroad search is required.
2.12.3 Hierarchy Structure
Breast neoplasms,
malignant andunspecified (SMQ)(20000149)

Breast malignant tumours(SMQ)(20000198)

Breast tumours ofunspecified malignancy(SMQ)(20000199)

Figure 2-2. Hierarchy Structure of Breast neoplasms, malignant andunspecified (SMQ)
2.12.4 Notes on Implementation and/or Expectation of Query Results
Breast neoplasms, malignant and unspecified (SMQ) has narrow and broad searchterms. The detailed notes are documented in section 1.5.2.1.
2.12.5 List of References for Breast neoplasms, malignant and unspecified(SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of
Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H, Veronesi, U., Oxford Textbook of Oncology. 1995.

•

European Group on Tumour Markers (EGTM). http://egtm.web.med.unimuenchen.de.

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2.13

Cardiac arrhythmias (SMQ)(Production Release September 2006)
2.13.1 Definition•

Arrhythmia is any disorder of the formation or conduction of the cardiac impulse.

•

Arrhythmia may be primary, due to electrophysiological disorder, or secondary,caused by hemodynamic or other abnormalities.

•

Arrhythmias are divided into two main groups:
 Bradyarrhythmias
 Tachyarrhythmias

2.13.2 Inclusion/Exclusion Criteria•

Included All types of conditions which are related to cardiac arrhythmias, including
conduction disturbances and repolarization defects. It includes appropriate
ECG, investigations and heart rate terms•

Excluded Cardiac pacemaker related procedures and investigations and heart rate
related terms referring to normal values or not stating an abnormality (e.g. PT
Heart rate normal and PT Heart rate)

NOTE: SMQ Torsade de pointes/QT prolongation is a separate level 1 SMQ. For the
analysis of all cardiac arrhythmia cases, it is recommended to include Torsade depointes/QT prolongation (SMQ) in the search.
NOTE: In Version 12.1, the following sub-SMQs were modified in scope to include both
broad and narrow search terms (formerly included only broad terms):
Arrhythmia related investigations, signs and symptoms (SMQ)
Congenital and neonatal arrhythmias (SMQ)
Supraventricular tachyarrhythmias (SMQ)
Ventricular tachyarrhythmias (SMQ)
NOTE: In Version 12.1, the following sub-SMQs were modified in scope to include only
narrow search terms (formerly included only broad terms):
Bradyarrhythmia terms, nonspecific (SMQ)
Cardiac arrhythmia terms, nonspecific (SMQ)
Conduction defects (SMQ)
Disorders of sinus node function (SMQ)
Tachyarrhythmia terms, nonspecific (SMQ)
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2.13.3 Hierarchy Structure

Cardiac arrhythmias(20000049)
Cardiac arrhythmia terms (incl
bradyarrhythmias andtachyarrhythmias)(20000050)

Arrhythmia related
investigations,signs and symptoms(20000051)

Bradyarrhythmias (incl conduction
defects and disorders of sinus nodefunction)(20000053)

Cardiac arrythmia
terms, nonspecific(20000162)

Conduction
defects(20000056)

Disorders ofsinus nodefunction(20000055)

Bradyarrhythmia
terms,
nonspecific(20000163)

Congenital andneonatal arrhythmias(20000052)

Tachyarrhythmias (inclsupraventricular and ventriculartachyarrhythmias)(20000054)

Supraventriculartachyarrhythmias(20000057)

Ventriculartachyarrhythmias(20000058)

Tachyarrhythmia
terms, nonspecific(20000164)

Figure 2-3. Hierarchy Structure of Cardiac arrhythmias (SMQ)In Version 12.0, per user’s request, Cardiac arrhythmia terms, nonspecific (SMQ) was
added at level 3 to group the PTs that have been linked to Cardiac arrhythmia terms(incl bradyarrhythmias and tachyarrhythmias) (SMQ) but did not belong to any of its
sub-SMQs. Unlike other level 3 sub-SMQs (e.g., Bradyarrhythmias (incl conduction
defects and disorders of sinus node function) (SMQ)), Cardiac arrhythmia terms,
nonspecific (SMQ) is not a standalone SMQ topic. It should only be used as part of its
superordinate SMQ topic - Cardiac arrhythmia terms (incl bradyarrhythmias andtachyarrhythmias) (SMQ).
For the same purpose, Bradyarrhythmia terms, nonspecific (SMQ) was added at level 4
to group the PTs that had been linked to Bradyarrhythmias (incl conduction defects anddisorders of sinus node function) (SMQ) and Tachyarrhythmia terms, nonspecific (SMQ)
was added at level 4 to group PTs that had been linked to Tachyarrhythmias (inclsupraventricular and ventricular tachyarrhythmias) (SMQ). Both Bradyarrhythmia terms,
nonspecific (SMQ) and Tachyarrhythmia terms, nonspecific (SMQ) are not standalone
SMQ topics. They should only be used as part of their superordinate SMQ topics.
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2.13.4 Notes on Implementation and/or Expectation of Query Results
Cardiac arrhythmias (SMQ) is a hierarchical SMQ with both broad and narrow searchterms.
The following seven sub-SMQs have both Broad and Narrow Search Terms. Other thanthe hierarchy structure, the implementation for this SMQ is similar to the nonhierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.
•

Arrhythmia related investigations, signs and symptoms (SMQ)•

Bradyarrhythmias (incl conduction defects and disorders of sinus node function)
(SMQ)

•

Cardiac arrhythmia terms (incl bradyarrhythmias and tachyarrhythmias (SMQ)•

Congenital and neonatal arrhythmias (SMQ)•

Supraventricular tachyarrhythmias (SMQ)•

Tachyarrhythmias (incl supraventricular and ventricular tachyarrhythmias) (SMQ)•

Ventricular tachyarrhythmias (SMQ)

The following five sub-SMQs have only narrow search terms. Therefore, the narrowsearch and broad search return the same result. The detailed notes are documented in
section 1.5.2.1.
•

Bradyarrhythmia terms, nonspecific (SMQ)•

Cardiac arrhythmia terms, nonspecific (SMQ)•

Conduction defects (SMQ)•

Disorders of sinus node function (SMQ)•

Tachyarrhythmia terms, nonspecific (SMQ)

Because terms for supporting investigations, signs and symptoms are grouped in subSMQ Arrhythmia related investigations, signs and symptoms (SMQ), subordinate SMQs
of Cardiac arrhythmias (SMQ), which contain only diagnosis and pathognomonic sign,
symptom, or investigation result terms, are not independent queries. For example, tofind relevant cases of “conduction defects,” those retrieved by sub-SMQ Conduction
defects (SMQ) may not be sufficient. Cases retrieved by terms for supporting
investigation results, such as ECG test terms (located in sub-SMQ Arrhythmia related
investigations, signs and symptoms (SMQ)) may need to be included to get a complete
set of relevant cases. Similar to Biliary disorders (SMQ), some level of manualintervention is required when applying subordinate SMQs. Medical judgment may need
to be applied.
2.13.5 List of References for Cardiac arrhythmias (SMQ)•

Harrison’s Textbook of Internal Medicine.

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2.14

Cardiac failure (SMQ)(Production Release March 2007)
2.14.1 Definition•

A condition in which the heart is unable to pump an adequate amount of blood tomeet metabolic and physiological needs of body•

Classified on basis of severity according to criteria set by New York Heart
Association (NYHA)
 Classes I to IV starting from no limitation of physical activity to slight ormarked limitation, up to the inability to carry out any physical activity without
discomfort•

Clinical findings vary but include: dependent edema, raised jugular venous
pressure, hepatomegaly, pulmonary congestion/edema, tachycardia,
cardiomegaly, and dyspnea•

Cardiac ejection fraction is less than 35%.

2.14.2 Inclusion/Exclusion Criteria
This SMQ does not make a distinction between left and right ventricular failure.
•

Included: Narrow scope:o Terms describing existing cardiac failure in its various forms with orwithout right/left ventricular specifiedo A small number of terms for symptoms, signs, investigational findings, andprocedures that are pathognomonic of the condition
 Broad scope:•oSigns, symptoms or investigational findings highly suggestive of current
or past evidence for this conditionoCardiac cirrhosis

Excluded: Causality terms of cardiac failure, such as ventricular tachyarrhythmia or
myocardial infarction
 Signs and symptoms that may result from cardiac failure, but are shared withso many other etiologies that they would merely serve to add noise or
confusion to the search (e.g., dyspnea other than paroxysmal nocturnal
dyspnea and orthopnea)
 General effects of cardiac failure on the liver and kidney

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2.14.3 Algorithm
The CIOMS Working Group discussed in detail whether an algorithm could be applied
to this SMQ based on the definition of cardiac failure provided. Such an algorithm,
however, has not been tested by the CIOMS Working Group. Therefore, the Working
Group is requesting users to comment on the practical relevance of an algorithm
approach. Such an algorithm could involve broad terms as follows: one edema term,
one dyspnea term plus one clinical/sign/symptom or investigation, making up threeterms in total.
2.14.4 Notes on Implementation and/or Expectation of Query Results
Cardiac failure (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.14.5 List of References for Cardiac failure (SMQ)•

Council for International Organisations of Medical Sciences (CIOMS).
Reporting Adverse Drug Reactions. Definition of terms and criteria for theiruse. 1999: p 64-65.

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2.15

Cardiomyopathy (SMQ)(Production Release September 2008)
2.15.1 Definition•

Cardiomyopathy: general diagnostic term designating
 Primary non-inflammatory disease of heart muscle
 Often of obscure or unknown etiology
 Not the result of:o Ischemia

o Hypertension

o Congenital anomaly

o Valvular diseaseo Pericardial disease Usually subdivided into the following forms:
o Dilatedo Hypertrophic
o Restrictive•

According to World Health Organization (WHO): Only those disorders in which pathological process involves only
myocardium Cause is unknown Not part of a disease affecting other organs
 Also called “primary cardiomyopathy”

2.15.2 Inclusion/Exclusion Criteria•

Included: PTs containing "cardiomyopathy" or "myocarditis" Cardiomyopathy-related PTs linked to HLGT Myocardial disorders
 Terms for hypertensive cardiomyopathy (e.g., PT Hypertensive
cardiomyopathy) and its associated findings (e.g., PT Ventricular
hypertrophy)
 Terms for inflammatory conditions that may result in cardiomyopathy (e.g.,
PT Cardiac sarcoidosis)

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 Terms for ischemic conditions that may result in cardiomyopathy (e.g., PT
Ischaemic cardiomyopathy)
 PTs for secondary forms of cardiomyopathy
 PTs for metabolic influences that may lead to cardiomyopathy (e.g., PT
Cardiomyopathy alcoholic) Cardiomyopathy-related PTs linked to HLGT Cardiac and vascularinvestigations (excl enzyme tests)
 PTs Heart and lung transplant, PT Heart transplant, and PT Ventricularassist device insertion (linked to HLT Cardiac therapeutic procedures
NEC) Postural hypotension terms
 Cardiac biopsy terms•

Excluded: Terms for coronary heart diseases
 Terms for valvular diseases
 Terms for pericardial diseases
 Terms for epicardial diseases
 Terms for endocardial diseases
 PT Myectomy (linked to HLT Muscle therapeutic procedures)
 All congenital terms, e.g., PT Arrhythmogenic right ventricular dysplasia,
PT Congenital cardiovascular anomaly, PT Heart disease congenital, PT
Uhl’s anomaly, etc.
 Terms for laboratory findings and test results (e.g. PT Atrial natriuretic
peptide increased) that are not specific for heart failure

NOTE: The narrow search is very specific, and cardiomyopathy – seen from thereporting and adverse event coding perspective – does not have very specific signs or
symptoms. PT Dyspnoea might create substantial “noise” in retrieval of cases andtherefore may be excluded from a query.
In testing, most cases were retrieved by the broad search terms of Cardiac failure(SMQ) (and were not also retrieved by narrow search terms).
Users may also consider the broad search terms from Cardiac failure (SMQ) as a morecomprehensive list of heart failure signs and symptoms which may be of additional
potential relevance to the identification of cases of cardiomyopathy.
2.15.3 Notes on Implementation and/or Expectation of Query Results
Cardiomyopathy (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
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2.15.4 List of References for Cardiomyopathy (SMQ)•

Dorland’s Illustrated Medical Dictionary, Saunders, Philadelphia, 2000.

•

Towbin JA, Lipshultz SE.: Genetics of neonatal cardiomyopathy. Curr Opin
Cardiol. 1999 May;14(3):250-62.

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2.16

Central nervous system vascular disorders (SMQ)[Production Release September 2006; Renamed in
March 2015 from former name: Cerebrovasculardisorders (SMQ)]

2.16.1 Definition•

Concerns central nervous system hemorrhages and cerebrovascular accidents
 Divided into the two main groups of ischemic and hemorrhagic central
nervous system vascular disorders Additional small group contains terms not covered by these main groups

2.16.2 Inclusion/Exclusion Criteria•

Included: Terms for conditions related to cerebrovascular disorders irrespective ofcause and irrespective of acuteness or chronicity
 Congenital cerebrovascular disorder terms
 Cerebrovascular disorder terms related to infections
 Terms describing cerebrovascular procedures•

Excluded: Cerebrovascular disorder terms clearly related to accidents and injuries,

e.g. PT Traumatic intracranial haemorrhage

NOTE: For searches related to retinal vascular pathology, subscribers have several
available options including Retinal disorders (SMQ), Embolic and thrombotic events(SMQ) as well as the creation of a modified MedDRA query based on an SMQ.
NOTE: The CIOMS WG for SMQs reviewed phase II feedback on this SMQ at their May
2006 meeting. A MedDRA subscriber had recommended the addition of several signs
and symptoms terms that were already present in the broad search. In addition, a term
for memory impairment was suggested, but the WG agreed not to include such a term
as it was felt to be non-specific.
NOTE: The terms in Conditions associated with central nervous system haemorrhages
and cerebrovascular accidents (SMQ) reflect the most common and classic signs andsymptoms of cerebrovascular accidents.

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2.16.3 Hierarchy Structure

Central nervous system vasculardisorders(20000060)

Central nervous systemhaemorrhages andcerebrovascular conditions(20000061)

Ischaemic
central nervous system
vascular conditions(20000063)

Central nervous system vasculardisorders, not specified as
haemorrhagic or ischaemic(20000165)

Haemorrhagic
central nervous system
vascular conditions(20000064)

Conditions associated with central
nervous system haemorrhages andcerebrovascular accidents(20000166)

Figure 2-4. Hierarchy Structure of Central nervous system vasculardisorders (SMQ)
NOTE: Four SMQs were renamed in MedDRA Version 18.0 to more precisely represent
that the respective SMQ terms may pertain to both the brain and the spinal cord of thecentral nervous system:
Previous SMQ NameNew SMQ Name

Cerebrovascular disorders (SMQ)

Central nervous system vascular disorders(SMQ)

Cerebrovascular disorders, not specified as
haemorrhagic or ischaemic (SMQ)

Central nervous system vascular disorders,
not specified as haemorrhagic or ischaemic(SMQ)

Ischaemic cerebrovascular conditions (SMQ)

Ischaemic central nervous system vascularconditions (SMQ)

Haemorrhagic cerebrovascular conditions(SMQ)

Haemorrhagic central nervous system
vascular conditions (SMQ)

Level 2 SMQ Central nervous system haemorrhages and cerebrovascular conditions(SMQ) is divided into “narrow” and “broad” terms. The “narrow” group is divided into
two Level 3 SMQs, namely, Ischaemic central nervous system vascular conditions(SMQ) and SMQ Haemorrhagic central nervous system vascular conditions (SMQ).
In Version 12.0, per user’s request, Cerebrovascular disorders, not specified as
haemorrhagic or ischaemic (SMQ) was added at level 2 to group the PTs that had been
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linked to Cerebrovascular disorders (SMQ) but did not belong to the level 2 sub-SMQ
Central nervous system haemorrhages and cerebrovascular conditions (SMQ). Unlike
Central nervous system haemorrhages and cerebrovascular conditions (SMQ),
Cerebrovascular disorders, not specified as haemorrhagic or ischaemic (SMQ) is not a
standalone SMQ topic. It should only be used as part of its superordinate SMQ topic Cerebrovascular disorders (SMQ).
For the same purpose, Conditions associated with central nervous systemhaemorrhages and cerebrovascular accidents (SMQ) was added at level 3 to group thebroad terms that had been linked to Central nervous system haemorrhages andcerebrovascular conditions (SMQ). Conditions associated with central nervous systemhaemorrhages and cerebrovascular accidents (SMQ) is not a standalone SMQ topic. It
should only be used as part of its superordinate SMQ topic.
NOTE: Prior to Version 16.1, the terms in Conditions associated with central nervous
system haemorrhages and cerebrovascular accidents (SMQ) were broad scope only. In
Version 16.1, the terms included in Conditions associated with central nervous systemhaemorrhages and cerebrovascular accidents (SMQ) have been reclassified to beeither broad or narrow in scope.
NOTE: The names of the sub-SMQs in the CIOMS WG documentation differ from thisbulleted summary as follows:

CIOMS WG Document

Introductory Guide for Standardised
MedDRA Queries (SMQs)

SMQ 1.2 Other cerebrovasculardisordersThis sub-SMQ has been removed. All
sub-ordinate PTs, formerly in SMQ 1.2
Other cerebrovascular disorders arelinked to the level 2 sub-SMQ
Cerebrovascular disorders, notspecified as haemorrhagic or
ischaemic.

SMQ 1.1.1 Narrow search central
nervous system haemorrhages andcerebrovascular accidents

SMQ Central nervous systemhaemorrhages and cerebrovascularconditions [NOTE: This is ahierarchical SMQ which includes thefollowing three subordinate SMQs:
Conditions associated with central
nervous system haemorrhages andcerebrovascular accidents (SMQ) withnarrow and broad terms; Haemorrhagic
central nervous system vascularconditions (SMQ) and Ischaemic

SMQ 1.1.2 Broad search central
nervous system haemorrhages andcerebrovascular accidents

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central nervous system vascularconditions (SMQ)with only narrowterms each.
SMQ 1.2.1 Narrow search othercerebrovascular disorders

Merged into the level 1 SMQ

SMQ 1.2.2 Broad search othercerebrovascular disorders

Merged into the level 1 SMQ

Table 2-1. Link Table between CIOMS WG Document and SMQ Introductory Guide
for Central nervous system vascular disorders (SMQ)
2.16.4 Notes on Implementation and/or Expectation of Query Results
Central nervous system vascular disorders (SMQ) is a hierarchical SMQ with bothnarrow and broad search terms. Other than the hierarchy structure, the implementation
for this SMQ is similar to the non-hierarchical SMQs with narrow and broad searchterms (see section 1.5.2.1). The superordinate SMQ can be applied by combining theterms in the subordinate SMQs.
2.16.5 List of References for Central nervous system vascular disorders (SMQ)•

The Merck Manual (Seventeenth Edition), 1999.

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2.17

Chronic kidney disease (SMQ)(Production Release March 2013)
2.17.1 Definition•

Chronic kidney disease (CKD) = heterogeneous disorders affecting kidney
structure and function•

Variable presentation related to cause, pathology, severity and rate ofprogression•

Symptoms include: anorexia, nausea, vomiting, stomatitis, dysgeusia, nocturia,
lassitude, fatigue, pruritus, decreased mental acuity, muscle twitches andcramps, water retention, undernutrition, gastrointestinal ulceration and bleeding,
peripheral neuropathies, and seizures•

Diagnosis is based on laboratory testing of renal function and sometimes renal
biopsy•Treatment directed at the underlying condition but includes fluid and electrolyte
management, erythropoietin for anemia, dialysis or transplantation•

CKD may result from a number of causes including: Vascular disease:o Renal artery stenosiso C-ANCA-positive, P-ANCA-positive and ANCA-negative vasculitides
o Atheroembolio Hypertensive nephrosclerosiso Renal vein thrombosis

 Primary glomerular disease:oMembranous nephropathyo Immunoglobulin A (IgA) nephropathyo Focal and segmental glomerulosclerosiso Minimal change diseaseo Membranoproliferative glomerulonephritiso Rapidly progressive (crescentic) glomerulonephritis
 Secondary glomerular disease:o Diabetes mellitus

o Systemic lupus erythematosus
o Rheumatoid arthritis
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o Mixed connective tissue diseaseo Sclerodermao Goodpasture syndromeo Wegener granulomatosiso Mixed cryoglobulinemiao Postinfectious glomerulonephritis
o Endocarditis

o Hepatitis B and Co Syphiliso Human immunodeficiency virus (HIV)o Parasitic infectiono Heroin use
o Goldo Penicillamineo Amyloidosiso Light chain deposition diseaseo Neoplasiao Thrombotic thrombocytopenic purpurao Hemolytic-uremic syndromeo Henoch- Schönlein purpurao Alport syndromeo Reflux nephropathy

 Tubulointerstitial disease:o Drugs (e.g., sulfa, allopurinol)o Infection (viral, bacterial, parasitic)o Sjögren syndromeo Chronic hypokalemia and chronic hypercalcemia
o Sarcoidosis

o Multiple myeloma cast nephropathyo Heavy metals

o Radiation nephritis
o Polycystic kidneys
o Cystinosis

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 Urinary tract obstruction:o Urolithiasis

o Benign prostatic hypertrophyo Tumors

o Retroperitoneal fibrosiso Urethral strictureo Neurogenic bladder•Markers of kidney damage in addition to proteinuria include: Urine sediment abnormalities
 Abnormalities on imaging studies•

Two major outcomes of CKD include: Loss of kidney function leading to failure Development of cardiovascular disease•

High blood pressure is both a cause and a complication of CKD and isassociated with a faster loss of kidney function and development ofcardiovascular disease•

Additional complications include: Anemia Malnutrition
 Bone disease and disorders of calcium and phosphorus metabolism
 Neuropathies•

Criteria for CKD established by the National Kidney Foundation:
 Kidney damage for ≥3 months (structural or functional abnormalities) with orwithout decreased glomerular filtration rate manifested by either:o Pathological abnormalities; oro Markers of kidney damage (urine or blood abnormalities, or abnormalities
in imaging tests) Glomerular filtration rate <60 mL/min/1.73m2 for ≥3 months, with or without
kidney damage•

Five stages of CKD are defined as follows:

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Stage

Description

GFR(mL/min/1.73m)

1Kidney damage with normal or ↑ GFR≥90

2

Kidney damage with normal or ↓ GFR

60-89

3

Moderate ↓ GFR

30-59

4

Severe ↓ GFR

15-29

5

Kidney failure<15 (or dialysis)

2.17.2 Inclusion/Exclusion criteria•

Included: Terms related to the definition including signs and symptoms and long term
consequences of CKD (e.g., PT Chronic kidney disese, PT Chronic kidneydisease-mineral and bone disorder, and PT Oedema due to renal disease) Terms for pertinent laboratory tests including those qualified with “abnormal”(e.g., PT Glomerular filtration rate abnormal)
 Terms for therapeutic procedures associated with CKD (e.g., PT Peritoneal
dialysis)•

Excluded: Terms for underlying causes or risk factors for development of CKD (e.g., PT
Diabetes mellitus)­

Exceptions are nephropathies and other etiologic terms related directly torenal disease (e.g., included are terms such as PT Diabetic nephropathy,
but not PT Diabetes mellitus)­

PT Hypertension – along with several other terms that proved noisy on
testing – is excluded (see the CIOMS SMQ Working Group’s original
documentation for details)

 Terms for nonspecific symptoms likely to return considerable of “noise” (e.g.,
PT Nausea, PT Fatigue)
 Congenital and neonatal terms
 Renal transplant complications and rejection terms, except PT Chronic
allograft nephropathy

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NOTE: In Version 18.0, in accordance with recent International Society of Nephrology
classification and terminology, LLT Chronic kidney disease was swapped with PT Renal
failure chronic, resulting in new PT Chronic kidney disease.
NOTE: After testing of candidate SMQ Chronic kidney disease in both regulatory andcompany databases, several additional “untested” PTs were added to the term list of the
SMQ based on medical judgment. Please see the original CIOMS SMQ Working Group
documentation for additional details.
2.17.3 List of References for Chronic kidney disease (SMQ)•

Levey AS, Coresh J. Chronic kidney disease. The Lancet published online
August 15, 2011. DOI:10.1016/S0140-6736(11)60178-5•

Merck Manuals Online Medical Library for Health Professionals, Chronic Kidney
Disease, accessed 2011-09-26:
http://www.merckmanuals.com/professional/genitourinary_disorders/renal_failure/chronic_kidney_disease.html•

Verrelli, M. et al Chronic renal failure. eMedicine, accessed 2011-09-26:
http://emedicine.medscape.com/article/238798-overview•

Harrison’s On-line (Harrison’s Principles of Internal Medicine, 17e), Ch. 280,
Chronic Kidney Disease, accessed 2011-09-26
http://accessmedicine.com/content.aspx?aID=9130075&searchStr=kidney+failur
e%2c+chronic#9130075•

K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation,
Classification and Stratification. Am J Kidney Dis 39:S1-S266, 2002 (suppl 1)

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2.18

Conjunctival disorders (SMQ)(Production Release September 2009)
2.18.1 Definition•

Conjunctiva: mucous membrane investing Anterior surface of eye (bulbar conjunctiva)
 Posterior surface of eyelids (palpebral conjunctiva)•

Disorders that affect conjunctiva:
 Acute conjunctivitis (viral, bacterial, inclusion, seasonal/allergic)
 Chronic conjunctivitis (trachoma, perennial allergic, vernal
keratoconjunctivitis)•

Trauma (subconjunctival hemorrhage, foreign bodies, lacerations) Degenerative conditions (Cogan’s senile plaque, pinguecula, pterygium,
concretions, retention cysts)
 Blistering mucocutaneous diseases (cicatrical pemphigoid, Stevens-Johnson
syndrome) Pigmented lesions
 Tumors•

Symptoms vary according to underlying problem; some common features are:
 Complaints of a red eye Epiphora (excess tears)o Irritation, such as a foreign body sensation, due to presence of follicles orpapillaeo Itching – hallmark of allergic conjunctivitis but may also occur in blepharitis
or keratoconjunctivitis siccao Pain – generally mild. In absence of trauma, significant pain is unusualo Complaints of a discharge
2.18.2 Inclusion/Exclusion criteria•

Included:­Terms for irritation, inflammation, degeneration, deposit, and other nontraumatic and non-infectious conjunctival conditions­

Terms for investigations related to conjunctiva (e.g., PT Biopsy conjunctiva
abnormal)­Terms for conjunctiva procedures (e.g., PT Conjunctivoplasty)

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Terms for conjunctival neoplasms (e.g., PT Benign neoplasm of conjunctiva)­

PT Allergic keratitis because LLT Allergic keratoconjunctivitis is linked to thisPT and would likely retrieve relevant cases­

Terms where the origin of the event could be either infectious or noninfectious (see Exclusion criteria regarding exceptions) (e.g., PT Conjunctival
cyst)

Excluded: Terms for signs and symptoms of conjunctival disorders that could be sharedwith other eye disorders
 Terms for known causes of or syndromes associated with conjunctival
disorders (e.g., PT Pemphigoid) Terms that clearly indicate infections of conjunctiva (e.g., PT Conjunctivitis
bacterial) Terms related to conjunctival trauma (e.g., PT Chemical burns of eye) except
if the term may relate directly to application of an eye product (e.g., PT
Conjunctival abrasion)
 Congenital terms
 Scleral terms

2.18.3 Notes on Implementation and/or Expectation of Query Results
Conjunctival disorders (SMQ) has only narrow search terms. Therefore, the narrowsearch and broad search return the same result. The detailed notes are documented in
section 1.5.2.1.
2.18.4 List of References for Conjunctival disorders (SMQ)•

Scott, O. Conjunctival problems. Patient UK,
http://www.patient.co.uk/showdoc/40025324/, May 2008.

•

Conjunctival disorders. Merck Manual, 17th edition, pp 710 – 717, 1999.

•

Stedman’s Medical Dictionary, 27th Edition.

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2.19

Convulsions (SMQ)(Production Release March 2007)
2.19.1 Definition•

Seizure: paroxysmal event due to abnormal, excessive, hypersynchronous
discharges from an aggregate of central nervous system (CNS) neurons
 Manifestations range from dramatic convulsive activity to experiential
phenomena not readily discernible by an observer.

•

Epilepsy: recurrent seizures due to a chronic, underlying process; not a single
disease entity•

Convulsions are the motor component of cerebral seizures.
 Characterized by contractions of skeletal muscles, appearing abruptly andinvoluntarily
 Contractions may be tonic or clonic and they may be focal or generalized•

International Classification of Epileptic Seizures (1981):
 Partial seizures
o Simple partial seizures (with motor, sensory, autonomic, or psychic
signs)o Complex partial seizureso Partial seizures with secondary generalization
 Primarily generalized seizures
o Absence (petit mal)o Tonic clonic (grand mal)o Tonic

o Atonico Myoclonic Unclassified seizures
o Neonatal seizure
o Infantile spasms

2.19.2 Inclusion/Exclusion Criteria•

Included: PTs containing the words “convulsions”, “epilepsy” or “ictus”; irrespectiveof whether the form of seizure involved muscular movement (e.g. PT Petit
mal epilepsy)

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 Terms indicative for complications after convulsions (e.g. PT Postictal
paralysis) Relevant supporting terms from SOC Investigations containing the word
“abnormal” in the broad search Terms representing various signs and symptoms of convulsive events(e.g. PT Tongue biting) Congenital and genetic disorders if convulsions are a primary presenting
component of the disease or syndrome (e.g. PT Baltic myoclonic epilepsy)
 Treatment and/or prophylaxis related terms (e.g. PT Convulsion
prophylaxis)
 Diagnoses which are difficult to distinguish from seizures (e.g. PT
Narcolepsy)•

Excluded: Terms for SOC Investigations with the qualifier “normal” and those with noqualifier PTs describing “incontinence” were non-specific and retrieved irrelevantcases
 PTs Loss of consciousness and PT Depressed level of consciousness
contributed considerable “noise”
 PTs that only described movement without mentioning seizure (e.g. PT
Myoclonus)

2.19.3 Notes on Implementation and/or Expectation of Query Results
Convulsions (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.19.4 List of References for Convulsions (SMQ)•

Harrison’s online, Chapter 348, accessed on 29 May 2005
http://accessmedicine.com/public/about_am.aspx•

Bankowski Z, Bruppacher R, Crusius I et al. Reporting adverse drug
reactions, definition of 1. Terms and criteria for their use. Council forInternational Organizations of Medical Sciences (CIOMS), 1999. Pages 2425.

•

Commission on Classification and Terminology of the International League
Against Epilepsy. Proposal for revised clinical and electroencephalographic
classification of epileptic seizures. Epilepsia 22:489-501, 1981.

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2.20

Corneal disorders (SMQ)(Production Release March 2009)
2.20.1 Definition•

Corneal disorders grouped into: Refractive errors due to irregular curvature (myopia, hyperopia, andastigmatism)
 External eye conditions affecting cornea (allergies, conjunctivitis, Sjogren’s
syndrome)
 Corneal disorders:o Corneal infections

o Corneal dystrophieso Pterygiumo Drug associated conditions such as Stevens-Johnson syndrome•

SMQ defined to include corneal disorders with associated specific and selected
non specific signs and symptoms involving one or more layers of cornea
 Epithelium Bowman’s membrane Stroma Descemet’s membrane Endothelium

2.20.2 Inclusion/Exclusion Criteria•

Included: All terms involving the cornea•

Excluded: Congenital corneal disorders
 Infections involving cornea
 Physical injuries involving cornea

NOTE: Non specific terms such as PT Blindness, PT Visual impairment, and PT
Visual acuity reduced were removed after testing because they contributed
considerable noise. PT Stevens-Johnson syndrome was also removed after testing
because it represents a broader disorder and eye involvement occurs only in somecases.
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2.20.3 Notes on Implementation and/or Expectation of Query Results
Corneal disorders (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.20.4 List of References for Corneal disorders (SMQ)•

Anon. Facts about the Cornea and Corneal Disease. National Institutes of
Health, National Eye Institute. December 2007.
(http://www.nei.nih.gov/health/cornealdisease/index.asp#0)•

Hollander DA; Aldave AJ Drug-induced corneal complications. Curr Opin
Ophthalmol 2004 Dec;15(6):541-8.

•

Dart J. Corneal toxicity: the epithelium and stroma in iatrogenic and factitious
disease. Eye 2003 Nov; 17 (8):886-92.

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2.21

Dementia (SMQ)(Production Release March 2007)
2.21.1 Definition•

Dementia is defined as deterioration or loss of cognitive functions that impairs
activities of daily living (ADLs).

•

Numerous known causes:
 Metabolic-toxic (e.g., vitamin B12 deficiency) Structural (e.g., Alzheimer’s disease) Infectious (e.g., HIV-related)•Drug-associated (generally reversible) includes anticholinergics, sedatives
and barbiturates•

Other forms of dementia:
 Alzheimer’s disease (characterized by amyloid plaques and neurofibrillarytangles in the central nervous system) Vascular dementia (10% to 20% of cases); may co-exist with Alzheimer’s
disease Some medications (e.g., sleeping pills, anticholinergics, H2 blockers) are
known to exacerbate dementia of other etiologies.

•

Additional definitions from multiple references: Progressive loss of cognitive and intellectual function; disorientation,
impaired memory, judgment, and intellect, and a shallow labile affect Deterioration in cognitive abilities; impairs previously successful
performance of ADLs. Judgment, comprehension, orientation, learning,calculation, problem solving, mood and behavior may be affected. Deficits
in executive function – mental activity involved in planning, initiating andregulating behavior
 Cognitive impairment (memory, orientation, language), loss of functional
autonomy, neuropsychiatric signs/symptoms (agitation, apathy, delusions,aggressiveness)•

Modified DSM-IV criteria for dementia:
 Memory impairment
 One or more of the following cognitive disturbances:o Aphasiao Apraxia

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o Agnosia

o Disturbance in executive functioningo Impairment of social or occupational functioning•

Modified DSM-IV criteria for Alzheimer’s disease: Exclusion of other causes
 Loss of neurons in cerebral cortex subcortical structures
 Memory loss, inability to learn new information, language problems(especially word finding), mood swings, personality changes, problems
performing ADLs, diminished abstract thinking, diminished judgment,
irritability, hostility, agitation, aphasia, visuospatial difficulties, strange
behavior, emotional lability, behavioral disorganization, confusion,“sundowning”.

2.21.2 Inclusion/Exclusion Criteria•

Included: Terms that relate to the general definition of dementia (as describedabove)
 Alzheimer’s disease terms (because of the possibility that the reporter
assumes that dementia is Alzheimer’s and reports it as such) Vascular dementia
 Although testing results for Amnesia and hallucination terms did not show
useful, CIOMS WG decided to keep these terms in the SMQ. Specifically,
PT Amnestic disorder has been added
 PT Delusion and PT Delusional disorder, unspecified type are included inthis SMQ. For other more specific types of delusional disorders, one may
refer to the SMQ Psychosis and psychotic disorders.

•Excluded: Other specific diseases manifesting with dementia (e.g., normal pressurehydrocephalus) Pseudodementia
 Three PTs – Disturbance in attention, Insomnia, and Irritability – were
initially included but were subsequently removed based on testing results.

NOTE: In v15.0, new PT Substance-induced psychotic disorder was added, and several
LLTs that were previously subordinate to PT Psychotic disorder (such as: LLT Drug
psychoses, other; LLT Unspecified drug psychosis; LLT Steroid psychosis) were moved
to this new PT. Accordingly, these LLTs are no longer included in Dementia(SMQ), although PT Psychotic disorder remains a broad scope term in this SMQ. It was
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judged that the concepts represented by PT Substance-induced psychotic disorder do
not have a robust relevance to the identification of reports of dementia. PT Substanceinduced psychotic disorder may be electively included in a query by the user if relevantto the product or to the patient population being studied.
NOTE: In Version 13.1, Dementia (SMQ) was modified in scope to include both narrowand broad search terms. This SMQ formerly included only broad terms.
2.21.3 Notes on Implementation and/or Expectation of Query Results
Dementia (SMQ) has both narrow and broad search terms. The detailed notes are
documented in Section 1.5.2.1.
2.21.4 List of References for Dementia (SMQ)•

Stedman’s Medical Dictionary, 27th Edition, 2000.

•

Harrison’s Principles of Internal Medicine, 14th Edition, 1998, pp 142 – 149.

•

The Merck Manual 17th edition, 1999, pp 1393 – 1400.

•

Fago, JP. Dementia: Causes, Evaluation, and Management. Hospital
Practice. www.hosppract.com/.

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2.22

Demyelination (SMQ)(Production Release September 2008)
2.22.1 Definition•

Group of diseases of nervous system with damage and destruction of myelin
sheaths surrounding nerve fibers•

Axons may be damaged as well•

Mechanism of myelin damage may be different in various diseases•

Impairs conduction of signals in affected nerves•

Causes impairment in sensation, movement, cognition, or other functions•

Most common demyelinating disease is multiple sclerosis•

Other examples include central pontine myelinolysis, progressive multifocal
leukoencephalopathy, and subacute combined degeneration of spinal cord•

Demyelination: loss of myelin with preservation of the axons or fiber tracts
 Central demyelination occurs within central nervous system (e.g., multiple
sclerosis) Peripheral demyelination affects peripheral nervous system (e.g., GuillainBarre syndrome) Other causes:
o Genetico Autoimmune reactiono Immunological disorders

o Nutritional or metabolic disordero Toxins (including some used in therapy such as anti-mitotic agents andradiotherapy)o Unknown
2.22.2 Inclusion/Exclusion Criteria•

Included: Terms for peripheral and central demyelinating diseases (e.g., PT Multiple
sclerosis, PT Guillain-Barre syndrome, and PT MELAS syndrome) Terms containing the root “demyel” (e.g., PT Demyelinating polyneuropathy
and PT Chronic inflammatory demyelinating polyradiculoneuropathy)
 Terms for cranial nerve disorders specific to demyelinating disorders (e.g., PT
Optic neuritis)

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 Terms for encephalomyelitis and leukoencephalopathies related todemyelination (e.g., PT Acute haemorrhagic leukoencephalitis and PT
Progressive multifocal leukoencephalopathy)
 Terms for very specific signs or symptoms that are not included in SMQ
Peripheral neuropathy or SMQ Guillain-Barre syndrome are included in broad
terms (see NOTE below) (e.g., PT Lhermitte's sign and PT Saccadic eye
movement) PT Trigeminal neuralgia is included in broad terms due to possible
association with multiple sclerosis or other demyelinating conditions
 Terms representing a disability scale which is highly specific for MS ( e.g., PT

Expanded disability status scale score increased)•

Excluded: Congenital terms
 Terms for dysmyelinating diseases
 Terms for causes of demyelination (e.g., PT Alcoholism, PT Vitamin B12
deficiency)
 Terms for signs and symptoms that are already included in SMQ Peripheral
neuropathy or SMQ Guillain-Barre syndrome (e.g., PT Paraesthesia, PT
Areflexia, PT Muscular weakness)
 Terms for signs and symptoms that are very non-specific or represent
advanced demyelination (e.g., PT Dizziness, PT Fatigue, PT Anal
incontinence and PT Muscle spasticity) Investigational test terms, in general, are excluded with the exception of very
specific diagnostic and prognostic concepts (e.g., PT Expanded disability
status scale score increased) Terms for non-specific neuropathies and cranial nerve disorders
 HIV terms
 The following PTs: PT Polyneuropathy in malignant disease, PT Plasma cell
myeloma, PT POEMS syndrome, PT Lyme disease, PT Waldenstrom's
macroglobulinaemia, and PT Optic neuritis meningococcal

NOTE: If searching for a de novo signal of demyelination, it is recommended to use thenarrow and broad terms in this SMQ and also SMQ Peripheral neuropathy and SMQ
Guillain-Barre syndrome. Broad terms for signs and symptoms of demyelinating
diseases were excluded because they are in SMQ Peripheral neuropathy and SMQ
Guillain-Barre syndrome. Some broad terms were also excluded as being too nonspecific, related to advanced demyelination, or because of poor performance in SMQ

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testing. These excluded terms (see Tables 1 and 2 in the original CIOMS WG
documentation) may be included in a search at the user’s discretion.
2.22.3 Notes on Implementation and/or Expectation of Query Results
Demyelination (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.22.4 List of References for Demyelination (SMQ) http://www.uvm.edu/~jkessler/NP/neumyshe.htm#anchor4438902.
 Gale Encyclopedia of Neurological Disorders. 2005. The Gale Group, Inc.
 Stedman’s Medical Dictionary 26th ed.
 Demyelinating Diseases. Walter R. Timperley, M.D. Lecture. 2000.
http://www.dokkyomed.ac.jp/dep-k/cli-path/a-super/super-demyeli.html

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2.23

Depression and suicide/self-injury (SMQ)(Production Release March 2006)

2.23.1 Definition•

Depression is a morbid mental state dominated by a lowering of mood Often includes a variety of associated symptoms, particularly anxiety,agitation, feelings of unworthiness, suicidal ideas, alteration of appetite andsexual function, psychomotor retardation, sleep disturbance, and various
somatic signs and symptoms•

Etiology is complex and is thought to reflect changes in brain neurotransmitters,
particularly norepinephrine, serotonin, and dopamine•

May follow a severe psychosocial stressor•

Often associated with chronic medical conditions (such as diabetes, myocardial
infarction, carcinomas, stroke)•

Associated with a variety of medications (such as antihypertensive drugs, oral
contraceptives, and corticosteroids)•

Patients also frequently develop other psychiatric conditions, most notableanxiety or panic disorders, and alcohol or substance abuse•

Thoughts of death, suicidal ideation, and suicide attempts are frequent
complications of depression•

Diagnostic criteria as described in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) of depression-related disorders
include the presence of depressed mood or markedly diminished interest or
pleasure in all, or almost all, activities for most of the day, nearly every day

2.23.2 Inclusion/Exclusion Criteria•

Included: Relevant PTs selected by comparing the DSM-IV diagnostic criteria for Major
Depressive Episode, Major Depressive Disorder, Minor Depressive Disorder,
Dysthymic Disorder, and Substance-Induced Mood Disorder.
 PTs related to depression or depression-related symptoms, depressed oraltered mood, feelings of guilt or despair, psychomotor retardation oragitation, specific depression-related sleep disturbances, substance abuse,suicide, and psychiatric therapies suggestive of depression.
 PT Intentional overdose and PT Poisoning deliberate are included in the
narrow search of the Suicide/self-injury (SMQ) because their LLTs aresuggestive of suicide or self-injury.

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 The insomnia-related PTs, PT Terminal insomnia, PT Initial insomnia, and PT
Middle insomnia are somewhat more specific to the type of insomnia often
reported in depressed patients and they were included in the SMQ.
 As the result of the 18-24 month review of this SMQ by the CIOMS WG team,abuse and dependence concepts are included as broad scope terms for thelevel 1 SMQ Depression and suicide/self-injury.
•

Excluded: PTs for anxiety not associated with depression, agitation, restlessness,fatigue, or weight changes
 PT Insomnia because it only creates “noise” based on Phase I testing

2.23.3 Hierarchy Structure
Depression and suicide/selfinjury(20000035)

Suicide/self-injury(20000037)

Depression (exclsuicide and self injury)(20000167)

Figure 2-5. Hierarchy Structure of Depression and suicide/self-injury (SMQ)
This SMQ has a two-level hierarchy consisting of a comprehensive search of
depression (first level) terms and a sub-SMQ specific for suicide and self-injury (second
level):•

Depression and suicide/self-injury (SMQ): including depression specific terms,
which are grouped under Depression (excl suicide and self injury) (SMQ), and allterms under Suicide/self-injury (SMQ).

•

Suicide/self-injury (SMQ): only narrow search is proposed as separate narrowand broad searches were determined not necessary by the SMQ Working Group.

In Version 12.0, per user’s request, Depression (excl suicide and self injury) (SMQ) was
added at level 2 to group the PTs that had been linked to Depression and suicide/selfinjury (SMQ) but did not belong to the level 2 sub-SMQ Suicide/self-injury (SMQ).
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Unlike Suicide/self-injury (SMQ), Depression (excl suicide and self injury) (SMQ) is nota standalone SMQ topic. It should only be used as part of its superordinate SMQ topic Depression and suicide/self-injury (SMQ).
2.23.4 Notes on Implementation and/or Expectation of Query Results
Depression and suicide/self-injury (SMQ) is a hierarchical SMQ. The parent SMQ(Depression and suicide/self-injury (SMQ)) has both narrow and broad search terms.
However the sub-SMQ (Suicide/self-injury (SMQ)) has only narrow search terms. Thus,
the sub-SMQ’s narrow and broad searches would return the same result. Other thanthe hierarchy structure, the implementation for this SMQ is similar to the nonhierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.
2.23.5 List of References for Depression and suicide/self-injury (SMQ)•

Definitions and basic requirements for the use of terms for reporting adverse
drug reactions (IV). Pharmacoepidemiology and Drug Safety 1993; 2:149153.

•

Depression. Reporting Adverse Drug Reactions: Definitions of Terms andCriteria for Their Use. Bankowski Z, Bruppacher R, Crusius I et al (Eds).
Council for International Organizations of Medical Sciences: Geneva, 1999,
pg. 43.

•Kando JC, Wells BG, and Hayes PE. Depressive disorders.
Pharmacotherapy: A Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert
RL, Yee GC et al (Eds). McGraw-Hill: New York, 2002, pg. 1243-1264.

•

Major depressive episode. Diagnostic and Statistical Manual of Mental
Disorders (4th Ed). American Psychiatric Association: Washington DC, 1994,
pg. 320-327.

•

Major depressive disorder. Diagnostic and Statistical Manual of Mental
Disorders (4th Ed). American Psychiatric Association: Washington DC, 1994,
pg. 370-375.

•

Substance-induced mood disorder. Diagnostic and Statistical Manual of
Mental Disorders (4th Ed). American Psychiatric Association: Washington
DC, 1994, pg. 370-375.

•

Dysthymic disorder. Diagnostic and Statistical Manual of Mental Disorders(4th Ed). American Psychiatric Association: Washington DC, 1994, pg. 345350.

•

Minor depressive disorder. Diagnostic and Statistical Manual of Mental
Disorders (4th Ed). American Psychiatric Association: Washington DC, 1994,
pg. 719-721.

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2.24

Drug abuse, dependence and withdrawal (SMQ)(Production Release September 2007)

2.24.1 Definition•

Drug abuse: Habitual use of drugs:o Not needed for therapeutic purposes (e.g., to alter mood)o To effect a body function unnecessarily (e.g., laxative)o Non-medical use of drugs

 Prevalence of cocaine, other psychostimulant abuse appears to be
increasing in some metropolitan areas
 Initiation and persistence of drug abuse determined by complex interactionof:o Pharmacologic properties and relative availability of drug, thepersonality and the expectation of the user, and the environmental
context in which the drug is usedo Personality and expectation of user, and the environmental context inwhich the drug is usedo Environmental context of drug usage
 Polydrug abuse is increasingly common
 May be an acute or a chronic intoxication
 Symptoms vary according to pharmacologic properties, dose, and regularuse of drug•

Withdrawal:
 Abrupt cessation of use in a habituated person
 A substance specific syndrome follows cessation or reduction in intake ofa psychoactive substance previously used regularly Withdrawal symptoms vary according to psychoactive substance used:
o Generally “opposite” the acute effects of drugo Include nonspecific symptoms e.g., nausea, diarrhea or obstipation,
profuse sweating, increase in respiratory rate, tachycardia
o Common symptoms include anxiety, restlessness, irritability, insomnia,
impaired attention

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2.24.2 Inclusion/Exclusion Criteria•

Included: Drug abuse/dependence:o All terms containing “abuse,” “intentional misuse,” “illicit drug,” or“dependence” included as narrow terms
o Terms observed with abuse but which also occur without abuse (e.g. ,“increased tolerance” or “overdose” or “drug level increased” or “drugtoxicity”) included as broad terms
o Terms indicating neonatal events
 Withdrawal:o All terms containing “drug withdrawal” included as narrow terms

o Terms only containing “withdrawal” or “rebound” included as broadterms
o Terms indicating neonatal events
NOTE: Between the original version of this SMQ (based on MedDRA Version 9.1) and
MedDRA Version 10.0, originally included PT Rebound hypertension was demoted toan LLT linked to PT Hypertension. Because PT Hypertension is non-specific and has
linked LLTs unrelated to drug withdrawal, PT Hypertension has not been added to thisSMQ. When applying this SMQ, users should keep in mind that there may be cases ofinterest linked to LLT Rebound hypertension.
•

Excluded: Drug abuse/dependence:o Terms for symptoms of drug abuse or drug intoxicationo Terms for laboratory values indicating increased level of specific drugs
due to the fact that some such terms (e.g., PT Analgesic drug level
above therapeutic) were initially included and tested but were
subsequently deleted following discussion by CIOMS WG team.
 Terms related to alcohol and nicotine abuse Medication error/maladministration terms are generally excluded except
for terms related to inappropriate use of medication, such as incorrect site,
incorrect route, as they may signify drug abuse.
 Withdrawal:o Terms for symptoms of drug withdrawal (too nonspecific and create toomuch “noise”)
o Terms related to alcohol and nicotine withdrawal

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o Terms for “withdrawal” that do not fit the definition for this SMQ, i.e.,
drugs that are neither psychoactive, nor used habitually.
2.24.3 Hierarchy Structure
Drug abuse,dependence
and withdrawal(20000100)

Drug abuse anddependence(20000101)

Drug
withdrawal(20000102)

Figure 2-6. Hierarchy Structure of Drug abuse, dependence and withdrawal(SMQ)
NOTE: (added in Version 17.1) This SMQ does not contain signs and symptoms often
associated with drug abuse and dependence, including neurological signs andsymptoms like dizziness, disturbances in consciousness, anxiety symptoms, andperception disturbances such as hallucinations, etc., which are mostly found in SOC
Nervous system disorders and SOC Psychiatric disorders. These types of terms were
not added to the SMQ due to their potential to introduce “noise”, and because,
depending on the drug in question, the manifestations of drug abuse and dependence
may vary significantly. Nevertheless, they should be taken into account if deemed
appropriate for a particular search.
NOTE: In Version 16.0, Level 2 SMQ Drug abuse was renamed to SMQ Drug abuseand dependence.
NOTE: The original CIOMS WG documentation refers to this SMQ as SMQ Drug abuse
and withdrawal. It also refers to sub-SMQ Drug withdrawal as SMQ Withdrawal.
2.24.4 Notes on Implementation and/or Expectation of Query Results
Drug abuse, dependence and withdrawal (SMQ) is a hierarchical SMQ with narrow andbroad search terms. Other than the hierarchy structure, the implementation for this
SMQ is similar to the non-hierarchical SMQs with narrow and broad search terms (seesection 1.5.2.1). The superordinate SMQ can be applied by combining the terms in thesubordinate SMQs.

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2.24.5 List of References for Drug abuse, dependence and withdrawal (SMQ)•

Stedman’s Medical dictionary 5th Edition, Lippincrott, Williams & Wilkins, 2005.

•

Harrison’s Principles of internal Medicine, 16th Edition, McGraw Hill, 2005.

•

Huang B, Dawson DA, Stinson FS, Hasin DS, Ruan WJ, Saha TD, Smith SM,
Goldstein RB, Grant BF. Prevalence, correlates, and comorbidity of nonmedicalprescription drug use and drug use disorders in the United States: Results of the
National Epidemiologic Survey on Alcohol and Related Conditions. J Clin
Psychiatry 2006 Jul;67(7):1062-73.

•

Isaacson JH, Hopper JA, Alford DP, Parran T. Prescription drug use and abuse.
Risk factors, red flags, and prevention strategies. Postgrad Med 2005.
Jul;118(1):19-26•

Haydon E, Rehm J, Fischer B, Monga N, Adlaf E. Prescription drug abuse in
Canada and the diversion of prescription drugs into the illicit drug market. Can J
Public Health 2005 Nov-Dec;96(6):459-61.

•

Woody GE, Senay EC, Geller A, Adams EH, Inciardi JA, Schnoll S AU - Munoz
A TI - An independent assessment of MEDWatch reporting forabuse/dependence and withdrawal from Ultram (tramadol hydrochloride). Drug
Alcohol Depend 2003 Nov 24;72(2):163-8.

•

Brady KT, Lydiard RB, Brady JV. Assessing abuse liability in clinical trials. Drug
Alcohol Depend 2003 Jun 5;70(3 Suppl):S87-95.

•

Johnson MD, Heriza TJ, St Dennis C. How to spot illicit drug abuse in yourpatients. Postgrad Med 1999 Oct 1;106(4):199-200.

•

Widlitz M, Marin DB. Substance abuse in older adults. An overview. Geriatrics
2002 Dec;57(12):29-34.

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2.25

Drug reaction with eosinophilia and systemic symptoms syndrome (SMQ)(Production Release March 2016)

2.25.1 Definition•

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe,potentially life-threatening, delayed-onset drug reaction characterized by skineruption, fever, hematologic abnormalities (eosinophilia, atypical lymphocytes),
lymphadenopathy, and internal organ involvement. Although initially reported with
antiepileptic medications, the syndrome has also been reported with othermedications. It is associated with a highly variable clinical presentation, withpatients exhibiting a wide array of symptoms. As a result, there is a lack ofstandardization of both the diagnostic criteria and the nomenclature.

•

Determining the true incidence of DRESS has proven difficult, but estimates
range from 1:1000 to 1:10000.

•

The precise pathogenic mechanisms of DRESS are unknown; however, it isthought to be the result of a combination of genetic and immunologic factors.
The medical literature provides a number of hypotheses.
 Detoxification defects in the drug metabolism pathway may result in toxic
metabolite formation and lead to an immune response.
 Drugs metabolized by slow acetylation may lead to an accumulation oflymphotoxic metabolites.
 Drug-mediated release of cytokines may play a role in the immune
mechanisms for DRESS; for example, interleukin-5 release may activate
eosinophils.
 Drug-mediated reactivation of herpes virus (HHV-6, HHV-7, Epstein-Barr)may induce or amplify the immune reaction.
 In recent years, certain HLA alleles have been found to be associated withspecific drugs causing DRESS. In some cases, the HLA allele appears to
predict the particular manifestations that the patient experiences.

•

A number of drugs have been reported in association with DRESS, including: allopurinol
 carbamazepine dapsone lamotrigine
 mexiletine
 minocycline
 nevirapine
 oxcarbazepine phenobarbital phenytoin
 sulfasalazine

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 telepravir
 vancomycin
Other drugs with fewer literature reports of DRESS include (not a comprehensivelist): amoxicillin/clavulanic acid, amitriptyline, atorvastatin, aspirin, captopril,
cefadroxil, celecoxib, chlorambucil, clomipramine, codeine phosphate,cotrimoxazole/cefixime, cyanamide, efalizumab, esomeprazole,hydroxychloroquine, ibuprofen, imatinib, olanzapine, phenylbutazone, quinine
and thiamine, salazosulfapyridine, sodium meglumine ioxitalamate, sodium
valproate/ethosuximide, spironolactone, streptomycin, strontium ranelate,sulfamethoxazole, tribenoside, and zonisamide.
•

DRESS is diagnosed on the basis of clinical presentation as described above.
There is no “gold standard” for diagnosis of DRESS; however, several groups
have proposed diagnostic criteria which were considered in the term selection for
Drug reaction with eosinophilia and systemic symptoms syndrome (SMQ).

•

Descriptions of the following diagnostic criteria are included in the original
documentation for this SMQ: Phenotype Standardization Project(PSP);RegiSCAR; and the Japanese consensus group.

•

Treatment includes:
 Stopping the offending medication and providing supportive care
 Systemic steroids may be used to manage cutaneous manifestations andinternal organ involvement•

DRESS is associated with a mortality rate of up to 10%. Early recognition anddrug withdrawal are critical in improving outcomes and preventing fatalities.

•

The differential diagnosis for DRESS includes (but is not limited to): connective tissues diseases
 idiopathic hypereosinophilia
 hypereosinophilic syndrome angioimmunoblastic lymphadenopathy
 Stevens-Johnson syndrome toxic epidermal necrolysis
 acute generalized exanthematous pustulosis
 Kawasaki disease serum sickness
 lymphoma pseudolymphoma
 various acute viral infections (e.g., Epstein-Barr, hepatitis, influenza,
cytomegalovirus, and human immunodeficiency virus).

•

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 Included:
Cases that report:o Onset of symptoms within three months of starting therapy with a drug,ANDo Evidence of involvement of the skin and/or an extracutaneous organsystem, AND
o At least two of the following:
Fever
Eosinophilia (and/or atypical lymphocytes)
Lymphadenopathy•

Excluded:Cases are excluded that:o Did not report a temporal relationship between suspect drug and reaction;
note: this may include cases in which the multiple signs & symptoms
associated with DRESS did not occur within one month of each other (e.g.
skin eruption followed by lymphadenopathy and fever 6 months later)o Did not meet the inclusion criteria aboveo Reported a condition listed in the differential diagnosis section, or casesthat described another more likely diagnosis
o Are categorized as “toxic drug-induced exanthema.” These include cases
in which patients have an exanthem and fever, but other manifestations
have not been detected because laboratory tests were either not
performed or could not be done.

2.25.2 Inclusion/Exclusion Criteria•

Included Terms directly referring to DRESS syndrome, e.g., PT Drug reaction witheosinophilia and systemic symptoms and PT Pseudolymphoma (included as
narrow scope terms, Category A)
 Terms related to skin manifestations and systemic involvement/internal organ
damage commonly seen in DRESS cases, including corresponding
investigation terms, e.g., PT Dermatitis exfoliative, PT Hepatic failure, PT
Hepatic enzyme increased (included as broad scope terms, category B)
 Other relevant terms related to mucocutaneous involvement commonly seen
in DRESS cases, e.g., PT Mucocutaneous rash, PT Mucosal ulceration(included as broad scope terms, category B)
 Terms related to viral reactivation, e.g., PT Cytomegalovirus infection(included as broad scope terms, category B)
 Terms related to general hypersensitivity, e.g., PT Drug hypersensitivity(included as broad scope terms, category B)
 Terms related to fever, e.g., PT Hyperpyrexia (included as broad scope
terms, category C)

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 Terms related to lymphadenopathy (included as broad scope terms, categoryD) Terms related to hematologic abnormalities commonly seen in DRESS cases,
e.g., PT Eosinophilia (included as broad scope terms, category E)•

Excluded Congenital terms
 Unqualified investigation terms
 Infectious etiologies
 Terms related to “site” conditions, e.g., PT Administration site
lymphadenopathy

2.25.3 Algorithm
The categories are defined as follows:
Category A- Narrow search terms
Category B- Terms related to organ damage, including skin involvement, viralreactivation, general hypersensitivity
Category C- Terms related to fever
Category D- Terms related to lymphadenopathy
Category E- Terms related to hematologic abnormalities commonly seen in
DRESS cases
A report is considered a relevant case for further review if it includes:
A term from Category A (Narrow terms)
OR
At least one term from Category B and a term from two of the three categories C,
D, E
In summary: A or (B and C and D) or (B and C and E) or (B and D and E)
2.25.4 Notes on Implementation and/or Expectation of Query Results
Drug reaction with eosinophilia and systemic symptoms syndrome (SMQ) is analgorithmic SMQ. The algorithm is a combination of broad search terms among various
categories to further refine the identification of cases of interest. Use of the broad
search for this SMQ is only meaningful if applied with an algorithm. This SMQ isintended to identify relevant cases for further medical review, which may then apply ascoring method in the evaluation of retrieved cases. Users should consider using theRegiSCAR criteria for DRESS to score cases for inclusion; however, information
provided in spontaneous postmarketing reports is generally limited and it may provedifficult to apply these criteria, thus potentially resulting in the exclusion of relevantcases.

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PT Acute generalised exanthematous pustulosis, PT Stevens-Johnson syndrome, PT
Toxic epidermal necrolysis, PT Hypersensitivity, and PT Drug hypersensitivity were
found in testing to retrieve cases of interest in older data, but were less useful for more
recent data. The final decision was made to keep these PTs in Category B (skin/organ
involvement). When searching older data for DRESS, it is recommended tosimultaneously use Severe cutaneous adverse reactions (SMQ), Drug reaction witheosinophilia and systemic symptoms syndrome (SMQ), PT Drug hypersensitivity, andPT Hypersensitivity
2.25.5
List of References for Drug reaction with eosinophilia and systemic
symptoms syndrome (SMQ)•

Cacoub P, Musette P, Descamps V. The DRESS syndrome: a literature review.
Am J Med 2011;124:588-97.

•

Tas S, Simonart T. Management of drug rash with eosinophilia and systemic
symptoms (DRESS syndrome): an update. Dermatology 2003;206:353-6.

•

Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug
hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic
Symptoms: DRESS). Semin Cutan Med Surg 1996;15(4):250-7.

•

Pirmohamed M, Friedman PS, Molokhia M, et al. Phenotype standardization for
immune-mediated drug-induced skin injury. Clin Pharmacol Ther
2011;89(6):896-901.

•

Chaiken BH, Goldberg BI, Segal JP. Dilantin sensitivity. Report of a case ofhepatitis with jaundice, pyrexia, and exfoliative dermatiitis. N Engl J Med
1950;242(23):897-8.

•

Saltzstein SL, Ackerman LV. Lymphadenopathy induced by anticonvulsant drugs
and mimicking clinically pathologically malignant lymphomas. Cancer
1959;12(1):164-82.

•

Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinicalpattern of cutaneous side-effects of drugs with systemic syndromes: does a
DRESS syndrome really exist. Br J Dermatol 2007;156:609-11.

•

Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms(DRESS): a clinical update and review of current thinking. Clin Experimen
Dermatol 2011;36(1):6-11•

Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is thepathogenesis? Arch dermatol 2001;137(3):357-64.

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Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS):
A reaction induced by a complex interplay among herpesviruses and antiviral andantidrug immune responses. Allergol Int 2006;55:1-8.

•

Phillips EJ, Chung WH, Mockenhaupt M, et al. Drug hypersensitivity:
pharmacogenetics and clinical syndromes. J All Clin Immunol 2011;127(Suppl
3):S60-6.

•

RegiSCAR website. Heep://regiscar.uni-freiburg.de/. Accessed April 5, 2012.

•

Incivek (telaprevir) Prescribing Information. Vertex Pharmaceuticals Inc.
Cambridge;MA. June 2012.

•

Shaughnessy KK, Bouchard SM, Mohr MR, et al. Minocycline-incudes drug
reaction with eosinophilia and systemic symptoms (DRESS) syndrome: asystematic review. Drug Saf 2009;32(5):391-408.

•

Ganeva M, et al. Carbamazepine-induced drug reaction with eosinophilia andsystemic symptoms (DRESS) syndrome: report of four cases and brief review. Int
J Dermatol 2008;47(8):853-60.

•

Elzagallaai AA, Knowles SR, Rieder MJ, et al. Patch testing for the diagnosis of
anticonvulsant hypersensitivity syndrome: a systematic review. Drug Saf
2009;32(5):391-408.

•

Chen YC, Chir HC, Chu CY. Drug reaction with eosinophilia and systemic
symptoms: a retrospective study of 60 cases. Arch Dermatol
2010;146(12):1373-9.

•

Pirmohamed M, Aithal GP, Behr E, et al. The phenotype standardization project:
improving pharmacogenetic studies of serious adverse drug reactions. Clin
Pharmacol Ther 2011;89(6):784-5.

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2.26

Dyslipidaemia (SMQ)(Production Release November 2005)
2.26.1 Definition•

Defined as altered, most often excessive, concentration of lipids (cholesterol
and/or triglycerides) in blood•

Result of a genetic predisposition, secondary causes, or of a combination of both•

Five forms:
 Hypercholesterolemia Hypertriglyceridemia Combined hyperlipidaemia
 Secondary dyslipidaemia
 Hypolipidaemia•

Cholesterol-carrying lipoproteins are differentiated on the basis of their buoyant
properties as LDL, VLDL, and HDL and may vary on the amount of cholesterol
present in each particle, in the number of circulating particles, or both•With the exception of high HDL, elevated concentration of lipid in blood,
particularly cholesterol, is one of the major risk factors for atherosclerosis•

Hypercholesterolemia and hypertriglyceridemia per se do not produce specificsymptoms, unless associated with the disease of an organ involved in themetabolism of lipid (e.g., pancreatitis)•

Some clinical manifestations of atherosclerosis occur after decades of silent
onset and progression of lesions•

Acute hypercholesterolemia is not known to occur as adverse response to drug•

Acute hypertriglyceridaemia may be the expression of excessive (binge-like)consumption of fat-rich foods or alcohol, or it may relate to diabetes – especiallywhen not properly controlled – or pancreatitis

2.26.2 Inclusion/Exclusion Criteria•

Included: Terms with roots of “lipid,” “cholesterol,” “triglyceride,” and “lipoprotein”
 Medical terms closely related to lipids, lipoproteins, cholesterol andtriglycerides in blood
 Terms were derived from three SOCs (SOC Metabolism and nutrition
disorders, SOC Investigations, and SOC Congenital, familial and genetic
disorders)

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 Nine terms representing familial alterations of lipid metabolism (to retrieve
cases describing inborn disorder of lipoprotein metabolism that may havebeen aggravated (or improved)) ICD-9 classification of “Disorders of lipoid metabolism” was also used as areference During the 18-24 month review, the CIOMS WG development team confirmed
that, based on the testing results, lipid investigation result terms that are
relevant to this SMQ are: blood cholesterol, blood triglycerides, andhyperlipidemia. Other lipid test result terms did not retrieve cases of interest.
•

Excluded: Terms for lipid storage diseases, e.g., PT Gaucher’s disease The following terms not directly pertinent to the scope of this SMQ: PT
Cholesterosis, PT Fat embolism, all “lipoid” containing terms (e.g., PT
Pneumonia lipoid), PT Lipid proteinosis, PT Lipaemia retinalis, PT Lipiduria,
PT Lipoprotein deficiency, and PT Low density lipoprotein apheresis

2.26.3 Notes on Implementation and/or Expectation of Query Results
Dyslipidaemia (SMQ) has only narrow search terms. Therefore, the narrow search andbroad search return the same result. The detailed notes are documented in section
1.5.2.1.
2.26.4 List of References for Dyslipidaemia (SMQ)•

Harrison’s Principles of Internal Medicine, 16th Edition.

•

Ross R: Atherosclerosis - an inflammatory disease. N Engl J Med 340:115-126,
1999.

•

Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult
Treatment Panel III – Third Report of the National Cholesterol Education Program(NCEP) NIH - U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES - NIH
Publication No.02-5215, September 2002.

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2.27

Embolic and thrombotic events (SMQ)(Production Release March 2007)

2.27.1 Definition•

Thrombosis arises from the interplay of many influences. Virchow observed thatthe main influences in the pathogenesis of thrombosis are disturbances of thevessel wall, of the blood components, and of the dynamics of flow•

Thrombotic disorders are diseases characterized by formation of a thrombus that
obstructs vascular blood flow locally or detaches and embolizes to occlude bloodflow downstream•

Embolism is the sudden blocking of a vessel by a clot or foreign material which
has been brought to its site of lodgement by the blood current.

•(Thrombo-)phlebitis is an inflammation of a vein (phlebitis) associated withthrombus formation (thrombosis).

2.27.2 Inclusion/Exclusion Criteria•

Included: Embolism and thrombosis from HLGT Embolism and thrombosis
 PT Budd-Chiari syndrome and PT Paget-Schroetter syndrome Infarction- and stroke-related events
 Terms that are procedure-related (e.g. PT Thrombectomy, PT
Thromboembolectomy)
 Prophylaxis terms related to embolism and thrombosis
 Investigation terms related to embolism and thrombosis
 Thrombophlebitis terms related to embolism and thrombosis
 Terms referring to occlusion of arteries and veins associated with embolism
and/or thrombosis
 Terms referring to mesenteric events related to embolism and thrombosis
 Amaurosis terms, PT Cerebrovascular accident and PT Haemorrhagic
infarction
 Terms referring to transient (ischemic) events related to embolism andthrombosis
 Terms referring to diplegia, hemiparesis, hemiplegia, hemiplegia transient,monoparesis, monoplegia, paresis, paraparesis, paraplegia, quadriparesisand quadriplegia are included (terms referring to palsy, paresis, plegia andparalysis with no probable relationship to embolism and thrombosis are
excluded)

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 PT Shunt occlusion, PT Thrombosis in device, PT Implant site thrombosis
and PT Shunt thrombosis
 Terms referring to embolism and thrombosis in the cerebrum or cerebellum•

Excluded: Risk factor terms (e.g. related to hyperviscosity, or to hereditary,infective/septic or autoimmune causes) Laboratory test terms without indication of result (i.e., the unqualified testterm)
 Air, cement and fat emboli terms
 Terms for non-specific vessel anomalies Terms referring to palsy, paresis, plegia and paralysis with no probablerelationship to embolism and thrombosis (terms referring to diplegia,
hemiparesis, hemiplegia, hemiplegia transient, monoparesis, monoplegia,paresis, paraparesis, paraplegia, quadriparesis and quadriplegia are
included).

2.27.3 Hierarchy Structure

Embolic and thrombotic
events(20000081)

Embolic and thrombotic
events, arterial(20000082)

Embolic and thrombotic
events, vessel typeunspecified and mixed
arterial and venous(20000083)

Embolic and thrombotic
events, venous(20000084)

Figure 2-7. Hierarchy Structure of Embolic and thrombotic events (SMQ)

Embolic and thrombotic events (SMQ) (Level 1) is divided into three Level 2 sub-SMQs:

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Embolic and thrombotic events, arterial (SMQ) (PTs designated as narrow searchterms)•

Embolic and thrombotic events, venous (SMQ) (PTs designated as narrow searchterms)•SMQ Embolic and thrombotic events, vessel type unspecified and mixed arterial
and venous (SMQ) (PTs designated as broad search terms)

NOTE: The names of the sub-SMQs in the CIOMS WG documentation differ fromthis Introductory Guide summary as follows:

CIOMS WG Document

This Document

SMQ Embolic and thrombotic events,
arterial, venous, non-specific

Embolic and thrombotic events (SMQ)SMQ Embolic and thrombotic events,
arterial only

Embolic and thrombotic events, arterial(SMQ)

SMQ Embolic and thrombotic events,
venous only

Embolic and thrombotic events, venous(SMQ)

SMQ Embolic and thrombotic events,
non-specific

Embolic and thrombotic events, vessel
type unspecified and mixed arterial andvenous (SMQ)

Table 2-2. Link Table between CIOMS WG Document and SMQ Introductory
Guide for Embolic and thrombotic events (SMQ)•

The term “sub-SMQ” corresponds to the “sub-group” as described in the CIOMS
documentation.

•

In order to get all relevant terms of embolism and thrombosis, it may benecessary to combine the sub-SMQs of this SMQ.
Central nervous system vascular disorders (SMQ) [formerly, Cerebrovasculardisorders (SMQ)], Vasculitis (SMQ), and Thrombophlebitis (SMQ) should also betaken into consideration.

NOTE: In Version 14.0, Embolic and thrombotic events, vessel type unspecified andmixed arterial and venous (SMQ) was modified in scope to include only narrow searchterms. This SMQ formerly included only broad terms.
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2.27.4 Notes on Implementation and/or Expectation of Query Results
The Embolic and thrombotic events (SMQ) is a hierarchical SMQ, and has only narrowterms. Therefore, the narrow search and broad search return the same result. The
detailed notes are documented in section 1.5.2.1.
2.27.5 List of References for Embolic and thrombotic events (SMQ)•

Concise Oxford Textbook of Medicine. Ledingham, John G. G., Warrell, David A.
1st Edition © 2000 Oxford University Press.

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2.28

Eosinophilic pneumonia (SMQ)(Production Release March 2009)2.28.1 Definition•

Eosinophilic pneumonias are characterized by accumulation of eosinophils inalveolar spaces, interstitium, or both. Peripheral eosinophilia is common.

•

Causes include: Infections (especially helminthic) Drug-induced pneumonitis (e.g., antibiotics, phenytoin, l-tryptophan) Inhaled toxins (e.g., cocaine)
 Systemic disease (e.g., Churg Strauss syndrome) Allergic bronchopulmonary aspergillosis•

Diagnosis based on: Eosinophilia in peripheral blood (>450/μL), bronchoalveolar lavage fluid (>5%of differential), or lung biopsy
 Opacities on chest X-ray (sometimes called PIE or pulmonary infiltrates witheosinophilia syndrome)•

Chronic eosinophilic pneumonia
 Unknown etiology. Suspected to be allergic diathesis.
 Fulminant illness with cough, fever, weight loss, accompanied by or precededby asthma in 50% of cases
 Bilateral peripheral pulmonary opacities described as “photographic negative”
of pulmonary edema are virtually pathognomonic•

Acute eosinophilic pneumonia
 Unknown etiology but may be acute hypersensitivity reaction to unidentified
inhaled antigen
 Acute febrile illness with cough, dyspnea, malaise, myalgias, night sweats,and pleuritic chest pain•

Loeffler’s syndrome Characterized by absent or mild respiratory symptoms, fleeting migratory
pulmonary opacities, and peripheral blood eosinophilia
 Etiology may be parasitic infections, especially Ascaris lumbricoides, but
identifiable agent often not found

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2.28.2 Inclusion/Exclusion Criteria•

Included: Specific terms related to eosinophilic pulmonary disease such as PT
Eosinophilic pneumonia, PT Pulmonary eosinophilia, and PT Loeffler’s
syndrome are included in the narrow search Terms for a variety of pulmonary conditions that are not specificallyeosinophilic but possibly indicative of pneumonia are included in the broad
search (e.g., PT Alveolitis and PT Lung infiltration)
 Terms for clear clinical symptoms of pneumonia are included in the broad
search (e.g., PT Hypoxia and PT Hyperventilation)
 Based on testing with the algorithm, two very nonspecific terms, PT
Pneumonia and PT Myalgia, are included in the broad search Terms relating to peripheral blood eosinophils containing the word “abnormal”(e.g., PT Eosinophil count abnormal).

•Excluded: All infections, fibrosis, sarcoidosis, and hemorrhage terms
 Terms for nonspecific signs and symptoms of pneumonia (e.g., PT Coughand PT Dyspnoea)
 Terms for eosinophilic conditions elsewhere than the lung (e.g., PT
Eosinophilic colitis, PT Eosinophilic myocarditis) Terms relating to peripheral blood eosinophils containing the word “normal”(e.g., PT Eosinophil count normal)
 Terms relating to peripheral blood eosinophils without a qualifier (e.g., PT
Eosinophil count) Neonatal terms
 Terms indicating an inherited disorder Terms for tumors or malignancies of the lung

NOTE: Two nonspecific terms, PT Pneumonia and PT Myalgia, are included in the
broad search. If the broad search is used without the algorithm, these terms may need
to be excluded as being too noisy.

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2.28.3 Algorithm
Eosinophilic pneumonia (SMQ) consists of:•

Narrow search (Category A or narrow scope) containing specific PTs that
describe eosinophilic pneumonia•

Broad search contains additional terms (broad scope) which are added to thoseincluded in the narrow search. The broad scope terms are divided into two
categories: Category B: Eosinophilia terms
 Category C: Terms possibly indicative of pneumonia and the two nonspecificterms PT Pneumonia and PT Myalgia.

Cases to be selected for further review would include any cases reporting at least oneof the PTs listed for Category A (narrow scope terms) or any case reporting a
combination of at least one PT from each of the two groups of PTs listed as Categories
B and C of broad scope terms. A or (B and C).
2.28.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Eosinophilic pneumonia (SMQ) is analgorithmic SMQ. The algorithm is a combination of broad search terms among various
categories to further refine the identification of cases of interest. The algorithm can be
implemented in a post-retrieval process as noted below:•

First, retrieve relevant cases by applying the SMQ query as a narrow and broad
searches (see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination to screen thecases retrieved above. For small data sets of retrieved cases, the algorithm may
be applied on manual review of cases. The algorithm for Eosinophilic pneumonia(SMQ) is A or (B and C). Cases filtered by the algorithm can be listed for output.

2.28.5 List of References for Eosinophilic pneumonia (SMQ)•

The Merck Manual assessed online as
http://www.merck.com/mmpe/sec05/ch055/ch055d.html .

•Harrisons Principles of Internal Medicine, McGraw Hill accessed online as
http://www.accessmedicine.com/search/searchAMResult.aspx?searchStr=Eosino
philic+pneumonia+&rootTerm=eosinophilic+pneumonias&searchtype=1&rootID=
12837&gobacklink=1&drug=1

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2.29

Extrapyramidal syndrome (SMQ)(Production Release March 2007)
2.29.1 Definition•

Drug-induced movement disorders may occur in association with levodopa or
dopamine agonist therapy or drugs with central dopamine receptor antagonist
properties, anticholinergic drugs, some anticonvulsant drugs, and amphetamines•

Definition: disturbance of motor function caused by lesions or dysfunctions of theextrapyramidal motor system
 May present as hyperkinetic-hypotonic or as akinetic-rigid disorder•

Drug-induced Parkinsonism, dystonia, akathisia, and tardive dyskinesia, and theirassociated clinical findings are included concepts in this SMQ.

•

Sub-SMQs for:
 Akathisia: subjective feelings of restlessness, objective signs of restlessness,or both Dyskinesia (including tardive dyskinesia): involuntary choreoathetoid
movements commonly involving orofacial region, fingers, and toes. Athetoid
movements of head, neck, and hips may also occur.
 Dystonia: brief or prolonged contractions of muscles resulting in abnormal
movements or postures, including oculogyric crises, tongue protrusion,
trismus, torticollis, laryngeal-pharyngeal dystonias, and dystonic postures ofthe limbs and trunk Parkinson’s-like events: triad of resting tremor, rigidity and bradykinesia that
can appear identical to Idiopathic Parkinson’s disease. Other Parkinson’s-likefeatures include bradyphrenia (slowed thinking), excessive salivation,
drooling, shuffling gait, micrographia, hypophonia, and diminished posturalreflexes.

2.29.2 Inclusion/Exclusion Criteria•

Included: Parkinson’s disease and parkinsonism terms, including clinical signs andsymptoms
 Other forms of extrapyramidal disorders such as non-Parkinson-associatedtremors, focal dystonias (e.g., torticollis), drug-associated movement
disorders (e.g., tardive dyskinesia), and akathisia
 Neonatal terms related to the above Associated investigations

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o PT Tremor created some “noise” in phase I testing; however, due to its
power to pick up most of the reports in the positive controls during phase I
testing, this PT remains in the list of terms selected for this SMQ.
o PT Blepharospasm is included in subgroup Dystonia (SMQ): Although PT
Blepharospasm has been included in subgroup Dystonia (SMQ), there
had been some post-testing discussion about the utility of this broad
search term to the SMQ overall. Thus, the WG team would greatly
appreciate users comments on the utility of this particular term.
•

Excluded: Progressive supranuclear palsy
 Cortical-basal ganglionic degeneration
 Striatonigral degeneration
 Machado-Joseph disease (spinocerebellar ataxia type 3)
 Neuroleptic malignant syndrome Tourette’s disorder Tremor of non-extrapyramidal origin (essential tremor, intention tremor, head
titubation)
 PT Excessive eye blinking
 PT Restless legs syndrome PT Myotonia
 PT Dyspnoea
 Terms for neonatal Parkinson-like events (e.g., PT Foetal hypokinesia)

2.29.3 Hierarchy Structure

Extrapyramidal
syndrome(20000095)

Akathisia(20000096)

Dyskinesia(20000097)

Dystonia(20000098)

Parkinson-likeevents(20000099)

Figure 2-8. Hierarchy Structure of Extrapyramidal syndrome (SMQ)

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2.29.4 Notes on Implementation and/or Expectation of Query Results
Extrapyramidal syndrome (SMQ) is a hierarchical SMQ with narrow and broad searchterms. Other than the hierarchy structure, the implementation for this SMQ is similar to
the non-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1).
The superordinate SMQ can be applied by combining the terms in the subordinate
SMQs.
2.29.5 List of References for Extrapyramidal syndrome (SMQ)•

Stedman’s Medical Dictionary, 27th edition, 2000.

•

Harrison’s Principles of Internal Medicine, 14th edition, 1998, p 2356 – 63.

•

CIOMS, Reporting Adverse Drug Reactions, 1999, p 29 – 30.

•

Kaplan & Sadock’s Synopsis of Psychiatry: Behavioral sciences and clinicalpsychiatry, 8th edition, 1998, pp 955-963.

•

The case of the frozen addicts by J W Langston and Jon Palfreman –Publisher New York: Pantheon Books © 1995 ISBN: 0679424652 OCLC:
31608154.

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2.30

Extravasation events (injections, infusions and implants) (SMQ)(Production Release September 2007)

2.30.1 Definition•

Extravasation of drug product administered by venous access is a local
complication can be associated with pain and swelling Can be associated with pain and swelling Some products (e.g., certain chemotherapeutic agents) may be associatedwith more serious sequelae including tissues necrosis•

May be caused by: Damage to posterior wall of vein or occlusion of vein proximal to injection site
 Occlusion of vein proximal to injection site•

Extravasation broadly defined as discharge or escape of blood or other fluid
normally found in a vessel or tube, into surrounding tissues
 For purposes of this SMQ, “extravasation” relates to complication of drugdelivery (injection, effusion, etc.) or to a device
 Includes potential sequelae of extravasation
 Pain, erythema, and swelling are typically observed

2.30.2 Inclusion/Exclusion Criteria•

Included: Terms with “extravasation” that are related to drug delivery or devices
 PT Extravasationo PT Extravasation is unassociated with any drug delivery mechanism (it isin SOC General disorders and administration site conditions)o Based on pharmaceutical company testing results, it retrieved cases ofinterest and was determined to be suitable for inclusion
 Terms with “injection”, “infusion”, “implant”, “catheter,” “vascular access,” and“device” when combined with “induration”, “edema”, “effusion”, “swelling”,“irritation”, “necrosis”, and “ulcer”
o Individual terms with such combinations were subsequently selected forinclusion based on their relevance to scope of SMQ
 For future maintenance of this SMQ, PT terms with “instillation” could beconsidered for inclusion if they fit definition of SMQ
 Terms for administration site pain and erythema (see NOTE below)

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Excluded: PT Extravasation blood and PT Extravasation of urine
 PT Contrast media reaction
 PT Wrong technique in product usage process PT Systemic leakage
 “Application site” terms (See NOTE below)
 PT Injection site reaction and other plain “site reaction” PTs (e.g., PT Infusionsite reaction) as these are non-specific

NOTE: Administration site pain and erythema are symptoms of extravasation (and are
currently included in this SMQ) but can occur without it. These terms could retrieve
more cases of interest than is practical in certain databases, depending on coding
practices. This should be borne in mind when applying this SMQ.
NOTE: In general, “application site” terms are considered not appropriate for the scopeof this SMQ, even though they did retrieve a few cases of interest during pre-production
testing. MedDRA users should consider – based on their own data – if “application site”
terms may have been used when coding cases related to extravasation and include
relevant terms as needed.
NOTE: Users should consider including cases coded to LLT Catheter-related
complication. This term is not currently linked to an included PT in this SMQ, but may
retrieve cases of interest.
2.30.3 Notes on Implementation and/or Expectation of Query Results
Extravasation events (injections, infusions and implants) (SMQ) has narrow and broad
search terms. The detailed notes are documented in section 1.5.2.1.
2.30.4 List of References for Extravasation events (injections, infusions andimplants) (SMQ)•

Brown, S. Complications with the Use of Venous Access Devices. U.S.
Pharmacist. http://www.uspharmacist.com/
http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/ACF2FF9.cfm&pub_id=8&article_id=131.

•

Stedman’s Medical Dictionary, 27th Edition, 2000.

•

Wickham, R. Long-Term Central Venous Catheters: Issues for Care. Semin
Oncol Nurs 1992;8,2(May):133-147.

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2.31

Fertility disorders (SMQ)(Production Release September 2011)
2.31.1 Definition
•
•

•

•

•
•

•

During the development of SMQ Pregnancy and neonatal topics, the CIOMS
SMQ Working Group agreed that “fertility disorders” should be developed into a
Level 1 SMQInfertility:
 Failure to conceive (regardless of cause) after 1 year of unprotectedintercourse Up to 15% of couples of reproductive age are affected Trend by many women to delay child-bearing is also a factor
Both male and female factors are involved in infertility, each gender accounting
for approximately 35% of cases Combination of male and female factors accounts for 20% of infertility cases
 In remaining 10%, etiology is not known.
Some couples have normal results of standard infertility tests for infertility;
postulated etiologies are:
 Dysfunctional interaction between sperm and oocyte
 Poor quality of embryo
 Disruption at implantation site
Identifying a mutation or absence of a specific gene as reason for infertility may
be possible in the future
Certain lifestyle factors have been linked to risk of infertility:
 Environmental and occupational factors
 Toxic effects related to tobacco, marijuana, or other drugs
 Excessive exercise
 Inadequate diet associated with extreme weight loss or gain Advanced age
Drugs associated with development of infertility are:
 Antineoplastic therapies (cyclophosphamide, chlorambucil, etc.)
 Combinations of antineoplastic agents and steroid drugs
 Certain antibiotics
 Thyroid supplements
 Others

2.31.2 Inclusion/Exclusion criteria•

Included: Terms for medical conditions reflecting fertility problems (e.g., PT Premature
follicular ripening) Terms for procedures related to fertility (e.g., PT In vitro fertilisation)

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 Terms for investigations (abnormal) related to fertility issues (e.g., LLT Spermcount decreased)•

Excluded: Terms for sexual dysfunction that do not directly affect fertility (e.g., PT Libido
disorder) Terms for conditions that are the result of chromosomal abnormalities (e.g.,
PT Klinefelter's syndrome) or that are otherwise not likely to be drug
associated (e.g., PT Anorchism)

NOTE: For users that wish to search data for sexual dysfunction events/cases, please
note that almost all pertinent MedDRA terms can be found in two HLGTs, namely,
HLGT Sexual dysfunctions, disturbances and gender identity disorders and HLGT
Sexual function and fertility disorders.
2.31.3 List of References for Fertility disorders (SMQ)•

Puscheck, EE and Woodward, TL. Infertility. eMedicine, 21 December 2010,
http://emedicine.medscape.com/article/274143-overview.

•

Buchanan, JF and Davis, LJ. Drug-induced infertility. Drug Intell Clin Pharm,
1984, 18(2): 122 – 32.

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2.32

Gastrointestinal nonspecific inflammation and dysfunctional conditions(SMQ)(Production Release September 2007)

2.32.1 Definition•

The goal of this SMQ is gathering and ordering a number of gastrointestinal nonspecific conditions
 Constructed around symptoms frequently attributed to drugs, (e.g., nausea,
vomiting, dyspepsia, gastroesophageal reflux disease, diarrhea andconstipation)
 Applies to gastrointestinal tract from esophagus to rectum•

For this SMQ, “nonspecific” means conditions are possible manifestations ofmultiple diseases

2.32.2 Inclusion/Exclusion Criteria• Included:
 Any nonspecific functional condition affecting any part of the gastrointestinaltract
 Nonspecific inflammatory manifestations affecting any part of thegastrointestinal tract
 Nonspecific dysfunctional manifestations affecting any part of thegastrointestinal tract
 Disorders relative to mucosal erosions
 Terms from SOC Investigations
 Terms from SOC Surgical and medical procedures have been included•

Excluded: Any dysfunction or inflammation in oropharyngeal cavity
 Inflammatory or dysfunctional conditions which are independent, well defined
nosologic entities (e.g., PT Crohn's disease and PT Colitis ulcerative are notincluded) (See NOTE below)
 Infective gastroenteritis

NOTE: To search for cases of more specific pathology, the following SMQs could beconsidered: SMQ Acute pancreatitis; SMQ Gastrointestinal perforation, ulceration,
haemorrhage or obstruction; and SMQ Pseudomembranous colitis

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NOTE: The term Laxative abuse was initially part of the narrow scope of
Gastrointestinal nonspecific dysfunction (SMQ) as a PT. In Version 10.1, Laxative
abuse was demoted to an LLT under PT Drug abuse. In Version 20.0, PT Drug abuse
was demoted under new PT Drug use disorder. PT Drug use disorder is considered too
non-specific for Gastrointestinal nonspecific dysfunction (SMQ). Therefore, the term
Laxative abuse is no longer part of Gastrointestinal nonspecific dysfunction (SMQ). If auser finds the term Laxative abuse to be helpful in case identification, LLT Laxative
abuse could be added to the user's query
NOTE: In the original CIOMS WG documentation, the name of sub-SMQ
Gastrointestinal nonspecific symptoms and therapeutic procedures was SMQ
Gastrointestinal non-specific symptomatology and therapeutic procedures.
2.32.3 Hierarchy Structure

Gastrointestinal
nonspecific inflammationand dysfunctional
conditions(20000137)

Gastrointestinal
nonspecificinflammations(20000138)

Gastrointestinal
nonspecific dysfunctions(20000139)

Gastrointestinal
nonspecific symptoms
and therapeutic
procedures(20000140)

Figure 2-9. Hierarchy Structure of Gastrointestinal nonspecific inflammation anddysfunctional conditions (SMQ)

2.32.4 Notes on Implementation and/or Expectation of Query Results
Gastrointestinal nonspecific inflammation and dysfunctional conditions (SMQ) is ahierarchical SMQ with narrow and broad search terms. Other than the hierarchy
structure, the implementation for this SMQ is similar to the non-hierarchical SMQs withnarrow and broad search terms (see section 1.5.2.1). The superordinate SMQ can beapplied by combining the terms in the subordinate SMQs.

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2.32.5 List of References for Gastrointestinal nonspecific inflammation anddysfunctional conditions (SMQ)•

Harrison's Principles of Internal Medicine, 16th Edition.

•

Medline database.

•

The Merck Manual.

•

Dorland’s illustrated medical dictionary.

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2.33

Gastrointestinal perforation, ulceration, haemorrhage or obstruction (SMQ)(Production Release September 2007)

2.33.1 Definition•

Gastrointestinal perforation:
 Perforation: act of boring or piercing through a part or a hole madethrough a part or substance Gastrointestinal perforation – perforation of all layers of gastrointestinaltracto Uncovered – in direct contact with the whole peritoneal cavity
o Covered – localized by the omentum or other organs

 Characterized by localized or diffused peritonitis
o Manifested as generalized, rigidity of abdominal wall, severe pain andileus
Uncovered perforation is confirmed by demonstration of free gas in abdominal
cavity (X-ray of diaphragmatic region with patient in upright position)•

Ulceration:
 Local defect, or excavation, of surface of an organ or tissue
 Produced by sloughing of inflammatory necrotic tissue•

Gastrointestinal hemorrhage: Hemorrhage – escape of blood from any vessel or tissue
 Gastrointestinal hemorrhage – escape of blood from any part ofgastrointestinal tract•

Gastrointestinal obstruction:
 Obstruction – act of blocking or clogging or state or condition of being
clogged Gastrointestinal obstruction – hindrance to passage of gastrointestinal
contents

2.33.2 Inclusion/Exclusion Criteria•

Included: Terms related to perforation of any part of gastrointestinal tract
 Terms for ulcers of any part of gastrointestinal tract
 Terms for obstruction and stenosis of any part of gastrointestinal tract: apossible consequence of scarring due to ulceration

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 Terms for hemorrhage of any part of gastrointestinal tract
 Terms for medical and surgical procedures and for diagnostic
investigations related to perforation, ulceration, or hemorrhageo A group of non-specific diagnostic investigations and medical andsurgical procedures have been included because the phase I test on a
pharmaceutical company’s database indicated that these terms were
useful for identifying relevant cases.
•

Excluded: Terms related to gastrointestinal neoplasms, including malignant ulcers
 Terms for taste disorders
 Terms related to oropharyngeal lesions (user should consider
Oropharyngeal disorders (SMQ)) Terms for congenital disorders

NOTE: Prior to Version 16.1, the terms in Gastrointestinal perforation, ulcer,
haemorrhage, obstruction nonspecific findings/procedures (SMQ) were broad scope
only. In Version 16.1, the terms included in Gastrointestinal perforation, ulcer,
haemorrhage, obstruction nonspecific findings/procedures (SMQ) have been
reclassified to be either broad or narrow in scope.
NOTE: In Version 13.0, the following sub-search SMQs under Gastrointestinal
perforation, ulceration, haemorrhage or obstruction (SMQ) have been changed in scopefrom broad terms only to narrow terms only: Gastrointestinal haemorrhage (SMQ),
Gastrointestinal obstruction (SMQ), Gastrointestinal perforation (SMQ), andGastrointestinal ulceration (SMQ).

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2.33.3 Hierarchy Structure
Gastrointestinal perforation,
ulceration, haemorrhage orobstruction(20000103)

Gastrointestinal
perforation, ulcer,
haemorrhage,
obstruction
nonspecificfindings/
procedures(20000104)

Gastrointestinal
obstruction(20000105)

Gastrointestinal
ulceration(20000106)

Gastrointestinal
perforation(20000107)

Gastrointestinal
haemorrhage(20000108)

Figure 2-10. Hierarchy Structure of Gastrointestinal perforation, ulceration,
haemorrhage or obstruction (SMQ)•

Sub-SMQ Gastrointestinal perforation, ulcer, haemorrhage, obstruction
nonspecific findings/procedures is referred to as SMQ Non-specificinvestigations, medical and surgical procedures in the original CIOMS WG(pre-production) documentation.

•

To retrieve all relevant cases related to gastrointestinal perforation, ulceration,
haemorrhage, or obstruction, it may be necessary to combine the sub-SMQs,
resulting in a broad search. Additionally, Oropharyngeal disorders (SMQ)
should be taken into consideration.

2.33.4 Notes on Implementation and/or Expectation of Query Results
Gastrointestinal perforation, ulceration, haemorrhage or obstruction (SMQ) is ahierarchical SMQ with narrow and broad search terms. Other than the hierarchy
structure, the implementation for this SMQ is similar to the non-hierarchical SMQs withnarrow and broad search terms (see section 1.5.2.1). The superordinate SMQ can beapplied by combining the terms in the subordinate SMQs.
2.33.5 List of References for Gastrointestinal perforation, ulceration,
haemorrhage or obstruction (SMQ)•

Reporting Adverse Drug Reactions – Definitions of terms and criteria for theiruse. Council for International Organizations of Medical Sciences (CIOMS);
1999.

•

Dorland’s Illustrated Medical Dictionary – Saunders 2003, 30th Edition.

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2.34

Generalised convulsive seizures following immunisation (SMQ)(Production Release September 2012)

2.34.1 Definition•

Generalised convulsive seizures following immunisation (SMQ) was
developed to address the occurrence of this form of seizure as an adverse
event following immunization, in accordance with the Brighton Collaborationcase definition for “Generalized convulsive seizure as an adverse event
following immunization”“Seizure” is an abnormal paroxysmal discharge of cerebral neurons becauseof cortical hyperexcitability. Categories include: Partial seizures (i.e., focal or localization related seizures)
Generalized seizures• Generalized seizures are classified as: Atonic
 Tonic
 Clonic
 Tonic-clonic Myoclonic Absence••

Seizures are characterized by: Sudden, involuntary muscular contractions
 Sensory disturbances Autonomic dysfunction
 Behavioral abnormalities
 Impairment or loss of consciousness•

Generalized convulsive seizure: patient becomes unconscious and has
convulsions over whole body•

The Brighton Collaboration case definition of generalized convulsive seizure
as AEFI describes the following levels of diagnostic certainty:
 Level 1 of diagnostic certainty­ Witnessed sudden loss of consciousness AND­ Generalized, tonic, clonic, tonic-clonic, or atonic motor manifestations
 Level 2 of diagnostic certainty­ History of unconsciousness AND­ Generalized, tonic, clonic, tonic-conic, or atonic motor manifestations
 Level 3 of diagnostic certainty­ History of unconsciousness AND­ Other generalized motor manifestations

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2.34.2 Inclusion/Exclusion criteria•

Included: Terms that describe only forms of generalized convulsive seizures or that
may have been used to code such as event (e.g., PT Clonic convulsion)
 Terms for characteristic signs and symptoms of generalized convulsive
seizures especially as related to level of consciousness and generalized
motor manifestations (e.g., PT Tonic clonic movements)
 Terms for events in line with the Brighton Collaboration (BC) definitions ofand criteria for generalized convulsive seizures•

Excluded Terms for forms of seizure where there may be loss of consciousness but
without generalized motor manifestations (e.g., PT Petit mal epilepsy)
 Terms for forms of epilepsy where etiology is established and/or unrelated
to an Adverse Event Following Immunisation (AEFI) (e.g., PT Myoclonic
epilepsy and ragged-red fibres) Terms for investigations and procedures related to generalized convulsive
seizures (e.g., PT Electroencephalogram abnormal). The rationale for thisexclusion is that the BC definition states that generalized convulsive
seizure after immunization is usually of short duration, and diagnosis isfrequently based on clinical history alone. Also, investigations such as
electroencephalograms (EEGs) are rarely available, and if available,interpretation is complex (inter-ictal sensitivity of EEGs is about 40%)

NOTE: Based on testing of SMQ Generalised convulsive seizures following
immunisation, this SMQ is deemed not suitable for pharmaceutical products asseveral previously “narrow” PTs that are relevant for those products are not present inthis algorithmic SMQ.
2.34.3 Algorithm
To apply the algorithm for this SMQ, a report is considered a relevant case for further
review if:• It includes a term from Category A
OR•

It includes a term from Category B (terms related to level of consciousness
and other neurological events) and a term from Category C (terms for motor
manifestations and observed effects of generalized convulsions)

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2.34.4 List of References for Generalised convulsive seizures following
immunisation (SMQ)•

Ko, DY. Generalized tonic-clonic seizures.
http://emedicine.medscape.com/article/1184608-overview•

Bonhoeffer, J et al. Generalized convulsive seizure as an adverse event
following immunization: case definition and guidelines for data collection,
analysis, and presentation. Vaccine 22 (2004) 557–562

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2.35

Glaucoma (SMQ)(Production Release March 2008)
2.35.1 Definition•

Group of eye diseases characterized by increase in intraocular pressure
(IOP)

•

Causes pathologic changes in optic disk and typical defects in field of vision•

Serious loss of vision and blindness can be prevented with early treatment•

Two main types:
 Angle-closure glaucoma: drainage canals within eye are physically
blockedo Acute form: sudden increase in IOP due to buildup of aqueous humor.
Optic nerve damage and vision loss can occur within hours
o Chronic form: may cause vision damage without symptoms
 Open-angle glaucoma: drainage system remains open; may cause vision
damage without symptoms
oo•Most common form glaucoma
Symptoms include peripheral vision loss, mild, chronic headaches,blurred or foggy vision, difficulty adapting to darkness, and halosaround lights

Other types:
 Normal (or low) tension glaucoma: optic nerve is damaged although IOP isconsistently within normal range
 Childhood glaucoma: rare; starts in infancy, childhood, or adolescenceoSimilar to open-angle glaucoma; few, if any, early symptomsoThought to be inheritedoBlindness can result if left untreated Congenital glaucoma: usually appears soon after birth, although it may
also occur in first year of lifeooSigns include tearing, light sensitivity, and cloudiness of cornea
More common in boys; can affect one or both eyes

 Secondary glaucoma: increased IOP due to structural problem in eyeooMay be due to eye injury or other medical conditions
Treatment aimed at underlying cause and toward lowering IOP

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Causes of glaucoma
 Approximately 100,000 glaucoma cases in US have mutation of GLC1A
gene (chromosome 1); speculated that gene product may be involved ineye pressure regulation
 Increased risk with elevated IOP, family history, ethnic background, andolder ageooAfrican Americans have higher rates of glaucoma leading to blindness
Primary open-angle glaucoma is leading cause of blindness among
African Americans and Alaska Natives, occurring 6-8 times more often
than in whites, often in earlier stages of life Increased IOP is from either increased production or decreased drainage
of aqueous humor; pressure may damage optic nerve
 Other factors may contribute as people with normal IOP can get vision
loss from glaucoma. Also, some with high IOP never develop optic nerve
damage•Other symptoms include severe eye pain, facial pain, pupil non-reactive tolight, eye redness, blurred vision, nausea, vomiting, abdominal pain, andbulging eye

2.35.2 Inclusion/Exclusion Criteria•

Included: All PTs in HLGT Glaucoma and ocular hypertension
 Terms for diagnostic and therapeutic procedures
 Terms for related complications
 Narrow search terms: Only diagnostic terms, signs and symptoms,laboratory findings and procedural terms that are specific or clearly related
to glaucoma
 Broad search terms: Signs, symptoms, diagnoses, and test results thatare not exclusively specific to glaucoma but may have additional value byidentifying potential cases•

Excluded: Congenital terms, including terms for systemic congenital abnormalities(e.g. PT Anterior chamber cleavage syndrome, PT Prader-Willi syndrome)
 SOC Investigations terms with qualifier “normal” and those with noqualifier Terms for risk factors
 Terms for causes of secondary glaucoma other than developmental, (e.g.
iritis, uveitis, cataract, chemical or physical eye injuries)

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 Terms for headache, nausea, and vomiting (too broad)
NOTE: This SMQ is one of several SMQs developed or under development for
ophthalmological disorders. When the entire set of SMQs is developed, a search may
require use of more than one SMQ, or the entire group of SMQs, depending upon thegoal of the search.
2.35.3 Notes on Implementation and/or Expectation of Query Results
Glaucoma (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.35.4 List of References for Glaucoma (SMQ)•

Dorland’s Medical Dictionary.

•Merck Manual, Sec.8, Ch.100, Glaucoma.
http://www.merckmanuals.com/professional/index.html•

http://www.emedicinehealth.com/glaucoma_overview/article_em.htm•

http://www.ncbi.nlm.nih.gov/disease/Glaucoma.html•

Edward B. Feinberg, MD, MPH, Glaucoma, Encyclopedia update 7/24/2004.

•

http://www.nlm.nih.gov/medlineplus/ency/article/001620.htm#Definition.

•

e-Medicine – Glaucoma, Secondary Congenital – Article by Inci Irak, MD last
updated December 1, 2005 www.emedicine.com/oph/topic141.htm.

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2.36

Guillain-Barre syndrome (SMQ)(Production Release September 2007)
2.36.1 Definition•

Guillain-Barre syndrome (GBS) is an immune-mediated, acute inflammatory
demyelinating polyneuropathy (AIDP)•

Condition commonly follows a viral or mycoplasmal illness affecting the upper
respiratory or alimentary tracts•

Other antecedent events include certain vaccinations•

Immune responses directed toward infecting organisms likely cross-react withneural tissues including Schwann cell surface membrane (resulting in AIDP)or axonal membrane (acute axonal forms)•

GBS is usually characterized by: Weakness or paralysis affecting more than one limb, usually symmetrically Loss of tendon reflexes Increased cerebrospinal fluid (CSF) protein without pleocytosis•

Other features may include: Motor and sensory involvement
 Facial or cranial nerve involvement
 Electrophysiologic evidence of demyelination•

Acute form of GBS has a typically rapid evolution from hours to days, usuallyreaching maximum level of weakness within four weeks•

Condition is classified as chronic inflammatory demyelinating polyneuropathy(CIDP) if patient’s symptoms continue to progress beyond 4 weeks, or
relapses occur. Peak disability in CIDP usually occurs in two months.

2.36.2 Inclusion/Exclusion Criteria•

Included: PT Guillain-Barre syndrome, terms reflective of sub-types of GBS (e.g.,
PT Miller Fisher syndrome) and terms synonymous with GBS (e.g., PT
Chronic inflammatory demyelinating polyradiculoneuropathy)
 Paralysis and paresis terms (excluding congenital and non-symmetricalterms, e.g., PT Hemiparesis)
 Weakness/ muscular weakness and musculoskeletal terms (e.g., PT
Hypotonia, PT Muscular weakness, and PT Asthenia)

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 Related neurological and neuromuscular disorders (e.g., PT
Demyelination and PT Radiculopathy) Neurological signs and symptoms (e.g., PT Areflexia and PT Loss ofproprioception)
 Sensory and motor deficits (e.g., PT Extensor plantar response and PT
Sensorimotor disorder)
 Investigation terms supportive of GBS diagnosis (e.g., PT CSF proteinincreased and PT Electromyogram abnormal)•

Excluded: Congenital terms
 Trauma and injury terms (e.g., PT Peripheral nerve injury)
 Broad pain terms (e.g., PT Back pain) Hemiparalysis / hemiparesis terms
 Histopathology procedures – nerve and muscle (except PT Biopsy
peripheral nerve abnormal)
 Therapies for GBS (e.g., PT Plasmapheresis)

2.36.3 Algorithm
NOTE: Cases of interest can be retrieved without the algorithm. Several algorithms
were tested by the CIOMS WG during development of this SMQ, and none of themwere found to be superior. Because of this, an algorithm and categories are notincluded in the data files. However, application of an algorithm may be helpful when it isexpected that a large number of cases will be retrieved by broad scope terms. Users
who are interested in implementing an algorithmic approach for this SMQ are
encouraged to refer to the CIOMS WG documentation(https://www.meddra.org/standardised-meddra-queries) for detailed information on analgorithm for this SMQ, including category term lists.
Despite the difficulty for the CIOMS WG in selecting an algorithm, they asked the MSSO
to document the following recommended approach:Cases to be selected for further review would include any cases meeting any one of thecriteria listed below:•

At least one of the PTs listed for Category A (narrow scope) or•

Any case reporting at least two PTs from Category B or•

Any case reporting at least one PT from Category B and at least one PT from
Category C or•

Any case reporting at least one PT each from Categories B, C, and D•

Certain drugs with high numbers of reports for terms such as paresthesias,
hypoesthesias and muscular weakness, do capture more “noise” with the

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algorithm 2B and 1B+1C. It is recommended that for products such as thesealgorithm 1B + 1C + 1D is used is as it can eliminate much “noise” resulting infalse hits.
Categories are defined as follows:•

Category A (Narrow scope) PT Chronic inflammatory demyelinating polyneuropathy, PT
Demyelinating polyneuropathy, PT Guillain-Barre syndrome, and PT Miller
Fisher syndrome, which represent GBS and sub-types of GBS•

Category B (Broad) Very commonly seen signs and symptoms from well-documented cases of
Guillain-Barre syndrome and its variants (i.e., Category A) based on
testing from pharmaceutical company and Regulatory Authority
databases. Also, includes specific types of paresthesias andhypoesthesias. Most terms relate to paresthesias, hypoesthesias andneuropathies.

•

Category C (Broad) Commonly seen signs, symptoms and diagnostic laboratory work fromwell-documented cases of Guillain-Barre syndrome and its variants basedon testing•

Category D (Broad) Less frequently seen signs, symptoms and diagnostic laboratory work
based on testing and signs, symptoms and diagnostic laboratory work that
may be seen in Guillain-Barre syndrome and its variants, but were notobserved in the databases tested

2.36.4 Notes on Implementation and/or Expectation of Query Results
Guillain-Barre syndrome (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
2.36.5 List of References for Guillain-Barre syndrome (SMQ)•

Textbook of Clinical Neurology, 2nd Edition, pp1085-1089, 2003.

•

Cecil Textbook of Medicine, 22nd Edition, pp 2379-2381, 2004.

•

Harrison’s Internal Medicine, 16th Edition, pp 2513-2518, 2005.

•

Ferri F. Guillain-Barré syndrome. Ferri’s Clinical Advisor: Instant Diagnosis
and Treatment, 2006 ed. Available at
http://www.mdconsult.com/php/231760506-2/homepage•

Cha-Kim A. Guillain-Barré syndrome. eMedicine. Available at
http://www.emedicine.com/pmr/topic48.htm. Accessed May 22, 2006.

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Aarli JA. Role of Cytokines in Neurologic Disorders. Current Medicinal
Chemistry. 2003; 10:1931-1937.

•

Stedman's Medical Dictionary. 26th edition. Williams & Wilkins. Baltimore,
MD; 1995.

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2.37

Haematopoietic cytopenias (SMQ)(Production Release November 2005)
2.37.1 Definition•

Definitions and classifications of inherited and acquired bone marrow failure
provided in standard medical textbooks could not be used as a basis for thedefinition of this SMQ
 Those classifications do not differentiate between inherited diseases andacquired conditions
 They include a number of premalignant or malignant conditions•

There are CIOMS definitions of terms and usage criteria for aplastic anemia,
agranulocytosis, bone marrow depression, granulocytopenia, leukopenia,
neutropenia, and pancytopenia; however, it was not possible to strictly follow
those definitions
 The definitions include signs and symptoms of cytopenic conditions
 Some are nonspecific and are not considered worthwhile even for a broad
SMQ search Furthermore, the definitions include distinct ranges of laboratory values which
are not reflected in MedDRA terms

2.37.2 Inclusion/Exclusion Criteria•

Included: Terms referring to direct alterations of the hematopoiesis
 Hematological signs and diagnoses of bone marrow depression
 Hematological investigation results of bone marrow depression
 Specific diagnostic procedures
 “Neonatal” terms are included in the broad searches (the term “neonatal”
does not allow a conclusion whether the condition is of acquired or inheritedorigin) Certain “abnormal” terms are included in the broad searches•

Excluded: Clinical signs and symptoms
 Therapeutic procedure such as bone marrow transplant or stem celltransplant (because they are nonspecific)
 Strictly inherited (and thus not drug-induced) bone marrow diseases

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 Terms referring to hemolytic anemia, antibody associated anemia, irondeficiency anemia, and megaloblastic anemia
 Agranulocytosis is addressed in a separate SMQ.
 In general, inherited premalignant and malignant conditions are excluded.

NOTE: In Version 15.1, PT Haemoglobin decreased and PT Haemoglobin
abnormal were each added as broad search terms to PT to Haematopoietic
erythropenia (SMQ), on the basis of comprehensive testing using a wide varietyof drug data. Please be aware that although these terms were successful in
identifying cases of interest, they also were frequently associated with reports
unrelated to hematopoietic erythropenias.
NOTE: In Version 14.0, the word “haematopoietic” was added to the names ofthree sub-SMQs of SMQ Haematopoietic cytopenias to reflect the focus of these
SMQs on disorders of production, and not destruction, of blood cells. The nameof sub-SMQ Cytopenia and haematopoietic disorders affecting more than one
type of blood cell was also slightly modified:Original SMQ NameNew SMQ Name in MedDRA v14.0

Cytopenia and haematopoietic
disorders affecting more than
one type of blood cell

Haematopoietic cytopenias
affecting more than one type ofblood cell

Erythropenia

Haematopoietic erythropenia

Leukopenia

Haematopoietic leukopenia

Thrombocytopenia

Haematopoietic
thrombocytopenia

Table 2-3. Modifications of sub-SMQ names under Haematopoietic
cytopenias (SMQ) in V. 14.0

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2.37.3 Hierarchy Structure

Haematopoietic cytopenias(SMQ)(20000027)

Haematopoietic cytopenias
affecting more than one typeof blood cell (SMQ)(20000028)

Haematopoietic
erythropenia (SMQ)(20000029)

Haematopoietic
leukopenia (SMQ)(20000030)

Haematopoietic
thrombocytopenia(SMQ)(20000031)

Figure 2-11. Hierarchy Structure of Haematopoietic cytopenias (SMQ)
2.37.4 Notes on Implementation and/or Expectation of Query Results
Haematopoietic cytopenias (SMQ) is a hierarchical SMQ with narrow and broad searchterms. Other than the hierarchy structure, the implementation for this SMQ is similar to
the non-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1).
The superordinate SMQ can be applied by combining the terms in the subordinate
SMQs.
2.37.5 List of References for Haematopoietic cytopenias (SMQ)•CIOMS publication, “Reporting Adverse Drug Reactions: Definitions of Terms
and Criteria for their Use”.

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2.38

Haemodynamic oedema, effusions and fluid overload (SMQ)(Production Release March 2008)

2.38.1 Definition•

Drug-induced edema has been described for a number of medications•

Mechanisms:
 Enhanced sodium and water reabsorption by kidneys
 Potent vasodilators and calcium channel blockers (cause capillaryleakage) Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit renal prostaglandin
synthesis Other drug products associated with peripheral edema:o Antidepressantso Estrogens

o Corticosteroids

o COX-2 inhibitors•

Edema definition:
 Presence of abnormally large amounts of fluid in intercellular tissue
spaces Usually refers to demonstrable amounts of fluid in subcutaneous tissues
 May be localized (due to venous or lymphatic obstruction or increased
vascular permeability) or systemic (due to heart failure or renal disease) Sometimes designated by other terms according to site (ascites,hydrothorax, or hydropericardium) Massive generalized edema is called anasarca
 Synonyms: dropsy and hydrops•

Effusion definition:
 Escape of fluid from lymphatics or blood vessels into a cavity or tissues
 Results from altered hydrostatic forces

2.38.2 Inclusion/Exclusion Criteria•

Included: Terms consistent with definition, including terms for specific cavities andbody sites (e.g., PT Ascites)

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 Terms for therapy or management of edema (e.g., PT Cerebral oedema
management)
 Terms for fluid or volume overload conditions (e.g., PT Hypervolaemia)
 Terms for device- and administration-associated edemas and effusions(e.g., PT Catheter site oedema)•

Excluded: Terms related to procedure-associated edema, e.g., PT Post procedural
oedemao Exception: administration- and device-associated edema (e.g., PT
Catheter site oedema is included)
 Terms for edema that have remote or improbable association therapy(e.g., PT Pulmonary oedema post fume inhalation)
 Eye-related edema, swelling, and effusion terms
 PT Oedematous pancreatitis and PT Neoplasm swelling PT Peripheral venous diseaseo LLT Venous (o)edema was added to MedDRA Version 9.1, and iscurrently linked to PT Peripheral venous disease. Because peripheral
vascular disease and venous insufficiency are unlikely to be drugassociated, such terms are excluded Angioneurotic oedema as it is due to a well described immune-mediatedphenomenon
 Many of the terms that are in existing SMQ Angioedema, particularly theones that are relatively characteristic of that condition:o PT Allergic oedema, PT Breast oedema, PT Circumoral oedema, PT
Lip oedema, PT Epiglottic oedema, PT Face oedema, PT Gingival
oedema, PT Laryngeal oedema, PT Laryngotracheal oedema, PT Nasal
oedema, PT Nipple oedema, PT Oedema genital, PT Oedema mouth,
PT Palatal oedema, PT Periorbital oedema, PT Pharyngeal oedema,
PT Scrotal oedema, PT Tongue oedema, PT Tracheal oedema, PT
Vaginal oedema, PT Vulval oedema, PT Gingival swelling, PT
Oropharyngeal swelling, PT Auricular swelling, PT Breast swelling, PT
Nipple swelling, PT Penile swelling, PT Scrotal swelling, PT Lip
swelling, PT Swelling face, and PT Swollen tongue.

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2.38.3 Notes on Implementation and/or Expectation of Query Results
Haemodynamic oedema, effusions and fluid overload (SMQ) has only narrow searchterms. Therefore, the narrow search and broad search return the same result. The
detailed notes are documented in section 1.5.2.1.
2.38.4 List of References for Haemodynamic oedema, effusions and fluid
overload (SMQ)•

Schroth, BE. Evaluation and management of peripheral edema. J Amer Acad
Phys Assist, www.jaapa.com/.

•

Harrison’s Internal Medicine.

•

Dorland’s Medical Dictionary.

•

Stedman’s Medical Dictionary 27th Edition, 2000.

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2.39

Haemolytic disorders (SMQ)(Production Release April 2005)
2.39.1 Definition•

Hemolytic disorder is defined as anemia with signs of premature destructionof red blood cells and compensatory erythroid hyperplasia.

•

Hemolytic anemia is characterized by
 Increased reticulocyte values
 Increased unconjugated serum bilirubin Decreased (or absent) serum haptoglobin•

Causes can be grouped as follows: Internal abnormalities of red blood cells (e.g., enzyme defects,
hemoglobinopathies) Abnormalities of the red cell membrane (e.g., hereditary spherocytosis,
paroxysmal nocturnal hemoglobinuria, spur cell anemia) Extrinsic factors (e.g., splenomegaly, drug-induced antibodies,microangiopathic hemolysis, infections, toxins)

2.39.2 Inclusion/Exclusion Criteria•

Narrow scope: terms indicating hemolysis, i.e., containing the words“haemolysis” or “haemolytic,” are generally included. Blood group
incompatibilities as well as immunological signs or test results indicative forhemolysis are also included. The above conditions associated with“newborn” are included.

•

Broad scope: a few additional terms of laboratory findings which arepotentially, but not necessarily, due to hemolysis, are included.

•

PT Reticulocytosis is defined as broad scope due to its minimum value
based on Phase I testing.

•Non-specific symptoms of anemia, such as fatigue, have generally been
excluded.

•

Other signs, symptoms, and investigation findings that are not specific tohemolytic anemia, such as jaundice, icterus, flow murmur, increased LDH,
anemia (not otherwise specified), and bilirubinemia (not otherwise specified)are excluded.

•

The various types of hemoglobinopathies were generally excluded.
Hemolysis under such circumstances is one of the clinical expressions due

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to the underlying hemoglobinopathy rather than being influenced by drug
treatment.
•

Predisposing factors, such as inherited red blood cell enzyme abnormalities
and cell membrane defects, are excluded. However, PT Glucose-6phosphate dehydrogenase deficiency is not excluded, because haemolytic
anemia is a very frequent manifestation of glucose-6-phosphate
dehydrogenase deficiency.

•

Infection or intoxication terms that do not have “hemolysis” or “hemolytic”
stated explicitly are excluded.

2.39.3 Notes on Implementation and/or Expectation of Query Results
Haemolytic disorders (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.39.4 List of References for Haemolytic disorders (SMQ)•

Reporting Adverse Drug Reactions. Definitions and criteria for their use.
CIOMS publication, Geneva, 1999.

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2.40

Haemorrhages (SMQ)(Production Release March 2006)
2.40.1 Definition•

Hemorrhage is the escape of blood from the vessels; bleeding.

•

Small hemorrhages are classified according to size as petechiae (very small),purpura (up to 1cm), and ecchymoses (larger).

•

A large accumulation of blood within a tissue is called a hematoma.

2.40.2 Inclusion/Exclusion Criteria•

Included: Terms explicitly referring to hemorrhage, hematoma, bleeding,ecchymosis, purpura, petechiae, treatment forhematoma/bleeding/hemorrhage, and rupture of blood vessels, including
the heart and its chambers.
 PT Blood urine was included in Haemorrhage terms (excl laboratory
terms) (SMQ), and in Haemorrhage laboratory terms (SMQ), although it
could be interpreted as a laboratory test only without stating explicitly thatblood was present in urine.
o This term is usually used in order to describe the finding of blood in
urine.
o Note: Coders should have chosen PT Blood urine present if the intent
was to code blood being present in the urine (macroscopically even
without test).

•

Excluded: Terms referring to gastrointestinal obstructions
 Terms referring to ulcers and perforations without explicit mentioning of
bleeding Normal values of laboratory test terms, except PT Blood urine because it
could be a sign of blood in urine instead of only an unqualified
investigational term (see above) Hemorrhagic fever terms (e.g., PT Bolivian haemorrhagic fever) as they
are of infectious etiology and are not related to adverse drug reactions
 PT Cardiac tamponade, because the PT Pericardial haemorrhage isalready included in this SMQ and sufficiently describes this event

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2.40.3 Hierarchy Structure

Haemorrhages(20000038)

Haemorrhage terms(excl laboratory terms)(20000039)

Haemorrhage
laboratory terms(20000040)

Figure 2-12. Hierarchy Structure of Haemorrhages (SMQ)
This SMQ is a two-level hierarchy consisting of a comprehensive search forhemorrhages (first level) and two sub-SMQs (second level), namely:•

Haemorrhage terms (excl laboratory terms) (SMQ)•

Haemorrhage laboratory terms (SMQ)(NOTE: Sub-SMQ Haemorrhage terms (excl laboratory terms) corresponds to the“Haemorrhage, narrow” search described in the CIOMS documentation.)
2.40.4 Notes on Implementation and/or Expectation of Query Results
Haemorrhages (SMQ) is a hierarchical SMQ with narrow and broad search terms.
Other than the hierarchy structure, the implementation for this SMQ is similar to thenon-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.
2.40.5 List of References for Haemorrhages (SMQ)•

Dorland’s illustrated medical dictionary, Saunders, Philadelphia, 2000.

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2.41

Hearing and vestibular disorders (SMQ)(Production Release March 2009)

2.41.1 Definition•

SMQ is intended to include ear disorders that may be drug related•

Two sub-SMQs created for two functions of ear:
 Hearing Balance•

Hearing may be impaired, disturbed, or accentuated Hearing loss and abnormal hearing are not separated in this SMQ due tooverlap of the these conditions in certain patients•

In this SMQ, included terms are for vestibular disorders generally thatoriginate from inner ear•

Definition: hearing – ability to perceive sound; sensation of sound as opposed
to vibration
 Hearing impairment may result from:o A lesion in external auditory canal or middle ear (conductive hearingloss); oro A lesion in inner ear or VIIIth cranial nerve (sensorineural) Sensorineural hearing loss can be further differentiated as:oo•Sensory (cochlea); or
Neural (VIIIth cranial nerve)

Definition: vestibular – related to vestibule of ear
 Vestibular (inner ear) disorders can cause:oDizziness, vertigo, imbalance, hearing changes, nausea, fatigue,
anxiety, difficulty concentrating, and other symptoms

 Other effects on person's day-to-day functioning, ability to work,
relationships with family and friends, and quality of life
2.41.2 Inclusion/Exclusion Criteria•

Included: Terms for hearing disturbances of any type (loss as well as
accentuation/hyperacusis)
 Terms for balance disorders originating in inner ear

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 Narrow search terms included diagnoses
 Terms for signs, symptoms, and procedures are generally included inbroad search•

Excluded: Terms for disorders that originate from higher centers in the central
nervous system
 Terms for congenital causes
 Terms for infections/infectious causes Neoplasm terms
 Terms for CNS disorders that result in hearing problems (e.g.,cerebrovascular accident) or balance problems (e.g., cerebellar disorders) Terms for conditions resulting from physical trauma (e.g., PT Deafness
traumatic)

NOTE: Although dizziness has many causes and clearly can contribute noise, it wassuggested to leave PT Dizziness in the broad search (of sub-SMQ Vestibular disorders)as “vertigo” and “dizziness” may be used interchangeably.
2.41.3 Hierarchy Structure

Hearing and vestibular
disorders(20000170)

Hearing impairment(20000171)

Vestibular disorders(20000172)

Figure 2-13. Hierarchy Structure of Hearing and vestibular disorders (SMQ)

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2.41.4 Notes on Implementation and/or Expectation of Query Results
Hearing and vestibular disorders (SMQ) is a hierarchical SMQ with narrow and broad
search terms. Other than the hierarchy structure, the implementation for this SMQ issimilar to the non-hierarchical SMQs with narrow and broad search terms (see section
1.5.2.1). The superordinate SMQ can be applied by combining the terms in thesubordinate SMQs.
2.41.5 List of References for Hearing and vestibular disorders (SMQ)•

Stedman’s Medical Dictionary, 27th edition, 2000.

•

Merck Manual of Diagnosis and Therapy, 17th edition, 1999.

•

Vestibular Disorders Association, www.vestibular.org.

•

Otorhino-Laryngology, James B. Snow, Jr., 1979.

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2.42

Hepatic disorders (SMQ)(Production Release April 2005)
2.42.1 Definition
Hepatic disorders (SMQ) is relatively complicated because it covers events that relate toan entire organ system. It comprises•

A comprehensive search of all terms possibly related to the liver, irrespective
whether they are possible related to drug effects•

A number of sub-SMQs on some specific liver related topics•

Searches for terms for potentially drug related liver disorders

SMQ Code

SMQ Term

20000008

Liver related investigations, signs and symptoms (SMQ)

20000009

Cholestasis and jaundice of hepatic origin (SMQ)

20000010

Hepatitis, non-infectious (SMQ)

20000011

Liver neoplasms, malignant and unspecified (SMQ)

20000208

Liver malignant tumours (SMQ)

20000209

Liver tumours of unspecified malignancy (SMQ)

20000012

Liver neoplasms, benign (incl cysts and polyps) (SMQ)

20000013

Hepatic failure, fibrosis and cirrhosis and other liver damage-related
conditions (SMQ)

20000014

Congenital, familial, neonatal and genetic disorders of the liver (SMQ)

20000015

Liver-related coagulation and bleeding disturbances (SMQ)

20000016

Liver infections (SMQ)

20000017

Hepatic disorders specifically reported as alcohol-related (SMQ)

20000018

Pregnancy-related hepatic disorders (SMQ)
Table 2-4. Topics of Hepatic disorders (SMQ)

Each of the above topics is a standalone SMQ. Some of them are further grouped
hierarchically based on their relationship to drug adverse events (refer to the section“Hierarchy Structure” below).

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2.42.2 Inclusion/Exclusion Criteria•

The top level SMQ Hepatic disorders (SMQ) is intended to include all liverrelated terms.

•

SMQ Hepatic disorders only lists terms linking to primary SOCs but many termsof other SOCs also have secondary links to the SOC Hepatobiliary disorders.

•

The term “hepatitis” is frequently misused in adverse reaction reporting byreferring to any liver damage, whether or not histological lesions have been
confirmed. This problem cannot, of course, be solved by any SMQ and requires
an analysis of narratives and laboratory data fields.

•

Liver-related investigations, signs and symptoms (SMQ): Most of the terms ofthis sub-SMQ belong to HLGT Hepatobiliary investigations in SOC
Investigations. Many terms of this HLGT, however, relate to investigations assuch (without a qualifier term, such as “increased”) or to investigations with anormal outcome; these terms are not included in this search. In addition, thisSMQ contains all terms of HLT Hepatobiliary signs and symptoms in SOC
Hepatobiliary disorders and a few PT from other SOCs.

•

Cholestasis and jaundice of hepatic origin (SMQ): This search includes allconditions associated with jaundice or cholestasis of possible hepatic origin andtherefore excludes PTs indicating jaundice caused by haemolytic conditions,such as PT Jaundice extrahepatic obstructive. Various other etiologies are
excluded.

•

Liver neoplasms, malignant and unspecified (SMQ): All terms of this sub-SMQ
belong to HLGT Hepatobiliary neoplasms malignant and unspecified in SOC
Neoplasms benign, malignant and unspecified (incl cysts and polyps).
Metastastatic tumors to liver are excluded.

•

Liver neoplasms, benign (incl cysts and polyps) (SMQ): All terms of this subSMQ belong to SOC Neoplasms benign, malignant and unspecified (incl cysts
and polyps).

•

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions(SMQ): This sub-SMQ is not intended to be used alone generally, but incombination with Hepatitis non-infectious (SMQ). The SMQ does not include PT
Cardiac cirrhosis.

•

PT Liver injury is included in Hepatic failure, fibrosis and cirrhosis and other liver
damage-related conditions (SMQ). This term was added to the SMQ in
MedDRA Version 10.0. The expression "liver injury" is often interpreted as
chemical such as might occur as a result of drug exposure; however, in someinstances, it could also be used to denote trauma to the liver. Users should
review the types of cases retrieved by the PT carefully to determine if nontraumatic or traumatic liver injury has occurred•

Liver-related coagulation and bleeding disturbances (SMQ): This sub-SMQ
includes decreases of coagulation factor levels that may be due to reduced liver

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function, and changes in blood coagulation parameters depending on thesefactors. Terms in this sub-SMQ are from SOC Investigations.
•

Hepatic disorders specifically reported as alcohol-related (SMQ): This SMQ
contains terms specifically related to alcohol-associated disorders. These havenot been included in any of the other sub-SMQs since alcohol-related terms arenormally not searched for when looking for drug-induced liver injuries. Possible
alcohol-related events that also can have other caused (e.g., cirrhosis) have notbeen included in this sub-SMQ.

•

Pregnancy-related hepatic disorders (SMQ): This search contains terms
specifically related to pregnancy-associated disorders. These have not been
included in any of the other sub-SMQs since they are normally not searched forwhen looking for drug-induced liver injuries•

Terms solely associated with disorders of the gallbladder and the bile duct are
excluded.

•

Investigation terms without indicating a result or with a normal outcome areexcluded•

The inclusion of liver neoplasm search (20000011) was questioned by one
subscriber in Phase II testing because of its rareness. The Working Groupdecided to keep it based on the fact that it is possible although rare.

•Terms for liver conditions due to trauma are excluded.

NOTE: In Version 14.1, sub-SMQ Events specifically reported as alcohol-related SMQ)
was renamed to Hepatic disorders specifically reported as alcohol-related (SMQ),
representing a more precise description for this SMQ.
NOTE: In Version 14.0, two new sub-SMQs have been added to existing sub-SMQ
Liver neoplasms, malignant and unspecified to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.
NOTE: In Version 12.1, the following sub-SMQs were renamed:

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Former Sub-SMQ Namein Version 12.0

New Sub-SMQ Namein Version 12.1

Possible drug related hepatic disorders comprehensive search (SMQ)

Drug related hepatic disorders comprehensive search (SMQ)

Possible drug related hepatic disorders severe events only (SMQ)

Drug related hepatic disorders - severe events
only (SMQ)

Liver neoplasms, benign (SMQ)

Liver neoplasms, benign (incl cysts and polyps)(SMQ)

Possible liver-related coagulation andbleeding disturbances (SMQ)

Liver-related coagulation and bleeding
disturbances (SMQ)

Table 2-5. Modifications of sub-SMQ names under Hepatic disorders (SMQ)
in V. 12.1
NOTE: In Version 12.1, the following sub-SMQs were modified in scope to include both
broad and narrow search terms (formerly included only broad terms):
•
•
•
•
•
•

Cholestasis and jaundice of hepatic origin (SMQ)
Congenital, familial, neonatal and genetic disorders of the liver (SMQ)
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions (SMQ)
Hepatitis, non-infectious (SMQ)
Liver infections (SMQ)
Liver related investigations, signs and symptoms (SMQ)

NOTE: In Version 12.1, the following sub-SMQs were modified in scope to include
narrow search terms (formerly included only broad terms):
•
•
•
•
•

Hepatic disorders specifically reported as alcohol-related (SMQ)
Liver neoplasms, benign (incl cysts and polyps) (SMQ)
Liver neoplasms, malignant and unspecified (SMQ)
Liver-related coagulation and bleeding disturbances (SMQ)
Pregnancy-related hepatic disorders (SMQ)

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2.42.3 Hierarchy Structure

Hepatic disorders(SMQ)(20000005)

Drug related hepatic
disorders comprehensive
search (SMQ)(20000006)

Congenital, familial,
neonatal and genetic
disorders of the liver(SMQ)(20000014)

Liver infections (SMQ)(20000016)

Liver related
investigations, signs
and symptoms (SMQ)(20000008)

Drug related hepatic
disorders - severe
events only (SMQ)(20000007)

Hepatitis, noninfectious (SMQ)(20000010)

Liver neoplasms,
malignant andunspecified (SMQ)(20000011)

Liver malignant
tumours (SMQ)(20000208)

Hepatic disorders
specifically reported
as alcohol-related(SMQ)(20000017)

Cholestasis andjaundice of hepatic
origin (SMQ)(20000009)

Liver neoplasms,
benign (incl cysts andpolyps) (SMQ)(20000012)

Pregnancy-related
hepatic disorders(SMQ)(20000018)

Liver-related
coagulation andbleeding disturbances(SMQ)(20000015)
Hepatic failure, fibrosis andcirrhosis and other liver
damage-related conditions(SMQ)(20000013)

Liver tumours ofunspecified
malignancy (SMQ)(20000209)

Figure 2-14. Hierarchy Structure of Hepatic disorders (SMQ)
Hepatic disorders (SMQ) consists of a series of SMQs in a hierarchical relationship to
one another:•

The top SMQ Hepatic disorders (SMQ) is a comprehensive search of all terms
possibly related to the liver, irrespective of whether they are possibly related todrug effects.

•

Drug related hepatic disorders - comprehensive search (SMQ) excludes nondrug related events, such as congenital, infection, alcohol, and pregnancy related
events, from the top SMQ Hepatic disorders (SMQ) search.

•

Under Drug related hepatic disorders - comprehensive search (SMQ), anothersub-search for severe drug related liver toxicity is represented by Drug related
hepatic disorders - severe events only (SMQ).

2.42.4 Notes on Implementation and/or Expectation of Query Results
Hepatic disorders (SMQ) is a hierarchical SMQ with both broad and narrow searchterms.

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The following eight sub-SMQs have both broad and narrow search terms. Other thanthe hierarchy structure, the implementation for this SMQ is similar to the nonhierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.
•
•
•
•
•
•
•
•

Cholestasis and jaundice of hepatic origin (SMQ)
Congenital, familial, neonatal and genetic disorders of the liver (SMQ)
Drug related hepatic disorders - comprehensive search (SMQ)
Drug related hepatic disorders - severe events only (SMQ)
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions (SMQ)
Hepatitis, non-infectious (SMQ)
Liver infections (SMQ)
Liver related investigations, signs and symptoms (SMQ)

The following five sub-SMQs have only narrow search terms. Therefore, the narrowsearch and broad search return the same result. The detailed notes are documented in
section 1.5.2.1.
•
•
•
•
•

Hepatic disorders specifically reported as alcohol-related (SMQ)
Liver neoplasms, benign (incl cysts and polyps) (SMQ)
Liver neoplasms, malignant and unspecified (SMQ
Liver-related coagulation and bleeding disturbances (SMQ)
Pregnancy-related hepatic disorders (SMQ)

Because terms for supporting investigation, sign and symptom terms are grouped in
sub-SMQ Liver related investigations, signs and symptoms (SMQ), subordinate SMQs
of Hepatic disorders (SMQ), which contain only diagnosis and pathognomonic
investigation result, are not independent queries. For example, to find relevant cases of“liver infections”, those retrieved by sub-SMQ Liver infections (SMQ) may not be
sufficient. Cases retrieved by terms for supporting investigation result terms, such as
liver function tests (located in sub-SMQ Liver related investigations, signs andsymptoms (SMQ)) may need to be included to get a complete set of relevant cases.
Similar to Biliary disorders (SMQ) some level of manual intervention is required when
applying subordinate SMQs. Medical judgment may need to be applied.
2.42.5 List of References for Hepatic disorders (SMQ)•

Harrison’s Principles of Internal Medicine 16th ed, Mc Graw Hill, 2005, pp 18081880.

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2.43

Hostility/aggression (SMQ)(Production Release September 2007)

2.43.1 Definition•

Aggression: a form of behavior which leads to self-assertion; it may arise frominnate drives and/or a response to frustration; it may be manifested bydestructive and attacking behavior, by covert attitudes of hostility andobstructionism, or by a healthy self-expressive drive to mastery•

Hostility: a tendency to feel anger toward and to seek to inflict harm upon aperson or group

2.43.2 Inclusion/Exclusion Criteria•

Included: PT Screaming (as it may be a precursor of aggression or hostility, such as
in a patient with dementia)
 PT Gunshot wound, PT Drowning, PT Asphyxia, PT Human bite, PT Bite,
PT Imprisonment, PT Theft(as it is unclear if the patient was the victim or
perpetrator)
 PTs denoting high risk for hostility or aggression: PT Delusional disorder,
persecutory type; PT Jealous delusion; PT Mania; etc.
 PTs containing LLTs with high risk for hostility or aggression: PT Injury(LLT Criminal injury); PT Personality disorder (LLT Aggressive
personality); PT Psychiatric symptom (LLT Violence-related symptom)*;
PT Psychotic disorder (LLT Psychotic behaviour)** LLT Violence-related symptom and LLT Psychotic behaviour were
promoted to PT level in V10.1. As a result, PT Psychiatric symptom, withno related LLTs remaining underneath once LLT Violence-related
symptom was promoted, was removed from this SMQ.
 Symptoms/syndromes highly associated with hostility/aggression that arecommonly a part of the illness (e.g. reports including PT Bipolar disorder,
PT Bipolar I disorder, and PT Bipolar II disorder as events might contain apatient who was manic or hypomanic)
 PT Paranoia and PT Paranoid personality disorder (as they are high risk
for aggression or hostility) PT Irritability and PT Agitation (as fairly high risk for and highly associatedwith hostility/aggression)•

Excluded:

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 Suicide and self-injury related PTs, and dementia and delirium related PTs
were excluded due to the availability of SMQs for these conditions
 Psychosis related PTs that are not highly associated withhostility/aggression. (There is a separate SMQ Psychosis and psychotic
disorders).
 Alcohol and illicit drug PTs as they are not likely to be caused by
medications
 PT Thinking abnormal (too non-specific)
 PT Child maltreatment syndrome (as it denotes child as a victim, based onradiologic findings)
 Metabolic syndromes (hyperthyroidism, etc.) that could possibly lead tohostility/aggression were excluded as too non-specific Terms denoting the patient as a victim of crime or aggressive behavior(where it was clear the patient was the victim)
 “Abused” terms (e.g., LLT Verbally abused) rather than abuse terms were
excluded as not likely to be self -inflicted. However, in some databases it
may be necessary to include these terms because certain coding
practices may include “abused” in place of “abuse”.
 PT Asocial behaviour (not typically aggressive)
 Terms that are not specific for aggression: PT Negativism, and its
associated LLT Oppositional; PT Restlessness; PT Nervousness; PT
Anxiety; PT Frustration tolerance decreased; and PT Grandiosity
 PT Shoplifting (not pertaining to aggression or hostility) Mental retardation terms (most patients with mental retardation are nothostile/aggressive) PT Neuropsychological test abnormal and PT Psychiatric evaluation
abnormal (too broad)
2.43.3 Notes on Implementation and/or Expectation of Query Results
Hostility/aggression (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.43.4 List of References for Hostility/aggression (SMQ)•

Dorland's Illustrated Medical Dictionary, 29th Edition, 2000.

•

The On-Line Medical Dictionary, CancerWEB project, Dec 1998.

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2.44

Hyperglycaemia/new onset diabetes mellitus (SMQ)(Production Release March 2006)

2.44.1 Definition• Diagnosis of diabetes mellitus is usually based on elevated levels of fasting
plasma glucose or a random plasma glucose accompanied by classic
symptoms.
• Hyperglycemia in diabetes mellitus occurs as a result of reduced insulin
secretion, decreased glucose usage, or increased glucose production.
• Type I diabetes mellitus: About 10% of all cases
 Insulin deficiency resulting from autoimmune beta cell destruction (type IA)or idiopathic (type IB)•

Type II diabetes mellitus: About 90% of all cases Heterogeneous disorder of glucose metabolism characterized by variable
degrees of insulin resistance, impaired insulin secretion, and increased
hepatic glucose production•

Both types involve genetic susceptibility: For type I, interaction with some environmental exposure For type II, involves risk factors (e.g., obesity)•

Other less common etiologies:
 Specific genetic defects of insulin secretion or action
 Diseases of the exocrine pancreas (e.g., chronic pancreatitis) Endocrinopathies producing insulin counter-regulatory hormones (e.g.,
Cushing’s syndrome) Viral infections (e.g., cytomegalovirus)
 Certain drugs or chemicals
 Associated with other genetic syndromes (e.g., Down’s syndrome) Complication in about 4% of pregnancies•

Drugs have been associated with hyperglycemia that can progress to new onset
diabetes mellitus.
 Can mimic type I or II Mechanisms:

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o Diminished insulin production, inhibited insulin secretion, and reduced
beta cell volume (e.g., cyclosporine)o Autoimmune destruction of beta cells and increased insulin antibody
titers (e.g., interleukin-2)
o Hormone stimulated gluconeogenesis and decreased insulin sensitivity(e.g., glucocorticosteroids)
o Decreased insulin sensitivity (e.g. protease inhibitors)
 Often reversible by discontinuation of drug, or can be controlled with oral
antidiabetic agents and/or insulin• Common symptoms: polydipsia, polyphagia, polyuria, and weight loss
• Other metabolic abnormalities: hypercholesterolemia and/or hypertriglyceridemia• Insulin concentrations: Low in type I High early during type II; decrease as disease progresses• Acute complications: Diabetic ketoacidosis (DKA) particularly type I Nonketotic hyperosmolar state (NKHS) particularly type II diabeteso Both DKA and NKHS can result in neurologic symptoms that canprogress to coma.
• Long term complications are microvascular (e.g., retinopathy), macrovascular(e.g., coronary artery disease), and neuropathic (e.g., paresthesias).
 Microvascular effects appear to be related to degree of hyperglycemia.
 Macrovascular effects may be related to chronic hyperglycemia andpossible other concurrent factors (e.g., hypertension).
2.44.2 Inclusion/Exclusion Criteria•

Included: Terms representing acute manifestations of diabetes
mellitus/hyperglycemia
 Other terms representing:o Diabetes mellitus and major complications
 Abnormalities of insulin or glucose metabolism expected in patients withdiabetes mellitus or hyperglycemia
 Terms with roots of “diabet-,” “glucose,” “insulin,” “ketone,” and “ketosis”

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 Most terms led to HLGT Glucose metabolism disorders (incl diabetes
mellitus)o PTs linked to this HLGT were reviewed for suitability Narrow search terms were those considered to be very specifically related
to a new diagnosis of, or manifestations, signs, or symptoms of new onset
diabetes mellitus.
 Broad search terms, also indicative of new onset of diabetes, but lessspecific for it PT Ketosis, although a broad description that may capture cases not
related to hyperglycemia, was left in the SMQ because during Phase I
testing, several reports were captured where no other term has beenreported (i.e., it identified cases that would otherwise have been missed)
 PT Weight increased retrieved a large number of reports with “noise”
during Phase I testing. It was included because that the Working Groupagreed that it is relevant to the scope of this SMQ. It might be evaluatedby other MedDRA users.
 Certain PTs (Blood cholesterol increased, Blood triglycerides increased,
Weight decreased) need to be included for completeness sake, and if thenarrow search identifies a sufficient number of cases for a review thencases reporting only these PTs may not need to be reviewed further.
However, should the narrow search return an insufficient number of cases
for review, then cases reporting these PTs should be reviewed todetermine if the patient in those cases appear to be at high risk forsubsequent development of diabetes mellitus or hyperglycemia. Thisapproach may be database or product-dependent.
•

Excluded: Terms representing long term complications
 Infection terms and pancreatitis terms (based on phase I testing; notspecific enough for diabetes mellitus)

2.44.3 Notes on Implementation and/or Expectation of Query Results
Hyperglycaemia/new onset diabetes mellitus (SMQ) has narrow and broad searchterms. The detailed notes are documented in section 1.5.2.1.
2.44.4 List of References for Hyperglycaemia/new onset diabetes mellitus (SMQ)•

Oki JC and Isley WL. Diabetes mellitus. Pharmacotherapy: A Pathophysiologic
Approach (5th Ed). DiPiro JT, Talbert RL, Yee GC et al (Eds). McGraw-Hill:
New York, 2002. pg. 1335-1358.

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Powers AC. Diabetes mellitus. Harrison’s Principles of Internal Medicine (15thEd). Braunwald E, Fauci AS, Kasper DL et al (Eds). McGraw-Hill: New York,2001. pg. 2109-2137.

•

Vanrenterghem YFC. Which calcerineurin inhibitor is preferred in renaltransplantation: tacrolimus or cyclosporine? Curr Opin Nephrol Hypertension
1999; 8(6):669-674.

•

Fraenkel PG, Rutkove SB, Matheson JK et al. Induction of myasthenia gravis,
myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in apatient with renal cell cancer. J Immunother 2002; 25(4):373-378.

•

Costa J. Corticotrophins and corticosteroids. Meyler’s Side Effects of Drugs(14th Ed). Dukes MNG (Ed). Elsevier:Amsterdam, 2000. pg. 1364-1395.

•

Coates P. Miscellaneous hormones. . Meyler’s Side Effects of Drugs (14th Ed).
Dukes MNG (Ed). Elsevier:Amsterdam, 2000. pg. 1520-1526.

•

Heck AM, Yanovski LA, and Calis KA. Pituitary gland disorders.
Pharmacotherapy: A Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert
RL, Yee GC et al (Eds). McGraw-Hill: New York, 2002. pg. 1395-1411.

•

Currier J. Management of metabolic complications of therapy. AIDS 2002;
16(Suppl 4):S171-S176.

•

Fantry LE. Protease inhibitor-associated diabetes mellitus: a potential cause ofmorbidity and mortality. JAIDS 2003; 32: 243-244.

•

Henderson DC. Atypical antipsychotic-induced diabetes mellitus. CNS Drugs
2002; 16(2):77-89.

•

Citrome LL. The increase in risk of diabetes mellitus from exposure to secondgeneration antipsychotic agents. Drugs of Today 2004; 40(5):445-464.

•

Melkersson K and Dahl M-L. Adverse metabolic effects associated with atypicalantipsychotics: literature review and clinical implications. Drugs 2004; 64(7)701723.

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2.45

Hypersensitivity (SMQ)(Production Release March 2013)
2.45.1 Definition•

Aim of this SMQ: Support database searches for potentially drug/vaccine related
hypersensitivity/allergic reactions in connection with Risk Management Plans,
PSUR and other surveillance activities Designed to retrieve all types of cases possibly related to hypersensitivity/
allergic reactions
 Not intended to differentiate between different types of hypersensitivity
reactions such as the Coombs classification•

A number of SMQs for specific allergic conditions already exist (e.g. SMQ
Anaphylactic reaction, SMQ Angioedema)•“Hypersensitivity” is often used in a very general way to describe a large numberof conditions related to an exaggerated response of the body to a foreign agent
 A more restricted use is for allergic reactions of all types•

Many terms included in SMQ Hypersensitivity do not permit differentiation
between hypersensitivity/allergic reactions and other causes for the given eventand therefore further analysis of cases retrieved by the SMQ is required

2.45.2 Inclusion/Exclusion criteria•

Included: All terms indicative of potential drug/vaccine and other medical productrelated hypersensitivity/allergic conditionso Narrow = conditions for which allergy is one of the main causeso Broad = conditions for which other causes are more likely

 Terms for results of investigations indicative of hypersensitivity/allergy
NOTE: In a number of instances, for events having a similar phenomenologicalappearance, some PTs were included as either narrow or broad scope terms and some
not at all depending on the likelihood of a relationship to drug/vaccine administration.
For example, of the many rhinitis terms available in MedDRA, only PT Rhinitis allergic(narrow scope) and various seasonal/perennial rhinitis terms (broad scope) were
included. Similarly, of the various asthma-related terms, only PT Aspirin-exacerbatedrespiratory disease was included as narrow and PT Asthma, PT Asthma late onset, PT
Status asthmaticus, PT Asthmatic crisis, PT Infantile asthma, PT Occupational asthma
were included as broad scope terms.
•

Excluded:

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 Terms for autoimmune disorderso If, however, these conditions are required in a search, the user is referredto HLGT Autoimmune disorders which provides a comprehensive
grouping of such terms
 Terms for transplant rejections, which if required are covered by HLTTransplant rejections
 Terms for idiosyncratic reactions
o If these are required (reactions representing an abnormal reaction to adrug, not caused by allergy), the user is referred to PT Idiosyncratic drug
reaction Allergy terms related to other causes e.g. PT Allergy to animal, PT Allergy tometal, PT Food allergy
 Prophylaxis terms, e.g. PT Anaphylaxis prophylaxis, PT Asthma prophylaxis Urticaria terms relating to non-drug/vaccine related causes, e.g. PT Urticaria
vibratory
2.45.3 List of References for Hypersensitivity (SMQ)•[None provided]

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2.46

Hypertension (SMQ)(Production Release September 2008)
2.46.1 Definition•

Hypertension is defined as high arterial blood pressure•

Causes: Unknown (essential or idiopathic hypertension) Associated with other primary diseases (secondary hypertension)•

Various criteria for its threshold range from 140 mm Hg systolic and 90 mm
Hg diastolic to 200 mm Hg systolic and 110 mm Hg diastolic•

Per 2003 ESH/ESC Hypertension Guidelines and NHLBI, optimal bloodpressure is less than 120/80 mm Hg. Prehypertension is defined as bloodpressure120-139/80-89 mm Hg.

•

Newer definitions characterize hypertension as a complex progressive
cardiovascular syndrome•

Majority of patients are asymptomatic; hypertension only identified bymeasuring blood pressure•

Signs and symptoms:
 Headache (only in severe hypertension)
 Other possibly related complaints: Dizziness, flushed face, early
fatigability, palpitation, and nervousness
 Complaints referable to vascular effects: Epistaxis, hematuria and blurringof vision Common presentations of hypertensive emergencies: Chest pain,
dyspnoea, and neurologic deficit Neurologic presentations: Occipital headache, cerebral infarction or
hemorrhage, visual disturbance, or hypertensive encephalopathy•

No early pathological changes occur in primary hypertension. Ultimately,
generalized arteriolar sclerosis develops, particularly in the kidneys.

•

Hypertension is an important risk factor for cardiovascular events, such as
myocardial infarction and stroke. Early diagnosis and treatment is essential.

2.46.2 Inclusion/Exclusion Criteria•

Included: All terms referring to what is defined as primary/essential/idiopathic
hypertension

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 Secondary forms of hypertension e.g., caused by renal vascular orparenchymal diseases, or hypertension due to endocrine causalities, if
indicated as such (e.g., PT Endocrine hypertension, PT Renovascular
hypertension)
 PT Metabolic syndrome, because hypertension is part of the definition
 Pregnancy related hypertensive disorders, e.g., PT Pre-eclampsia, PT
HELLP syndrome Abnormal values involved in activation of the Renin-Angiotensin-System Abnormal values of sympathomimetic hormones/neurotransmitters
 Diagnostic markers and therapeutic procedural terms for hypertension,e.g., PT Catecholamines urine increased
 Terms referring to end-organ damages as long as the terms have“hypertensive” as part of the concept, e.g. PT Retinopathy hypertensive.
For a complete set of potential end organ damage terms more specific
SMQs need to be applied e.g. Ischaemic heart disease (SMQ), Central
nervous system haemorrhages and cerebrovascular accidents (SMQ)•

Excluded: Congenital conditions/disorders which may be associated with or lead to
hypertension, e.g., PT Congenital hyperthyroidism, PT Liddle's syndrome Pulmonary hypertension, portal hypertension, intracranial hypertension,
intraocular hypertension and their specific signs and symptoms
 Medical conditions including late organ effects that may be consequent tohypertension, e.g., myocardial infarction, stroke, atherosclerosis, unless“hypertensive” is part of their concept.
 Neurological manifestation of hypertensive encephalopathy in malignant
hypertension, e.g. brain edema, convulsion, coma Cardiovascular risk factors, e.g., central obesity, diabetes mellitus,
smoking, hyperlipidemias and many more
 Commonly observed signs and symptoms of hypertension, e.g., headacheand dizziness Terms referring to potential causes of secondary hypertension e.g., PT
Phaeochromocytoma, PT Cushing’s syndrome, PT Cushingoid and PT
Adrenal adenoma

NOTE: Users of this SMQ should consider searching for etiology, signs and symptoms
and consequence terms excluded from this SMQ (see Table 2 in original CIOMS WG
documentation) if hypertension may be a de novo signal. Users may also consider
using other SMQs, such as Ischaemic heart disease (SMQ) and Central nervous
system haemorrhages and cerebrovascular accidents (SMQ) to identify consequencesof hypertension.
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NOTE: In Version 14.0, Hypertension (SMQ) was modified in that all laboratory terms
that are not specific hypertension diagnostic concepts were changed from narrow to
broad scope. This SMQ formerly included only narrow terms.
2.46.3 Notes on Implementation and/or Expectation of Query Results
Hypertension (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.46.4 List of References for Hypertension (SMQ)•

Journal of Hypertension 2003, Vol 21 No 10.

•

Journal of Hypertension 1999, Vol 17 No 2.

•

Harrison’s Principles of Internal Medicine, 16th Ed (2005). Part 8, Sect. 4.

•

Dorland’s Medical Dictionary, 30th Edition, 2003.

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2.47

Hypoglycaemia (SMQ)(Production Release March 2016)
2.47.1 Definition Hypoglycemia is characterized by reduced plasma glucose to a level (usuallyless than 50 mg/dL) that may cause signs or symptoms (e.g., mental statuschanges). Hypoglycemia typically arises from abnormalities in the mechanisms
involved in glucose homeostasis.
 For the diagnosis of hypoglycemia, the “Whipple triad” is generally observed
as low blood sugar, presence of symptoms, and reversal of these symptoms
when the blood sugar level is restored to normal.
 The true prevalence is 5-10% of patients who present with symptoms
suggestive of hypoglycemia.
 Hypoglycemic symptoms are related to sympathetic activation and brain
dysfunction due to the decreased glucose levels. This results in sweating,
palpitations, tremulousness, anxiety, and hunger. Reduction in cerebral
glucose availability (neuroglycopenia) may cause confusion, difficulty withconcentration, irritability, hallucinations, focal impairment, coma andeventually death.
 Various forms and causes of hypoglycemia include: Drugs – ethanol, haloperidol, pentamidine, quinine, salicylates, sulfonamides("sulfa drugs") and oral hypoglycemic agents have been associated withhypoglycemia as have numerous other drugs.
 Surreptitious sulfonylurea use/abuse – self-induced hypoglycemia that may
be observed in healthcare workers or in relatives who care for diabetic family
members.
 Exogenous insulin – for example, insulin-producing tumors of the pancreas(islet cell tumors), and non–beta-cell tumors.
 Reactive hypoglycemia – idiopathic, due to alimentary problems (e.g.,patients with previous upper gastrointestinal surgery), or congenital enzyme
deficiencies (e.g., hereditary fructose intolerance).
 Fasting hypoglycemia
o Nesidioblastosis is a medical term for hyperinsulinemic hypoglycemia
attributed to excessive function of pancreatic beta cells with an abnormal
microscopic appearance. Most recently, nesidioblastosis has been used to
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describe a form of acquired hyperinsulinism with beta cell hyperplasia
found in adults, especially after gastrointestinal surgery.
o Inherited enzyme deficiencies and defects in fatty acid oxidation may also
be involved.
 Other causes of hypoglycemia include the following:o Autoimmune hypoglycemia
o Critical illnesses
o Exercise (diabetic patients)
o Pregnancy
o Renal glycosuria
o Ketotic hypoglycemia of childhoodo Adrenal insufficiency
o Hypopituitarismo Starvationo Laboratory test artifact
 Therapy for hypoglycemia is glucose. Other medications may be used based on
the underlying cause or accompanying symptoms.
2.47.2 Inclusion/Exclusion Criteria•

Included: Terms for various forms of hypoglycemia, which generally include the word
“hypoglycaemia” or a variant of “hypoglycaemia” in the term (e.g., PT
Hypoglycaemia unawareness)
 Terms for relevant laboratory findings supporting the diagnosis of
hypoglycemia (e.g. PT Blood glucose decreased) Terms for characteristic signs and symptoms of hypoglycemia (e.g., PT
Hunger, PT Incoherent)
 Terms for relevant therapeutic interventions that may signal a case of
hypoglycemia.

•

Excluded: Terms for etiologies of hypoglycemia (e.g., PT Insulinoma, PT Metabolic
surgery)
 Terms for congenital forms of hypoglycemia (e.g., PT Diencephalic syndromeof infancy)
 Terms that relate mainly to diabetes mellitus (e.g., PT Glucose tolerance
impaired)

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 Terms for non-specific symptoms that occur with hypoglycemia but are nothighly characteristic and could potentially cause “noise” (e.g., PT Abnormal
behaviour; PT Malaise; PT Fatigue)
2.47.3 Notes on Implementation and/or Expectation of Query Results
Hypoglycaemia (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
The broad scope search should be applied with caution because the generally
nonspecific nature of the signs and symptoms of hypoglycemia are likely to result inbackground noise. During testing, broad scope terms demonstrated poor differentiation
between the positive and negative controls.
2.47.4 List of References for Hypoglycaemia (SMQ)•

Hamdy, O. Hypoglycaemia. Medscape Reference.
http://emedicine.medscape.com/article/122122-overview#showall•

Merck Manual, 17th ed.

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2.48

Hyponatraemia/SIADH (SMQ)(Production Release September 2007)
2.48.1 Definition•

Hyponatremia has been reported in association with a variety of medical
conditions such as: Adrenal insufficiency, congestive heart failure, hepatic cirrhosis, nephritic
syndrome, hypothyroidism, psychogenic polydipsia, hyperglycemia, acuteor chronic renal failure, vomiting, diarrhea and SIADH•

Hyponatremia can be: Hypovolemic: associated with sodium and water depletion (as a result ofvomiting or diarrhea) Hypervolemic: associated with fluid overload and edema (as a result ofcongestive heart failure or nephritic syndrome) Isovolemic: associated with normal or modest extracellular volume
expansion (most common cause is SIADH)•

SIADH is associated with a variety of medical conditions such as: Neoplasms (particularly carcinomas), central nervous system (CNS)
disorders (stroke, intracranial hemorrhage or hematoma, encephalitis or
meningitis, or acute psychosis), or pulmonary disorders (pneumonia,
tuberculosis, asthma, or chronic obstructive pulmonary disease)•

Both hyponatremia and SIADH are also associated with a variety of drugs
such as: CNS active drugs: tricyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs),
trazodone, anticonvulsants (particularly carbamazepine), and theneuroleptics
 Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, Thiazide diuretics and furosemide Sulfonylureas (particularly chlorpropamide) Angiotensin-converting enzyme (ACE) inhibitors
 Many anti-neoplastic agents (particularly cyclophosphamide)•

Hyponatremia usually defined as serum sodium < 135 mEq/L
 If mild or gradual, may be asymptomatic If severe (serum sodium < 120 mEq/L) or rapid, presenting signs andsymptoms are suggestive of water intoxication

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o Cerebral edema symptoms: headache, mental confusion,
disorientation, encephalopathy, tremors, gait disturbances,convulsions, and comao Other symptoms: nausea, vomiting, and muscle weakness or cramps
o Other laboratory abnormalities (in addition to decreased serum
sodium): decreased plasma osmolality, increased or decreased urine
osmolality, and increased or decreased urine sodium concentration•

Diagnosis of SIADH based on exclusion of other causes of hyponatremia

2.48.2 Inclusion/Exclusion Criteria•

Included: Terms for the following concepts:
o Hyponatremiao SIADHo Laboratory indices for decreased serum sodium concentrationso Laboratory indices for decreased serum osmolalityo Laboratory indices for changes in urine sodium concentrationo Laboratory indices for changes in urine osmolality

o PT Water intoxication (since signs and symptoms of SIADH can mimic
this)o PT Brain oedema (based on SMQ testing results)
 Narrow search includes PTs specifically related to hyponatremia, SIADH,
and abnormal or decreased serum sodium or antidiuretic hormone
concentrations
 Broad search includes additional PTs for abnormalities of bloodelectrolytes or osmolality, or abnormalities of urine sodium or osmolality
suggestive of hyponatremia and/or SIADH, PT Water intoxication, and PT
Brain oedema•

Excluded: See NOTE below regarding cases retrieved by this SMQ.

NOTE: Diagnosis of hyponatremia and/or SIADH depends on presence of relevant
laboratory abnormalities. Since these laboratory tests are likely to have been performed
as part of the differential diagnosis and subsequently reported if abnormal for the more
severe CNS manifestations of these conditions (such as convulsions or coma), cases
reporting such severe manifestations and not also reporting the relevant abnormal
laboratory results are excluded from this SMQ. Similarly, cases reporting less severe
manifestations (such as nausea, vomiting, confusion, or headache) and not also
reporting relevant abnormal laboratory results are also excluded from this SMQ since if
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the less severe symptoms are the only reported events they are likely to be
uninformative and will contain insufficient information to asses a possible role ofhyponatremia and/or SIADH in the etiology of the reported events.
2.48.3 Notes on Implementation and/or Expectation of Query Results
Hyponatraemia/SIADH (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.48.4 List of References for Hyponatraemia/SIADH (SMQ)•

Foote EF. Syndrome of inappropriate antidiuretic hormone secretion anddiabetes insipidus. Drug-Induced Diseases: Prevention, Detection, andManagement. Tisdale JE and Miller DA (Eds). American Society of HealthSystem Pharmacists: Bethesda, MD, 2005. pg. 611-624.

•

Joy MS and Hladik GA. Disorders of sodium, water, calcium, and phosphorus
homeostasis. Pharmacotherapy: A Pathophysiologic Approach (5th Ed).
DiPiro JT, Talbert RL, and Yee GC et al (Eds). McGraw-Hill: New York, NY.
2002. pg. 953-979.

•

Robertson GL. Disorders of the neurohypophysis. Harrison’s Principles ofInternal Medicine (16th Ed). Kasper DL, Braunwald E, and Fauci AS et al(Eds). McGraw-Hill: New York, NY. 2005. pg. 2097-2104.

•

Singer GG and Brenner BM. Fluid and electrolyte disturbances. Harrison’s
Principles of Internal Medicine (16th Ed). Kasper DL, Braunwald E, and Fauci
AS et al (Eds). McGraw-Hill: New York, NY. 2005. pg. 252-263.

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2.49

Hypotonic-hyporesponsive episode (SMQ)(Production Release September 2011)

2.49.1 Definition•

Hypotonic-hyporesponsive episode (HHE) is characterized by: Sudden onset of reduced muscle tone Hyporesponsiveness (to verbal or other stimuli) Changed skin color (pallor, cyanosis)•

Has occurred after immunization with the following vaccines: Diphtheria
 Tetanus Haemophilus influenzae type b
 Hepatitis B vaccines•

Most reports followed administration of pertussis component vaccines•

More often associated with:
 Whole-cell vaccines than acellular types
 During primary immunization, generally following the first dose•

Unclear if observed phenomena are related to: Characteristics of the vaccine
 An immunologic phenomenon
 Toxic component(s) in the vaccine
 Combination of factors•

In US vaccine surveillance system (VAERS), slightly more females (53%)
than males experienced HHE, however, more reports of HHE in males havebeen noted in the Netherlands vaccine surveillance system•

Time to onset of signs after immunization is generally three to four hours but
can range from immediately to up to 48 hours post-immunization•

Episode typically lasts six to thirty minutes•

Up to one-third of cases also describe a fever•

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Level of Diagnostic Certainty
Parameter
Level 1

Level 2

Level 3

Responsiveness

Hyporesponsive
or unresponsive

Hyporesponsive
or unresponsive

Hyporesponsive
or unresponsive

Hyporesponsive
or unresponsive

Unknown

Muscle tone

Hypotonia

Hypotonia

Unknown

NormalHypotonia

Skin changes

Pallor or
cyanosisUnknown

Pallor or
cyanosis

Pallor or
cyanosis

Pallor or
cyanosisTable 2-6. Algorithmic levels of diagnostic certainty for Hypotonichyporesponsive episodes

2.49.2 Inclusion/Exclusion criteria•

Included: Terms for the diagnostic entity itself (PT Hypotonic-hyporesponsive
episode) Terms for signs and symptoms either directly or indirectly derived from the
BC definition of HHE (e.g., PT Cyanosis)•

Excluded: Terms which are not related to the diagnosis of HHE

NOTE: The BC definition specifically states that there are no laboratory studies that are
helpful in confirming the diagnosis of HHE. These should not be considered as
definitively excluded from the SMQ as future advancements in the diagnosis andtreatment of HHE may involve laboratory studies.
NOTE: Based on results of all tests, the BC Level 1 algorithm is the recommended
algorithm on which to base the SMQ (see Section 2.43.3)
2.49.3 Algorithm
The algorithm categories for SMQ Hypotonic-hyporesponsive episode are defined asfollows:•

Category A: Narrow terms•

Category B: Hypotonia•

Category C: Hyporesponsive

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Category D: Pallor/Cyanosis

To apply the algorithm for this SMQ, a report is considered a relevant case for further
review if:
A case of interest is one with:•

It includes a term from Category A (narrow scope)OR•

It includes at least one term from Category B + Category C + Category D

Users may choose to use additional algorithms.
2.49.4 List of References for Hypotonic-hyporesponsive episode (SMQ)•

Buettcher, M et al. Hypotonic-hyporesponsive episode (HHE) as an adverse
event following immunization in early childhood: case definition andguidelines for data collection, analysis, and presentation. Vaccine 2007; 25:5875 – 5881.

•

DuVernoy, TS, Braun, MM and the VAERS Working Group. Hypotonichyporesponsive episodes reported to the Vaccine Adverse Event Reporting
System (VAERS), 1996-1998. Pediatrics 2000; 106(4): e52.

•

Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates ofadverse reactions associated with DTP and DT immunizations in infants andchildren. Pediatrics. 1981;68(5):650-659.

•

Daptacel® [package insert]. Toronto, Ontario, Canada: Sanofi Pasteur
Limited; 2008.

•

Recombivax® [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.;2007.

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2.50

Interstitial lung disease (SMQ)(Production Release March 2006)
2.50.1 Definition•

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions thatinvolve the alveolar walls and perialveolar tissue.
 Are nonmalignant and are not caused by any defined infectious agents•

Initial response is inflammation in the air spaces and alveolar walls.
 If chronic, inflammation spreads to adjacent portions of interstitium andvasculature and eventually produces interstitial fibrosis.

•

Scarring and distortion of lung tissue leads to significant derangement of gas
exchange and ventilatory function.

•

Inflammation also can involve the conducting airways.
 Bronchiolitis obliterans associated with organizing pneumonia is probably

part of the spectrum of ILD.

•

ILDs have been difficult to classify because approximately 180 known
individual diseases are characterized by interstitial lung involvement (either
primary disease or part of a multiorgan process, e.g., collagen vasculardiseases).

•

ILDs can be classified into two groups:
 Known causes
 Unknown causes•

Each of these groups can be divided into subgroups:
 Presence of histologic evidence of granulomas in interstitial or vascularareas Absence of granulomas

2.50.2 Inclusion/Exclusion Criteria•

Included: Terms referring to lung diseases characterized by alveolitis, interstitialinflammation, and fibrosis

 ILDs with known cause and unknown cause
 ILDs with granulomas (e.g., sarcoidosis) and those without granulomas(e.g., Goodpasture’s syndrome).

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 Narrow search terms include those specifically indicating an interstitial

pulmonary reaction or possibly worsening of ILD under treatment with asuspect drug.
o Including ILDs with possible allergic component and interstitial lungreactions to radiationo Interstitial lung reactions to radiation would also be expected to be
included as these might signify increased sensitivity to radiation toxicity
combined with drug exposure and would thus still qualify as anadverse reactiono PT Lung infiltration is included in narrow search to increase sensitivity
based on the Phase I testing Broad search terms include those referring to interstitial pulmonary

disease, even if not expected to be a drug-related event (e.g., adultrespiratory distress syndrome and pulmonary hemorrhage syndrome
terms, which are indicative of ILD)•

Excluded: Signs and symptoms of interstitial lung disease Terms relating to infections and occupational exposure Terms not related to direct or allergic toxicity of suspect medical treatment
 Abnormal chest X-ray terms
 Non-cardiogenic pulmonary edema terms
 The following conditions are excluded unless the narrative indicates theinvolvement of interstitial pulmonary reaction: amyloidosis, inherited
insterstitial pulmonary diseases, gastrointestinal or liver disease, GVHD,
inorganic dust induced interstitial lung diseases

2.50.3 Notes on Implementation and/or Expectation of Query Results
Interstitial lung disease (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.

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2.51

Ischaemic colitis (SMQ)(Production Release March 2008)
2.51.1 Definition•

Ischaemic colitis is injury of large intestine that results from interruption of its
blood supply•

Caused by transient reduction in blood flow to colon•

Most patients are elderly, but also occurs in younger age groups associatedwith oral contraceptive use, vasculitis, and hypercoagulable states•

Clinical picture depends upon degree and rate of development of ischemia Acute fulminant ischaemic colitis:o Severe lower abdominal pain, rectal bleeding, and hypotensiono Dilatation of colon (severe cases)o Signs of peritonitis (severe cases) Subacute ischaemic colitis:o Most common clinical varianto Produces lesser degrees of pain and bleeding (occurring over several
days or weeks)•

Ischemic colitis is second most common cause of lower gastrointestinal
bleeding•

Diagnosis made by colonoscopy•

Usually develops in absence of major vessel occlusion•

Associated factors:
 Decreased cardiac output
 Arrhythmia
 Trauma Surgery (e.g., aorto-iliac surgery) Vasculitis
 Coagulation disorders Chronic obstructive pulmonary disease Irritable bowel syndrome Specific drugs

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More than two thirds of patients respond to conservative measures (IV fluids,
bowel rest, antibiotics). Surgery rarely required

2.51.2 Inclusion/Exclusion Criteria•

Included: Terms for ischemic colitis and other forms of colitis
 Terms for associated conditions that typically develop as a consequenceof ischemic colitis
 Related investigation terms•

Excluded: Terms that, in MedDRA, relate exclusively to infections
o NOTE: terms that have a primary link to SOC Infections and infestations
and a secondary link to another SOC are therefore included – e.g., PT
Colon gangrene Terms relating to gastrointestinal strictures and stenoses
 Terms for nonspecific clinical symptoms of ischemic colitis (e.g., PT
Abdominal pain) PT Melaenao Refers to upper gastrointestinal bleedingo Created too much noise during database testing(NOTE: In the broad search, terms describing hemorrhage tended to retrieve cases thatwere “noise” especially for one of the tested positive control products. The “noise” may
be considerable if the compound is used in patients with gastrointestinal disease.)
2.51.3 Notes on Implementation and/or Expectation of Query Results
Ischaemic colitis (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.51.4 List of References for Ischaemic colitis (SMQ)•

Satyaprasad V Alapati SV, Mihas AA. When to suspect ischemic colitis.
Postgrad Med 1999;105 (4).

•Michel Huguier et al.Ischemic colitis; Am J Surg 2006; 192: 679 – 684.

•

Higgins PDR, Davis KJ, Laine L. Systematic review: the epidemiology ofischaemic colitis. Aliment Pharmacol Ther 2004; 19; 729 – 738.

•

Harrison’s Principles of Internal Medicine, 11th edition 1987; 1297.

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2.52

Ischaemic heart disease (SMQ)(Production Release March 2006)
2.52.1 Definition•

Myocardial ischemia refers to lack of oxygen due to inadequate perfusion of
the myocardium; causes an imbalance between oxygen supply and demand.

•

Most common cause of myocardial ischemia is obstructive atherosclerotic
disease of epicardial coronary arteries.

2.52.2 Inclusion/Exclusion Criteria•

Included: All types of conditions related to myocardial ischemia•

Excluded: Terms representing known risk factors for myocardial ischemia
 PT Aspartate aminotransferase abnormal and PT Aspartate
aminotransferase increased are excluded because they retrieved a large
number of irrelevant cases in Phase I testing

NOTE: Original version of the broad searches included PT Aspartate aminotransferase
abnormal and PT Aspartate aminotransferase increased. These terms were removed
based on test results (retrieved a large number of irrelevant cases). If examining older
data (i.e., prior to year 2000), one might consider including these terms in the query.

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2.52.3 Hierarchy Structure

Ischaemic heartdisease(20000043)

Myocardial
infarction(20000047)

Other ischaemic
heart disease(20000168)

Figure 2-15. Hierarchy Structure of Ischaemic heart disease (SMQ)In Version 12.0, per user’s request, Other ischaemic heart disease (SMQ) was added at
level 2 to group the PTs that had been linked to Ischaemic heart disease (SMQ) but did
not belong to the level 2 sub-SMQ Myocardial infarction (SMQ). Unlike Myocardial
infarction (SMQ), Other ischaemic heart disease (SMQ) is not a standalone SMQ topic.
It should only be used as part of its superordinate SMQ topic - Ischaemic heart disease(SMQ).
2.52.4 Notes on Implementation and/or Expectation of Query Results
Ischaemic heart disease (SMQ) is a hierarchical SMQ with narrow and broad searchterms. Other than the hierarchy structure, the implementation for this SMQ is similar to
the non-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1).
The superordinate SMQ can be applied by combining the terms in the subordinate
SMQs.
2.52.5 List of References for Ischaemic heart disease (SMQ)•

Harrison’s textbook of Internal Medicine.

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2.53

Lack of efficacy/effect (SMQ)(Production Release November 2005)
2.53.1 Definition•“Efficacy” is defined as: Ability of an intervention to produce desired beneficial effect in expert
hands and under ideal circumstances In pharmacology, the ability of a drug, biologic, or device to produce
desired therapeutic effecto Independent of potency (amount of the product needed for desired
effect)•“Effect” is defined as the result produced by an action•

Lack of efficacy/effect is therefore evidence of less than the expected effect ofa product•

There might be subpopulations that have a higher risk for lack ofefficacy/effect; in order to identify such cases, one needs to consider types of
events that may be reported in such situations for the specific product andindication•

Some company databases may have created a “lack of efficacy” flag at acase level that may also be used to search for cases

2.53.2 Inclusion/Exclusion Criteria•

Included: “Generic” terms that apply to a broad cross section of products or productclasseso Applicability of this SMQ to Is restricted to drugs, blood
component/blood derivative biologics (e.g., packed red blood cells,
immune globulins), and cellular, tissue, and gene therapy biologics
 PT Drug tolerance was included in this SMQ in addition to PT Drug
tolerance increased
 “Additional product-specific terms” address vaccines, devices, andnarrowly defined products or product classes
 A modified SMQ relevant to vaccines is provided•

Excluded: Terms that applied to only narrowly defined products or product classes(e.g., antihypertensives, anti-hemophilic factors)
 Nonspecific terms (e.g., PT Inhibitory drug interaction)

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 Users that are interested in the retrieval of Lack of efficacy/effect cases for
vaccines, devices, and narrowly defined products or product classes arerecommended to review the appropriate section in the original CIOMS WG
document for Lack of efficacy/effect (SMQ).
2.53.3 Notes on Implementation and/or Expectation of Query Results
Lack of efficacy/effect (SMQ) has only narrow search terms. Therefore, the narrowsearch and broad search return the same result. The detailed notes are documented in
section 1.5.2.1.
2.53.4 List of References for Lack of efficacy/effect (SMQ)•

Dorland’s Illustrated Medical Dictionary, 30th Edition; 2003. pp 590-2.

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2.54

Lacrimal disorders (SMQ)(Production Release September 2009)
2.54.1 Definition•

Disorders that affect lacrimal gland and drainage system: Secretory dysfunction (lacrimal insufficiency)
 Blockage of nasolacrimal duct Occlusion/stenosis of punctum Lacrimal gland neoplasms
 Inflammations and infections•

Clinical manifestations: Excessive tear production
 Dry eyes•

Causes: Systemic diseases, e.g., rheumatoid arthritis
 Drugs (e.g., diuretics) which may also exacerbate symptoms of a dry eye

2.54.2 Inclusion/Exclusion criteria•

Included: Terms for lacrimal apparatus procedures (e.g., PT Dacryocystectomy)
 Terms for neoplasms of lacrimal gland and duct
 Terms for diseases and disorders of lacrimal gland and duct
 Terms for inflammations and infections of lacrimal apparatus•

Excluded: Terms for non-specific symptoms of acute dacryocystitis such as feverand leukocytosis
 Terms for congenital lacrimal conditions (e.g., PT Dacryostenosis
congenital) Terms for trauma to lacrimal system

NOTE: Following testing and discussions with the CIOMS SMQ Working Group, it was
decided that signs and symptoms of general eye disorders will be included in a separate
SMQ. Therefore, the final term list for SMQ Lacrimal disorders consists only of narrowterms.
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NOTE: PT Tearfulness was initially included in this SMQ as a broad term because it
relates to tears and because it was thought possible that some organizations may havecases coded to PT Tearfulness that represent increased lacrimation of a physiologic
nature (due to miscoding). Please note that this term is linked to SOC Psychiatricdisorders under HLT Mood alterations with depressive symptoms. Based on the resultsof testing in both industry and regulatory databases, the CIOMS Working Group decided
to leave all broad terms – including PT Tearfulness – out of the final term list for thisSMQ.
NOTE: LLT X-ray of nasolacrimal duct abnormal is linked to PT Face and mouth X-ray
abnormal, however, this PT has not been included in the term list for this SMQ because
it is too broad for inclusion. The SMQ user may wish to review cases coded to LLT Xray of nasolacrimal duct abnormal in addition to those retrieved by the included SMQ
terms.
2.54.3 Notes on Implementation and/or Expectation of Query Results
Lacrimal disorders (SMQ) has only narrow search terms. Therefore, the narrow searchand broad search return the same result. The detailed notes are documented in section
1.5.2.1.
2.54.4 List of References for Lacrimal disorders (SMQ)•

Elkington, AR and Khaw, PT. Eyelid and lacrimal disorders. BMJ. 1988
August 13; 297(6646): 473–477.

•

Westfall, CT. Lacrimal disease. Curr Opin Ophthalmol, 1995, 6;V: 100 – 104•

Thampy, H. Eyelid and lacrimal disorders.
http://www.firstinmedicine.com/summarysheets_files/Ophthalmology/Eyelid%
20and%20Lacrimal%20Disorders.pdf (specific url not currently accessible)•

Disorders of the lacrimal apparatus. Merck Manual, 17th edition, 1999.

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2.55

Lactic acidosis (SMQ)(Production Release November 2005)
2.55.1 Definition•

Lactic acidosis is a form of high anion gap metabolic acidosis (fall in blood pH
and reduced HCO3 accompanied by a compensatory increase in ventilation(especially Kussmaul respiration) resulting in decreased PCO2•

Intrinsic cardiac contractility may be depressed, but inotropic function can benormal because of catecholamine release•

Peripheral arterial vasodilatation and central vasoconstriction can be present;
the decrease in central and pulmonary vascular compliance predisposes topulmonary oedema•

Central nervous system function is depressed, with headache, lethargy,
stupor, and, in some cases, even coma•

Glucose intolerance may occur•

Characterized by an increase in plasma L-lactate, which may be secondary topoor tissue perfusion (type A) or to aerobic disorders (type B; includes drugs
and toxins)•

Acidosis is seldom significant unless blood lactate exceeds 5 mmol/l•Clinical presentation in type B lactic acidosis:
 Symptoms listed in order of frequency: hyperventilation or dyspnea, stupor
or coma, vomiting, drowsiness, and abdominal pain
 Onset of symptoms and signs is usually rapid accompanied bydeterioration in the level of consciousness (mild confusion to coma; maybe accompanied by profound lethargy)
 Definitive diagnosis depends on the identification of lactate as the organic
anion causing the acidosis

2.55.2 Inclusion/Exclusion Criteria•

Included: Relevant terms from SOC Investigations containing the word “abnormal”(e.g., PT Blood lactic acid abnormal) in the broad search PT Metabolic acidosis or PT Acidosis in the broad search

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Excluded: Terms for SOC Investigations with the qualifier “normal” and those with noqualifier PTs that indicate clearly that the type of acidosis is not a lactic acidosis,
but is of another etiology, e.g., PT Diabetic ketoacidosis
 Terms for foetal and neonatal events (e.g., PT Foetal acidosis)
 PTs indicating an inherited disorder, such as PT MELAS syndrome Terms representing other known causes of lactic acidosis (such as terms
for shock, anemia, malignancies, etc.)
 Other non-specific terms (e.g., PT Headache)2.55.3 Notes on Implementation and/or Expectation of Query Results
Lactic acidosis (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.55.4 List of References for Lactic acidosis (SMQ)•

Braunwald E, Fauci A, Kasper D. Harrison’s Principles of Internal Medicine. 15th
Edition, 2001 pp 285-9.

•

Weatherall D, Ledingham J and Warrell D. Oxford Textbook of Medicine. Third
edition, 1996; volume 2 pp 1541-44.

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2.56

Lens disorders (SMQ)(Production Release September 2008)
2.56.1 Definition•

Most common cause of reduced vision (particularly cataracts)•

Responsible for about 35% of cases of visual impairment•

Cataracts
 May result from a number of processes (mainly age-related) Usually progress slowly, but frequently only detected when reach a certain
level of severity, or during ophthalmological examination
 Symptoms often subtle (e.g., yellow vision) and often an anatomicallysevere cataract will not be associated with an equally severe functionalloss of vision
 Symptoms may include glare, blurred vision, altered color perception,change of refraction, and monocular diplopia•

A “sudden appearance” reported as an adverse event could actually result
from a pre-existing condition•

Care should be taken in evaluating apparent association between theselesions and drug therapy.

•

Definitions (from multiple sources): Aphakia: absence of lens; may occur congenitally or from trauma, but ismost commonly caused by extraction of a cataract

 Cataract:
 Congenital or acquired lack of clarity of the lens
 Clouding of the lens
 Opacity of lens or capsule of eye causing impairment of vision or
blindness
2.56.2 Inclusion/Exclusion Criteria•

Included: Terms for resulting complications such as PT Aphakia
 Therapeutic procedural terms and related complications
 Selected PTs linked to HLT Lens structural change, deposit anddegeneration (excl cataracts) (except PT Aphakia congenital which is
excluded), HLT Lens therapeutic procedures, and HLT Cataract conditions(excluding PT Cataract congenital) (see also exclusion criteria)

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Excluded: Terms for congenital disorders with cataract as part of the syndrome.
Please note that all congenital terms were initially considered for inclusion
and then excluded (after discussion at the CIOMS WG meeting in August
2007)
 Terms in SOC Investigations (no terms for ophthalmological examinations
were judged sufficiently specific to be included)
 Terms in SOC Social circumstances (no more specific terms than PT
Blindness were identified) Terms for infectious complication terms following cataract surgery
 Very broad terms, e.g. PT Congenital eye disorder, or PT Eye operation
 Terms for refractive and accommodative disorders The following terms were excluded: PT Posterior capsule rupture, PT
Exfoliation syndrome (which includes LLT Pseudoexfoliation of lens
capsule), PT Intraocular lens implant, PT Intraocular lens repositioning,
PT Removal of foreign body from lens, and PT Blindness (too nonspecific)
 Terms related to trauma

NOTE: As of Version 18.1, PT Phacocystectomy and PT Lenticular Operation are nolonger designated as excluded from Lens disorders (SMQ), and are thus added to the
SMQ because of their potential relevance to case identification.
NOTE: As of Version 18.0, the following terms are no longer designated as excluded
from Lens disorders (SMQ), and are thus added to the SMQ because of their potential
relevance to case identification: PT Lenticular opacities; PT Lenticular pigmentation;
and PT Posterior capsule opacification.
NOTE: This SMQ is one of several SMQs developed or under development for
ophthalmological disorders. When the entire set of SMQs is developed, a search may
require use of more than one SMQ, or the entire group of SMQs, depending upon thegoal of the search.
2.56.3 Notes on Implementation and/or Expectation of Query Results
Lens disorders (SMQ) has narrow and broad search terms. The detailed notes are
documented in Section 1.5.2.1.
2.56.4 List of References for Lens disorders (SMQ)•West S Epidemiology of cataract: accomplishments over 25 years and future
directions. Ophthalmic Epidemiol 2007 Jul-Aug;14(4):173-8.

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Abraham AG; Condon NG; West Gower E The new epidemiology of cataract.
Ophthalmol Clin North Am 2006 Dec;19(4):415-25.

•

Robman L; Taylor H External factors in the development of cataract Eye 2005
Oct;19(10):1074-82..

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2.57

Lipodystrophy (SMQ)(Production Release September 2009)
2.57.1 Definition•

HIV associated lipodystrophy: Abnormal central fat accumulation (lipohypertrophy)and localized lossof fat tissue (lipoatrophy)
 Some patients have only lipohypertrophy or only lipoatrophy; others
have a mixed clinical presentation (less common) Lipohypertrophy and lipoatrophy are distinct entities with different risk
factors and underlying metabolic processes•

Lipohypertrophy:
 Enlarged dorsocervical fat pad Circumferential expansion of the neck
 Breast enlargement
 Abdominal visceral fat accumulation•

Lipoatrophy:
 Peripheral fat wasting Loss of subcutaneous tissue in face, arms, legs, buttocks
 Involvement of face is most common (may confer a social stigma on
patient)•

Additional features of HIV lipodystrophy syndrome: Hyperlipidemia
 Insulin resistance Hyperinsulinemia Hyperglycemia
 Increased risk for development of diabetes mellitus and atherosclerosis•

Mechanisms for development of this syndrome are not completely
understood•

HIV-1 protease inhibitor drugs and nucleoside reverse transcriptase
inhibitors are implicated as follows: Decreased production of retinoic acid and triglyceride uptake
 Inhibition of mitochondrial DNA (mtDNA) polymerase gamma

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 Inhibition of lipid metabolism
 Prevention of development of adipocytes•

There is evidence suggesting decreased insulin sensitivity, beta-cell
dysfunction, and down-regulated estrogen receptor expression in adipose
tissue•HIV-1 – in absence of highly active antiretroviral treatment (HAART) –may itself cause dyslipidemia and lipodystrophy by various mechanisms•

Resting energy expenditure and lipid oxidation are higher in HAARTtreated HIV-positive patients with vs. without lipodystrophy•

Symptoms include: Increasing abdominal girth (increasing belt or waist size)
 Bloating/distension
 Fat accumulation in back of neck (buffalo hump)/increasing neck size Increasing breast size (including gynecomastia) with or without breastpain Other new fat accumulations:o Circumscribed (lipomas)

o General (e.g., increase chest size)•

Lipoatrophy findings:
 Marked depletion of fat in nasolabial and buccal fat pad Thinness of extremities with prominent veins Loss of volume in subgluteal region•

Laboratory findings:
 Hypertriglyceridemia Hypercholesterolemia Low levels of high density lipoprotein
 Hyperglycemia

2.57.2 Inclusion/Exclusion criteria•

Included: Terms for conditions of lipodystrophy, lipoatrophy, and lipohypertrophy(e.g., PT Lipodystrophy acquired) Terms for signs and symptoms of lipodystrophy (e.g., PT Fat tissue
increased, PT Central obesity)

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 Terms for related metabolic conditions characteristic of lipodystrophy in
HIV patients (e.g., PT Insulin resistance); see Exclusion criteria for
exceptions
 Terms for laboratory findings (and associated clinical conditions)characteristic of lipodystrophy in HIV patients (e.g., PT Bloodcholesterol increased, PT Hypertriglyceridaemia); note that laboratory
terms qualified by the word “abnormal” are also included (e.g., PT
Blood cholesterol abnormal)
 Terms for procedures associated with lipodystrophy (e.g., PT Lipoma
excision)•

Excluded: Terms for congenital conditions (e.g., PT Congenital generalised
lipodystrophy)
 PT HIV wasting syndrome as this is a distinct syndrome unrelated to
HIV associated lipodystrophy Terms for long term metabolic consequences associated withlipodystrophy such as terms related to atherosclerosis
 Diabetes mellitus and hyperglycemia terms (based on testing results)
 PT Obesity and PT Abdominal distension; in testing, these terms were
either very “noisy” or not efficient in returning cases of interest

NOTE: Users may wish to consider including PT Abdominal distension if they areinterested in events related to pre-natal exposure to antiretroviral therapy as thisevent has been described in this setting
2.57.3 Notes on Implementation and/or Expectation of Query Results
Lipodystrophy (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.57.4 List of References for Lipodystrophy (SMQ)•

Robles, DT. Lipodystrophy, HIV. eMedicine, 24 June 2008.
http://www.emedicine.com/derm/topic877.htm•

WHO/Forum for Collaborative HIV Research Joint Meeting: ARV Drugs
Adverse Events, Case Definition, Grading, Laboratory Diagnosis andTreatment Monitoring, Background Document (Draft), 28 – 29
February 2008.

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2.58

Malignancies (SMQ)(Production Release March 2007)
2.58.1 Definition•

For a definition of malignant tumours, reference was made to relevant
textbooks (e.g. DeVita et al 2005, Peckham et al 1995)•

Malignancies (SMQ) includes terms for: all types of malignant or
unspecified tumours; malignancy related conditions; malignancy related
therapeutic and diagnostic procedures; and tumour markers. [Note:premalignant disorders are in a separate SMQ: Premalignant disorders(SMQ).]•

This SMQ consists of ten sub-SMQs which can be used separately or in
combination.

•

Malignancies (SMQ) is subdivided into four sub-SMQs:
 Malignant or unspecified tumours (SMQ) Malignancy related conditions (SMQ) Malignancy related therapeutic and diagnostic procedures (SMQ) Tumour markers (SMQ)•

Sub-SMQ Malignant or unspecified tumours (SMQ) contains all MedDRA
terms for malignant or unspecified tumors, which is further subdivided into
two separate sub-SMQs:
 Malignant tumours (SMQ) Tumours of unspecified malignancy (SMQ)•

Sub-SMQ Malignant tumours (SMQ) is subordinated by: Haematological malignant tumours (SMQ) Non-haematological malignant tumours (SMQ)•

Sub-SMQ Tumours of unspecified malignancy (SMQ) is subordinated by: Haematological tumours of unspecified malignancy (SMQ) Non-haematological tumours of unspecified malignancy (SMQ)

2.58.2 Inclusion/Exclusion Criteria•

Included: Malignant or unspecified tumours (SMQ)o All MedDRA terms for malignant or unspecified tumors

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 Malignancy related conditions (SMQ)o Terms for malignancy related conditions
 Malignancy related therapeutic and diagnostic procedures (SMQ)o Terms for therapeutic and diagnostic procedures used to treat
malignancies
o Some of these procedures are also used for the treatment of
non-malignant conditions
 Tumour markers (SMQ)o MedDRA terms related to tumor markers
o For European Group on Tumour Markers, please reference theweb site at http://ar.iiarjournals.org/content/27/4A/1901•

Excluded: Cyst terms
 Terms related to benign tumors
 For Malignant or unspecified tumours (SMQ)o Terms for malignancy related conditions are excluded from thissub-SMQ.
o Nevus terms are excluded.

NOTE: In version 20.0, four additional sub-SMQs were added to Malignancies(SMQ) to further enhance specificity options for case identification:
Haematological malignant tumours (SMQ) and Non-haematological malignant
tumours (SMQ) were added as sub-SMQs of Malignant tumours (SMQ);
Haematological tumours of unspecified malignancy (SMQ) and Nonhaematological tumours of unspecified malignancy (SMQ) were added as subSMQs of Tumours of unspecified malignancy (SMQ). The entire hierarchy of subSMQs that comprise Malignancies (SMQ) is depicted in Figure 2-16.
NOTE: During development and testing phase, the WG identified PT
Prolactinoma (which has subsequently been demoted as an LLT under PT
Prolactin-producing pituitary tumour in Version 19.1) should be under benignclassification and recommended to remove this PT from the search list of
Malignant or unspecified tumours (SMQ). A change request was submitted to
the MSSO for the correction of MedDRA classification.
NOTE: Because liver ablation is an accepted procedure primarily used to treat
patients with unresectable hepatic malignancies, PT Liver ablation has been
added as a broad term to Liver malignant tumours (SMQ) in Version 17.0 tofacilitate case identification.

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NOTE: In Version 14.0, two new sub-SMQs have been added to sub-SMQ
Malignant or unspecified tumours to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a
combination of malignant and unspecified neoplasm events/cases.
NOTE: The sub-SMQ Malignant or unspecified tumours (SMQ), linked to
Malignancies (SMQ), is intended to represent all anatomical locations. If a user
is interested in tumors in a particular anatomical site, there are other SMQs andsub-SMQs for anatomical-specific malignant and unspecified neoplasms, such as
Prostate neoplasms, malignant and unspecified (SMQ), sub-SMQ Liverneoplasms, malignant and unspecified (SMQ).
NOTE: Malignancy related conditions (SMQ), together with terms in Malignant or
unspecified tumours (SMQ) and Malignancy related therapeutic and diagnostic
procedures (SMQ), will identify cases referring to malignancies and cases ofmalignancy related conditions or procedures reported for pre-existing
malignancies
NOTE: The sub-SMQ Malignancy related therapeutic and diagnostic procedures(SMQ) includes a variety of PTs which describe chemotherapy or radiotherapy
treatment. Please be aware, however, that there are some MedDRA LLTs which
relate to chemotherapeutic or radiotherapeutic associated adverse events andare not included in this sub-SMQ. Such LLTs are not linked to chemotherapy orradiotherapy PTs. The following are several examples:

SOC

PT

LLT

Metabolism and nutrition
disorders

Decreased appetite

Anorexia post chemotherapy

Blood and lymphatic systemdisordersAnaemia

Anaemia post chemotherapy

Gastrointestinal disorders

Diarrhoea

Diarrhoea post chemotherapy

Injury, poisoning and procedural
complications

Procedural vomiting

Vomiting post radiotherapy

Immune system disorders

Secondaryimmunodeficiency

Immunodeficiency secondary to
chemotherapy

Table 2-7. Terms not included in sub-SMQ Malignancy related
therapeutic and diagnostic procedures (SMQ)
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2.58.3 Hierarchy Structure
Malignancies(20000090)

Malignant or
unspecified tumours(20000091)

Haematologicalmalignant tumours(20000227)

Malignancy related
conditions(20000092)

Malignant tumours(20000194)

Tumours ofunspecified
malignancy(20000195)

Non- haematologicalmalignant tumours(20000228)

Haematologicaltumours ofunspecified
malignancy(20000229)

Malignancy related
therapeutic anddiagnostic procedures(20000093)

Tumour markers(20000094)

Non-haematologicaltumours ofunspecified
malignancy(20000230)

Figure 2-16. Hierarchy Structure of Malignancies (SMQ)

2.58.4 Notes on Implementation and/or Expectation of Query Results
Malignancies (SMQ) is a hierarchical SMQ with only narrow search terms.
Therefore, narrow search and broad search return the same result forsuperordinate and all subordinate SMQs. Other than the hierarchy structure, theimplementation for this SMQ is similar to the non-hierarchical SMQs with narrowand broad search terms (see section 1.5.2.1). The superordinate SMQ can beapplied by combining the terms in the subordinate SMQs.

2.58.5 List of References for Malignancies (SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practiceof Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H,.Veronesi, U. Oxford Textbook of Oncology.
1995.

•

European Group on Tumour Markers (EGTM). http://egtm.eu/

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2.59

Malignant lymphomas (SMQ)(Production Release March 2013)
2.59.1 Definition•

Lymphoma = heterogeneous group of malignancies generally divided into
non-Hodgkin lymphoma (NHL) and Hodgkin disease•NHL About 85% of lymphomas
 Median age at diagnosis is sixth decade Some forms of NHL – such as Burkitt lymphoma and lymphoblastic
lymphoma – occur in younger patients
 Classified by several different systems (e.g., Working Formulation,
REAL classification) based on morphology and clinical behavior.
 Variety of laboratory and imaging studies are used to evaluate andstage NHL Treatment depends on stage, grade, type and various patient
factors (symptoms, age, etc.)
 May result from:o Chromosomal translocationso Infections (Epstein-Barr virus [EBV] and hepatitis C virus)o Environmental factors (radiation exposure andchemotherapy)o Immunodeficiency stateso Chronic inflammation
 Clinical presentation depends on location of disease and biologic
characteristics (e.g., low grade vs. high grade) Peripheral adenopathy and B symptoms (fever, night sweats,
weight loss) are characteristic for some forms of NHL•

Hodgkin lymphoma
 Has histologic findings, biologic behavior, and clinical characteristics
distinct from NHL Excisional lymph node biopsy generally recommended to establish
diagnosis
 Various imaging studies used to determine disease stage
 Lymphadenopathy and constitutional B symptoms are characteristic
 Treated with multiagent chemotherapy, plus or minus radiation therapy
 Etiology of Hodgkin lymphoma has not been establishedo Certain infectious agents, e.g. EBV, may be involved
o HIV infected patients have a higher incidence
o Genetic predisposition may also play a role

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2.59.2 Inclusion/Exclusion criteria•

Included: Terms that describe various types of non-Hodgkin’s lymphoma (e.g.,
PT Mantle cell lymphoma stage III) Terms for various forms of Hodgkin’s disease/Hodgkin lymphoma (e.g.,
PT Hodgkin's disease nodular sclerosis refractory) Relevant investigation terms that have at least the potential to retrieve
cases of interest with minimal noise; these terms are generally broad
scope terms (e.g., PT Lymphocyte morphology abnormal)•

Excluded: Terms for congenital conditions
 Terms for lymphoproliferative disorders except select disorders suchas PT Post transplant lymphoproliferative disorder because of therelationship to immunosuppressive therapy and potential fordevelopment into lymphoma
 Terms for non-specific signs and symptoms of lymphoma. Almost all
signs and symptoms of lymphoma are non-specific. The mostcharacteristic sign of lymphoma – lymphadenopathy – can be seen
with a variety of non-lymphoma and non-neoplastic conditions.
Symptoms are typically constitutional, e.g. “B symptoms” such as
weight loss, fever, night sweats, etc.)
 Terms for histiocytoses

NOTE: Testing in a regulatory database determined that some cases of interest
were found with PT Pseudolymphoma for data entered in 2006 or earlier; formore recent cases, PT Pseudolymphoma did not retrieve relevant cases.
Inclusion of PT Pseudolymphoma in the broad scope for searches of data from2006 and earlier might be considered.
2.59.3 List of References for Malignant lymphomas (SMQ)••

Vinjamaram, S. Non-Hodgkin lymphoma.
http://emedicine.medscape.com/article/203399-overview
Dessain, SK. Hodgkin lymphoma.
http://emedicine.medscape.com/article/201886-overview

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2.60

Medication errors (SMQ)(Production Release March 2016)
2.60.1 Definition•

Medication errors are defined as any preventable events that may cause
or lead to inappropriate medication use or patient harm while themedication is in the control of the health care professional, patient or
consumer.
 Such events may be related to professional practice, health careproducts, procedures and systems, including prescribing, ordercommunication, product labeling, packaging and nomenclature,compounding, dispensing, distribution, administration, education,
monitoring and use.
 A medication error can ultimately result in an adverse drug reaction(medication error with an ADR) or may have no clinical consequences(medication error without an ADR).
 A medication error can also be intercepted prior to the patient’s
exposure to the error.
 A potential medication error is a scenario which does not involve an
actual patient, and represents circumstances or information capable ofleading to the occurrence of a medication error•

Medication errors cause a large number of ADRs annually: create a major public-health burden representing 18.7–56% of all
adverse drug events among hospital patients.
 may cause unintended harm
 are considered preventable.

•

Medication errors result from a variety of human (e.g., healthcare
professional; care giver; patient) and product-related reasons, forexample: miscommunication of drug orders due to poor handwriting
 confusion between drugs with similar names
 poor packaging design confusion of dosing units
 unclear instructions•

Medication errors can have an impact on: patients
 healthcare professionals

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 pharmaceutical manufacturers
 regulatory agencies
 health insurance providers
 national patient safety organisations
2.60.2 Inclusion/Exclusion Criteria•

Included: Terms referring to a medication error according to the above definition.
These terms are included as narrow scope terms.
 Terms which do not specifically represent a medication error, but havea significant potential to identify medication errors for their frequent
association with them, such as product label issue terms, productexposure terms, and terms referring to administration ofcontraindicated drugs or other unapproved uses. These terms are
generally included as broad scope terms.

•

Excluded: Intentional/deliberate use terms: by definition these are not medication
errors Product contamination terms
 Transmission of infectious agent terms
 Off label use terms
 Drug interaction terms
 Counterfeit product terms
 Drug incompatibility terms
 Exposure terms that do not refer to product or drug exposure such as
PT Exposure to body fluid Terms for non-specific and broad concepts that might produce
substantial “noise” in data retrieval, e.g., PT Device issue, PT Productquality issue, PT Poisoning, PT Treatment noncompliance2.60.3 Notes on Implementation and/or Expectation of Query Results
Medication errors (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
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2.60.4 List of References for Medication errors (SMQ)•

Creation of a better medication safety culture in Europe: Building up safe
medication practices Expert Group on Safe Medication Practices (2006).

•

Guideline on good pharmacovigilance practices (GVP). Module VI –Management and reporting of adverse reactions to medicinal products.

•

Center for Drug Evaluation and Research (CDER), the Division of
Medication Error Prevention and Analysis (DMEPA):
http://www.fda.gov/drugs/drugsafety/medicationerrors/•

Guidance for Industry. Safety Considerations for Product Design to
Minimize Medication Errors. U.S. Department of Health and Human
Services Food and Drug Administration Center for Drug Evaluation andResearch December 2012 Drug Safety.

•

European Medicine Agency: Medication errors.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/gener
al/general_content_000570.jsp•

Health Canada's role in the Management and Prevention of Harmful
Medication Incidents. http://www.hc-sc.gc.ca/dhp-mps/medeff/cmirpsscdpim-eng.php#a1

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2.61

Myelodysplastic syndrome (SMQ)(Production Release September 2013)
2.61.1 Definition
•
•

•
•
•

•
•

•

•
•

•
•

Myelodysplastic syndrome (MDS) = heterogeneous group of related clonal
disorders of hematopoiesis
Characterized by: Hyper- or hypocellular bone marrow Abnormal cell morphology
 Abnormal maturation
 Peripheral blood cytopenias
 Ineffective blood cell production
All three myeloid cell lineages (erythrocytic, granulocytic, andmegakaryocytic) may be involved.
Considered a premalignant condition
 Subgroup of patients often progresses to acute myelogenous leukemia(AML).
May present with:
 Anemia Thrombocytopenia Neutropenia
Diagnostic approach includes:
 Complete blood count with differential, peripheral blood smear
 Bone marrow studies
Treatment:
 Supportive therapy, including transfusions
 Possible bone marrow stimulation
 Cytotoxic chemotherapy
 Bone marrow transplantation has a limited role
May be caused by exposure to: Cytotoxic chemotherapy
 Radiation
 Viral infection
 Genotoxic chemicals (e.g., benzene)
May be primary (i.e., no known exposure) or secondary (i.e., related to
exposures described above)
Cytogenetics include patients with:
 Normal karyotype
 Balanced chromosomal abnormality and generation of fusion
oncogenes Complex karyotypes (usually more than three abnormalities)
May occur at any age but primarily affects the elderly
French-American-British classification:
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 RA with ringed sideroblasts (RARS) RA with excess blasts (RAEB; 6-20% myeloblasts)
 RAEB in transition to AML (RAEB-T; 21-30% myeloblasts)
 Chronic myelomonocytic leukemia (CMML)
2008 WHO classification:
 Refractory cytopenia with unilineage dysplasia
 RARS RAEB Refractory cytopenia with multilineage dysplasia
 MDS with isolated deletion of 5q
 MDS, unclassifiable Childhood MDS

2.61.2 Inclusion/Exclusion criteria•

Included: Terms for diseases/disorders as presented under internationalclassifications of MDS (e.g., PT Refractory anaemia with ringed
sideroblasts)
 Terms for relevant laboratory findings highly specific for MDS,
including some bone marrow terms (e.g., PT Bone marrow myelogram
abnormal) Terms for other associated conditions related to the clinical expressionof MDS, even if not associated with a single or specific investigation
result (e.g., PT Pancytopenia)
 Terms for therapeutic procedures highly specific for MDS (e.g., PT
Allogenic bone marrow transplantation therapy)•

Excluded: Terms for non-specific signs, symptoms and procedures related to thetrilineage cytopenias of MDS (e.g., PT Fatigue for anemia; PT
Contusion for thrombocytopenia, infection terms for neutropenia, etc.)
 Transfusion terms

NOTE: SMQ Myelodysplastic syndrome focuses on cases likely to represent thiscondition; hence, broad concepts that could represent findings in MDS – e.g., PT
Leukopenia – but could also represent a host of unrelated conditions are
specifically excluded from this SMQ. The user may wish to apply SMQ
Myelodysplastic syndrome initially to search for cases of interest; the user may
optionally wish to also apply SMQ Haematopoietic cytopenias to extend therange of cases that represent cytopenias and that may also describe forms of
MDS.

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2.61.3 List of References for Myelodysplastic syndrome (SMQ)••

Besa, EC, Woermann, UJ, Krishnan, K. Myelodysplastic syndrome.
eMedicine, 10 October 2011;
http://emedicine.medscape.com/article/207347-overview
Tefferi, A and Vardiman, JW. Myelodysplastic syndromes. N Engl J Med
2009, 361(19): 1872 - 1885

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2.62

Neuroleptic malignant syndrome (SMQ)(Production Release March 2006)

2.62.1 Definition•

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal
disorder characterized by hyperthermia, muscle rigidity, alteredconsciousness, and autonomic dysfunction as a complication of treatment
with neuroleptic drugs.

•

The mechanism by which NMS occurs appears to be related to theantidopaminergic activity of the neuroleptic drugs.

•

Symptoms similar to NMS have been reported: In non-schizophrenic patients treated with dopamine-depleting drugs(such as reserpine) Following withdrawal of indirect dopamine receptor agonists in patientswith Parkinson’s disease In association with intoxication from anticholinergic agents,

amphetamines, lithium carbonate, cocaine, and phencyclidine•

Diagnosis is usually based on the development of severe muscle rigidity
and elevated temperature in patients treated with neuroleptic drugs that isaccompanied by some combination of autonomic dysfunction(diaphoresis, incontinence, tachycardia, elevated or labile blood pressure),dysphagia, tremor, myoclonus, changes in consciousness ranging from
confusion to coma, mutism, leucocytosis, and laboratory evidence ofmuscle injury such as elevated creatine phosphokinase (CPK)•

There do not appear to be any major differences in the clinicalpresentation reported with the traditional neuroleptics and the newer
atypical antipsychotic agents.

2.62.2 Inclusion/Exclusion Criteria•

Included: PTs related to NMS and its major manifestations, such as fever,rigidity, myoclonus, tremor, muscle injury, altered consciousness,
autonomic dysfunction, leukocytosis, and increased CPK.

•

Excluded: There were no specific exclusion criteria used.

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2.62.3 Algorithm
Cases to be selected for further review would include any cases reporting at least
one of the PTs listed for Category A (narrow scope) or any case reporting somecombination of at least one PT from each of the three groups of PTs listed as
Categories B, C and D (broad scope).
•

Category A* (narrow scope) PT Neuroleptic malignant syndrome, PT Serotonin syndrome, or PT

Hyperthermia malignant representing specific reports of NMS or thesimilar conditions serotonin syndrome or malignant hyperthermia(which might be easily misdiagnosed as NMS).

•

Category B, C, and D* (broad scope): the definitions of category B, C, andD are as follows: Category B (fever-related PTs)
 Category C (muscle rigidity or injury-related PTs)
 Category D (other relevant NMS-related PTs, including investigation

results)*Note that Category A corresponds to Category 1 as described in the CIOMS
documentation. Categories B, C, and D correspond to Category 2 fever-related
search terms, Category 2 muscle rigidity/injury-related search terms, andCategory 2 other relevant NMS-related search terms, respectively.
2.62.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Neuroleptic malignant syndrome(SMQ) is an algorithmic SMQ. The algorithm is a combination of broad searchterms among various categories to further refine the identification of cases ofinterest. The algorithm can be implemented in a post-retrieval process as noted
below:•First, retrieve relevant cases by applying the SMQ query as anarrow/broad SMQ (see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination toscreen the cases retrieved above. For small data sets of retrieved cases,
the algorithm may be applied on manual review of cases. The algorithm
for Neuroleptic malignant syndrome (SMQ) is A or (B and C and D).
Cases filtered by the algorithm can be listed for output.

2.62.5 List of References for Neuroleptic malignant syndrome (SMQ)•

Levenson JL. Neuroleptic malignant syndrome. Amer J Psychiatry 1985;
142(10):1137-1145.

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Caroff SN and Mann SC. Neuroleptic malignant syndrome. Medical
Clinics of North America 1993; 77(1):185-202.

•

Neuroleptic malignant syndrome. Diagnostic and Statistical Manual of
Mental Disorders (4th Ed). American Psychiatric Association: Washington
DC, 1994, pg. 739-742.

•

Velamoor VR. Neuroleptic malignant syndrome: recognition, prevention
and management. Drug Safety 1998; 19(1):73-82.

•

Neuroleptic malignant syndrome. Reporting Adverse Drug Reactions:Definitions of Terms and Criteria for Their Use. Bankowski Z, Bruppacher
R, Crusius I et al (Eds). Council for International Organizations of Medical
Sciences: Geneva, 1999, pg. 31-32.

•

Simpson GM, Pi EH, and Sramek JJ. Neuroleptic and antipsychotic
drugs. Meyler’s Side Effects of Drugs (14th Ed). Dukes MNG andAronson JK (Eds). Elsevier: New York, 2000, pg. 139-163.

•

Crismon ML and Dorson PG. Schizophrenia. Pharmacotherapy: A
Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert RL, Yee GC et al(Eds). McGraw-Hill: New York, 2002, pg. 1219-1242.

•

Hasan S and Buckley P. Novel antipsychotics and the neuroleptic
malignant syndrome: a review and critique. Amer J Psychiatry 1998;
155(8):1113-1116.

•

Caroff SN, Mann SC, and Campbell EC. Atypical antipsychotics andneuroleptic malignant syndrome. Psychiatric Annals 2000; 30(5):314-321.

•

Ananth J, Parameswaran S, and Gunatilake S et al. Neurolepetic
malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry
2004; 65(4):464-470.

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2.63

Noninfectious diarrhoea (SMQ)(Production Release September 2013)
2.63.1 Definition
•

•

•
•
•

•

SMQ Noninfectious diarrhoea intended to retrieve cases that may be drug
related May include antibiotic associated diarrhea not caused by Clostridium
difficile or other infectious pathogens
Diarrhea defined as: Increased frequency of bowel movements (>3 in 24 hours), and/or
 Decreased stool consistency, and/or Increased stool weight (>200g in 24 hours)
Common side effect of many classes of medications
Accounts for high percentage of all adverse drug effects
Hundreds of drugs have been implicated in causing diarrhea. Most
frequent are:
 Antibiotics
 Laxatives
 Antihypertensives
 Lactulose or sorbitol containing products
 Antineoplastics
 Antiretroviral drugs
 Magnesium containing compounds
 Antiarrhythmics
 Non-steroidal anti-inflammatory drugs
 Colchicine
 Antacids and acid-reducing agents
 Prostaglandin analogs
 Many supplements
Mechanisms of noninfectious diarrhea:
 Non-inflammatory (e.g., osmotic or secretory diarrhea)
 Inflammatory (e.g., cytotoxic effects of agents leading to intestinal
mucositis)

2.63.2 Inclusion/Exclusion criteria•

Included: Terms indicating diarrhea
 Terms for gastrointestinal inflammatory conditions mainly associatedwith diarrhea, such as enteritis, colitis, caecitis, jejunitis, gastroenteritis
concepts
 Terms for gastrointestinal signs for diarrhea, e.g. PT Anal incontinence Terms for laboratory concepts indicating non-infectious etiology fordiarrhea, e.g. PT Culture stool negative

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 Terms for therapy concepts for diarrhea, e.g. PT Antidiarrhoeal
supportive care•

Excluded: Terms with infective etiologies, e.g. PT Bacterial diarrhoea, PT
Pseudomembranous colitis
 Terms for malabsorption and intolerance syndromes commonly
associated with diarrhea, e.g. PT Lactose intolerance, PT Coeliac
disease, PT Intestinal resection, PT Short bowel syndrome Terms for diagnostic/etiology concepts where diarrhea is a common
sign, e.g. PT Diverticulitis, PTs indicating an inflammatory bowel
disease (such as PT Crohn's disease, PT Colitis ulcerative, PT
Inflammatory bowel disease, PT Mastocytic enterocolitis), PT
Carcinoid syndrome, PT Hyperthyroidism, PT Gastrointestinal
amyloidosis, PT Lupus enteritis, PT HIV enteropathy, PT Short-bowel
syndrome PT Necrotising colitis as testing did not show evidence of noninfectious origin in the reviewed cases

2.63.3 List of References for Noninfectious diarrhoea (SMQ)•

Chassany O, Michaux A, Bergmann JF. Drug-induced diarrhoea.
Drug Safety, 2000; 22(1):53-72

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2.64

Noninfectious encephalitis (SMQ)(Production Release September 2007)
2.64.1 Definition•

Encephalitis is defined as inflammation of the brain•

Commonly has an infectious etiology•

May also be drug-induced (focus of this SMQ)•

Mixed disorders such as encephalomyelitis, encephalomyeloradiculitis, or
encephalo-myelopathy may present with overlapping symptoms•

Signs and symptoms include: Acute febrile illness characteristic of meningitis
 Confusion Behavioral abnormalities, including frank psychosis Altered level of consciousness
 Focal or generalized seizures
 Focal neurological disturbances including aphasia, ataxia,
hemiparesis, involuntary movements, cranial nerve deficits•

Involvement of the hypothalamic-pituitary axis may result in temperaturedysregulation, diabetes insipidus, or development of SIADH•

Characteristic cerebrospinal fluid (CSF) profile consists of lymphocytic
pleocytosis, mildly elevated protein concentration and normal glucose
concentration•

MRI, CT, and EEG abnormalities may occur

2.64.2 Inclusion/Exclusion Criteria•

Included: Terms relating to irritability, confusion, stupor, coma, seizures, cranial
neuropathies, altered consciousness, personality changes, and paresis(in the broad search as they may be expected to cause noise) PT Psychiatric symptom (could be used to code various psychiatric
symptoms that might be reported with encephalitis)
 PTs containing “neonatal” (a possible drug-induced cause cannot be
excluded e.g., PT Coma neonatal)
 LLT Meningoencephalitis maps to PT Encephalitis and hence iscovered by inclusion of this PT

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 PT Musculoskeletal stiffness was included (in the broad search)
because it contains the LLTs Neck stiffness and LLT Back stiffness,despite the potential risk of retrieving cases with other LLTs such as
LLT Stiff fingers
 PTs for delirium (possible consequence of encephalitis, e.g., PT
Delirium and PT Delirium febrile)
 Investigation terms with a qualifier (e.g. PT Electroencephalogram
abnormal) Seizure terms except those with known etiology (such as PT
Hypoglycaemic seizure, see exclusion criteria)
 Terms relating to focal central nervous system signs, such as ataxia,
aphasia, and cortical blindness•

Excluded: PTs indicating an infectious origin (e.g. PT Encephalitis
cytomegalovirus, PT Encephalitis protozoal, PT Creutzfeldt-Jakob
disease, and PT Encephalitis lethargica - etiology of latter not clear
but believed to form part of spectrum of post-streptococcal autoimmune
diseases).
 PT Delirium tremens (generally associated with alcohol or anxiolytic
withdrawal, not encephalitis)
 PT Drug withdrawal convulsions (caused by a drug, not encephalitis)
 There are no MedDRA terms for encephalomyeloradiculitis
 PT Lupus encephalitis (unlikely drug related) PTs indicating a congenital/inherited disorder (e.g., PT Congenitalsyphilitic encephalitis) Nonspecific PTs relating to malaise, fever, headache, nausea,
vomiting, dehydration, sleep abnormalities, mood/anxiety (with the
exception of PT Mood altered), affect, vascular collapse and shock PTs indicating involvement of the hypothalamic-pituitary axis inencephalitis (such as PTs relating to temperature dysregulation,
diabetes insipidus, or the development of SIADH)
 PT Echoencephalogram abnormal (not typically used to diagnose
encephalitis)
 PT Encephalotomy (does not pertain to encephalitis)
 PT Hypoglycaemic seizure (having a stated etiology of hypoglycemia,
whereas other types of seizures were included)
 Investigation terms without a qualifier (e.g., PT Electroencephalogram)

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 Terms containing the word “normal” (e.g., PT Electroencephalogram
normal)2.64.3 Notes on Implementation and/or Expectation of Query Results
Noninfectious encephalitis (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.64.4 List of References for Noninfectious encephalitis (SMQ)•

Andreoli T, Behrman R, Bhattacharya B et al. Dorland’s Illustrated Medical
Dictionary, 30th edition, dated 2003. Saunders, Philadelphia.

•

Beehrs M and Berkow R. The Merck Manual of Diagnosis and Therapy.
17th edition; 1999: 1431-42.

•

Kasper D, Braunwald E, Fauci A, et al. Harrison’s Principles of Internal
Medicine. 16th edition, 2005, page 2480-83.

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2.65

Noninfectious encephalopathy/delirium (SMQ)(Production Release September 2007)

2.65.1 Definition•

Encephalopathy and delirium commonly have infectious or metabolic
etiologies•

May also be drug-induced (focus of this SMQ). In the case of metabolic
disorders, it is possible that drug plays a contributory or causative role forunderlying metabolic abnormality.

•

Encephalopathy and delirium may be reported synonymously; howeverdelirium may be narrower in scope•

Encephalopathy
 Defined as any degenerative or diffuse disease of the brain that alters
brain structure or function
 Many sub-forms including:o Biliaryo Demyelinatingo Wernicke’so Secondary to infections (e.g. HIV, cytomegalovirus)o Secondary to drug-induced metabolic disorders such as hepatic
encephalopathy, hyperammonemia, hypoglycemia, hyponatremia,
uremia.
o Leukoencephalopathy (encephalopathy with white matter lesions)
may be secondary to drug-induced hypertension
 Hallmark is altered mental state Other symptoms include lethargy, fluctuation of level of consciousness,
nystagmus, tremor, dementia, seizures, myoclonus, muscle weakness
 Cerebral edema is common•

Delirium (Acute confusional state) Delirium is a clinical state characterized by fluctuating disturbances incognition, mood, attention, arousal, and self-awareness May be due to primary brain diseases or secondary to other diseases.
Causes include:o Metabolico Toxic (drugs)
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o Structural (vascular occlusion and cerebral infarction)o Intracerebral hemorrhageo Primary or metastatic brain tumorso Infections

 Signs and symptoms include: clouding of consciousness withdisorientation, changes in personality and mood, delusions,hallucinations (commonly visual), paranoia, withdrawal, agitation,
disordered speech
2.65.2 Inclusion/Exclusion Criteria•

Included: Terms relating to irritability, confusion, drowsiness, stupor, coma,
seizures, altered consciousness and personality changes (in the broad
search as they are expected to possibly cause noise) PTs containing the terms “encephalopathy” or “delirium” (e.g. PT
Hepatic encephalopathy, PT Hypertensive encephalopathy, PT
Hypoglycaemic encephalopathy, PT Delirium febrile, and PT Uraemic
encephalopathy)
 PT Psychiatric symptom (testing showed that in some cultures it isused to code delirium) PTs containing “neonatal” (a possible drug-induced cause cannot be
excluded, e.g., PT Encephalopathy neonatal)
 PT Reye's syndrome (involves brain damage and subsequent
encephalopathy)
 LLT Bilirubin encephalopathy, mapping to PT Kernicterus (has beenreported in association with certain drugs taken in pregnancy e.g.,
trimethoprim/sulfamethoxazole) PT Subacute myelo-opticoneuropathy is a clinical syndrome reported
from Japan; hydroxyquinolones have been implicated as an etiologic
factor Investigation terms with a qualifier (e.g. PT Electroencephalogram
abnormal) Seizure terms except those with known etiology (such as PT
Hypoglycaemic seizure, see exclusion criteria)
 Coma and unconsciousness concepts except those with known
etiology (such as PT Coma acidotic, see Exclusion criteria)

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Excluded: PTs indicating an infectious origin (e.g., PT Creutzfeldt-Jakob disease,and PT Progressive multifocal leukoencephalopathy)
 PT Lupus encephalitis which contains LLT SLE encephalopathy(unlikely drug related) PTs indicating a congenital/inherited disorder such as PT Opsoclonus
myoclonus (contains LLT Myoclonic encephalopathy of infants), andPT MELAS Syndrome (which is mitochondrial encephalopathy, lactic
acidosis, and stroke) PT Mitochondrial encephalomyopathy and related diseases classified
as mitochondrial myopathies/encephalopathies
 PT Wernicke's encephalopathy (results from a deficiency in vitamin B1, often due to alcoholism) Nonspecific PTs relating to malaise, fever, headache, nausea,
vomiting, dehydration, sleep abnormalities, mood/anxiety (with the
exception of PT Mood altered), affect, vascular collapse and shock PT Echoencephalogram abnormal (not typically used to diagnose
encephalopathy or delirium)
 LLT Post-traumatic encephalopathy, mapping to PT Post concussion
syndrome (as it is an inter-current event) PT Encephalotomy (does not pertain to encephalopathy or delirium) PTs referring to possible causes of encephalopathy (such as
hyperammonemia, hypoglycemia, hyponatremia, uremia, hypertension,etc) were excluded PT Hypoglycaemic seizure (having a stated etiology of hypoglycemia,
whereas other types of seizures were included)
 Investigation terms without a qualifier (e.g., PT Electroencephalogram) Terms containing the word “normal” (e.g., PT Electroencephalogram
normal) Coma and unconsciousness concepts having a stated etiology (suchas PT Coma acidotic, PT Hyperglycaemic unconsciousness)

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2.65.3 Notes on Implementation and/or Expectation of Query Results
Noninfectious encephalopathy/delirium (SMQ) has narrow and broad searchterms. The detailed notes are documented in section 1.5.2.1.
2.65.4 List of References for Noninfectious encephalopathy/delirium (SMQ)•

Jain K. Drug induced neurological disorders. 2001; 2nd edition: p. 23.

•

National Institute of Neurological Disorders and Stroke, 2006.

•

Encephalopathy. Gale Encyclopedia of Neurological Disorders 2005. From
the Thomson Gale Group Inc.

•

Beehrs M and Berkow R. The Merck Manual of Diagnosis and Therapy.
17th edition; 1999: 362-3.

•

Beehrs M and Berkow R. The Merck Manual of Diagnosis and Therapy.
17th edition; 1999: Chapter 171.

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2.66

Noninfectious meningitis (SMQ)(Production Release September 2007)
2.66.1 Definition•

Meningitis is defined as an inflammation of the meninges•

Commonly has an infectious etiology•

May also be drug-induced (focus of this SMQ)•

Aseptic meningitis:
 Characterized by CSF mononuclear pleocytosis and an absence ofbacteria on examination and culture May be caused by viruses Rare but well-recognized complication of drug therapy
 Drug-induced aseptic meningitis (DIAM) has distinct presentation withfever, neck stiffness, headache, confusion, nausea and vomiting Major categories of causative agents are nonsteroidal antiinflammatory drugs (NSAIDs), antimicrobials, intravenous
immunoglobulins, monoclonal antibodies and vaccines•

Chronic meningitis: Meningeal inflammation lasting more than one month Causative agents include chemotherapy drugs that are injected directly
into the CSF (e.g., methotrexate), drugs used in organ transplantation(e.g., cyclosporine and OKT3) and even NSAIDs
 Symptoms similar to those of acute bacterial meningitis, but develop
more slowly and gradually; fever often less severe. Include headache,confusion, backache, weakness, numbness, and facial paralysis•

Mixed disorders such as encephalomyelitis, encephalomyeloradiculitis, or
encephalo-myelopathy may present with overlapping symptoms

2.66.2 Inclusion/Exclusion Criteria•

Included: Terms related to irritability, confusion, stupor, coma, seizures, cranial
neuropathies, altered consciousness and facial or cranial nerve paresis(in broad search as they are expected to possibly cause noise) PTs containing “neonatal” as a possible drug-induced cause cannot be
excluded (e.g., PT Somnolence neonatal)

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 PT Agitation and PT Agitation neonatal (may be reported in neonatesor children as a presenting sign of meningitis)
 LLT Meningoencephalitis maps to the PT Encephalitis and hence iscovered in the Encephalitis SMQ
 The PT Musculoskeletal stiffness was included (in the broad search)
because it contains the LLT Neck stiffness and LLT Back stiffness,despite the potential risk of retrieving cases with other LLTs such as
LLT Stiff fingers or LLT Limbs stiffness Seizure terms are included except those with explicit etiologies not
related to meningitis, such PT Hypoglycaemic seizure and PT Drugwithdrawal convulsions (see exclusion criteria below)•

Excluded: PTs indicating an infectious origin (e.g., PT Meningoencephalitis
adenoviral, PT Meningitis bacterial, etc.)
 As of the initial version of this SMQ, there are no MedDRA terms forencephalomyeloradiculitis.
 PT Waterhouse-Friderichsen syndrome (typical for a meningococcal
meningitis)
 PTs indicating a congenital/inherited disorder PTs related to neoplasms
 Nonspecific PTs relating to malaise, fever, headache, nausea,
vomiting, and dehydration
 PT Echoencephalogram abnormal (not typically used to diagnosemeningitis)
 PT Encephalotomy (does not pertain to meningitis)
 PT Hypoglycaemic seizure and PT Drug withdrawal convulsions(having explicit etiologies not related to meningitis), whereas othertypes of seizures were included

2.66.3 Notes on Implementation and/or Expectation of Query Results
Noninfectious meningitis (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.66.4 List of References for Noninfectious meningitis (SMQ)•

Andreoli T, Behrman R, Bhattacharya B et al. Dorland’s Illustrated Medical
Dictionary, 30th edition, dated 2003. Saunders, Philadelphia.

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Beehrs M and Berkow R. The Merck Manual of Diagnosis and Therapy.
17th edition; 1999: 1431-42.

•

Nettis E, Calogiuri E, Colanardi M, et al. Drug-induced aseptic meningitis.
Curr Drug Targets Immune Endocr Metabol Disord. 2003 Jun;3(2):143-9.

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2.67

Ocular infections (SMQ)(Production Release September 2010)
2.67.1 Definition•

Three main forms
 Affecting the cornea and conjunctiva
 Endophthalmitis (infection inside the eye) Infections of the ocular adnexa and orbit•

Treatment of eye infections
 Based on severity of symptoms and magnitude of possible outcome
 Severe conjunctivitis requires aggressive management with broad
spectrum antibiotics
 Vision loss can occur despite treatment
 Patients who have had recent surgery are at risk for developing
endophthalmitis•

Numerous bacterial, viral, and fungal organisms can cause ocular
infections

2.67.2 Inclusion/Exclusion criteria•

Included: All terms directly related to or describing an eye infection (e.g., PT
Candida endophthalmitis) – these are generally the narrow terms. This
includes infections of the orbital and periorbital structures: conjunctiva,
eyelids and lashes, lacrimal system, cornea, episclera, iris, retina andoptic nerve
 Terms that may not be actual infections terms but could represent
ocular infections (e.g., PT Uveitis) – these are generally broad terms•

Excluded: Terms for ocular disorders due to non-infective causes (e.g., allergy,
autoimmune conditions, injury)
 Terms for congenital and neonatal eye conditions
 Terms that are non-specific eye symptoms (e.g., PT Eye pain)

NOTE: Several of the broad search terms in this SMQ that sometimes, but notalways, have an infectious origin – such as PTs Conjunctivitis, Iritis, Optic neuritis
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and Uveitis – were noisy in the test databases. However, these terms may not
be noisy in other databases.
2.67.3 Notes on implementation and/or Expectation of query results
Ocular infections (SMQ) has narrow and broad search terms. The detailed notes
are documented in Section 1.5.2.1.
2.67.4 List of References for Ocular infections (SMQ)•

Donahue SP, Khoury JM, and Kowalski RP. Common ocular infections. A
prescriber's guide. Drugs. 1996 Oct;52(4):526-40.

•

Sherwal, BL and Verma, AK. Epidemiology of ocular infection due tobacteria and fungus – a prospective study. JK Science Vol. 10 No.3, JulySeptember 2008.

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2.68

Ocular motility disorders (SMQ)(Production Release September 2010)
2.68.1 Definition•

Ocular motility disorders Gaze palsy
 Internuclear ophthalmoplegia Oculomotor nerve lesions
 Trochlear nerve lesions
 Abducens nerve lesions
 Diabetic ophthalmoplegias
 Painful ophthalmoplegias
 Myesthenia gravis
 Ocular myopathies•

Extraocular muscles controlling eye movements:
 Medial and lateral rectus Inferior and superior rectus Superior and inferior oblique•

Cranial nerve palsies
 Oculomotor nerve palsy
o May be caused by brain injury, aneurysm, hemorrhage, tumor, ordiabeteso Affected eye turns outward when the unaffected eye looks straightahead; this causes double vision Trochlear nerve palsyo Often has no identified cause but may be due to head injury
o Both eyes or only one may be affectedo Affected eye is not able to turn inward or down. Double vision results Abducens nerve palsy
o May have a number of causes including head injury, tumors, multiple
sclerosis, aneurysms, CNS infection, etc.
o Affected eye cannot turn outward

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2.68.2 Inclusion/Exclusion criteria•

Included: Terms describing eye movement disorders (e.g., PT Ophthalmoplegia)
 Terms describing disorders of the relevant cranial nerves (e.g., PT IVthnerve paresis)
 Terms for signs and symptoms of ocular motility disorder (broad searchterms) – (e.g., PT Diplopia)•

Excluded: Non specific terms (e.g., PT Visual impairment)

NOTE: The CIOMS SMQ Working Group noted that users of Ocular motility disorders(SMQ) may want to cross refer to Extrapyramidal disorders (SMQ), particularly for older
databases where the coding may not be sufficiently specific to use “eye” terms.
2.68.3 Notes on implementation and/or Expectation of query results
Ocular motility disorders (SMQ) has narrow and broad search terms. The detailed
notes are documented in Section 1.5.2.1.
2.68.4 List of References for Ocular motility disorders (SMQ)•

Clinical Neurology, 7th edition. Simon, R, Greenberg, D and Aminoff, M. Ch.
4, Disturbances of vision.

•

Merck Manual. Palsies of Cranial Nerves That Control Eye Movement.
http://www.merck.com/mmhe/sec06/ch096/ch096d.html

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2.69

Optic nerve disorders (SMQ)(Production Release September 2008)
2.69.1 Definition•

Optic nerve transmits impulses generated by retinal photoreceptors to the
brain

•

Damage anywhere along the optic nerve or to visual areas of brain can resultin loss of vision•

No overall definition for optic nerve disorders; SMQ focuses on optic
neuropathy, optic neuritis (inflammation), and papilledema (swelling of optic
nerve)•

Causes of optic neuropathy:
 Toxins, including lead, methanol, ethylene glycol, tobacco or arsenic
 Compromised blood supply Nutritional deficiencies, especially vitamin B12
 Drugs, including chloramphenicol, isoniazid, ethambutol or digoxin•

Characteristics of loss of vision: May be rapid (minutes or hours) or gradual over 2-7 days One or both eyes affected, depending on cause
 Vision can range from almost normal to complete blindness Both eyes usually affected in optic neuropathy due to toxins or nutritional
deficiency
 Small area of vision loss at center of visual field slowly enlarges and canprogress to complete blindness

2.69.2 Inclusion/Exclusion Criteria•

Included: Narrow searcho All terms that contain “optic”

o Terms relating to the optic disco Terms for diseases that frequently affect the optic nerve, such as
multiple sclerosis
 Broad searcho Terms for signs and symptoms of visual disturbance
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o Terms relating to inflammation of cerebral vessels

o Nonspecific terms relating to cranial nerves or non-specified surgicalprocedures relating to the eye and orbita•

Excluded: Nonspecific brain abnormalities found by imaging techniques
 Congenital terms

NOTE: Nonspecific terms relating to the cranial nerves should be included in general orleft out as a whole.
NOTE: This SMQ is one of several SMQs developed or under development for
ophthalmological disorders. When the entire set of SMQs is developed, a search may
require use of more than one SMQ, or the entire group of SMQs, depending upon thegoal of the search.
2.69.3 Notes on Implementation and/or Expectation of Query Results
Optic nerve disorders (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.69.4 List of References for Optic nerve disorders (SMQ)•

Merck Manual Online, published by Merck Research Laboratories.
http://www.merckmanuals.com/professional/index.html

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2.70

Oropharyngeal disorders (SMQ)(Production Release September 2007)
2.70.1 Definition•

Oropharynx includes oral cavity bounded by: Buccal aspect of lips
 Palate Floor of mouth Posterior pharyngeal wall

2.70.2 Inclusion/Exclusion Criteria•

Included: Terms related to lesions and disorders falling wholly or partly within any
part of oral cavity or pharynx
 Oropharyngeal neoplasms, cysts, and pre-neoplastic lesions
 Oropharyngeal infections
 Gingival disorders
 For sub-SMQ Gingival disorders
o All terms with “gingival” including those that are not clearly infection or
neoplasms such as PT Gingival discolouration, PT Gingival
hypertrophyo Terms related to the gums such as PT Periodontal destruction and PT
Periodontitis
 For sub-SMQ Oropharyngeal allergic conditionso Terms for allergic conditions which can be observed within oral cavity
such as oedemas
 For sub-SMQ Oropharyngeal neoplasmso Terms for neoplasms that occur within oral cavity
 For sub-SMQ Oropharyngeal infectionso Terms for infections that can be observed within oral cavity, such as
those caused by viruses and bacteria
 For sub-SMQ Oropharyngeal conditions (excl neoplasms, infections andallergies): includes lesions not clearly related to specific infections,neoplasms or allergic reactions but due to the following etiology
o Injuries

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o Ulcerso Hypoesthesiaso Hemorrhages

o Unspecified disorders•

Excluded: Terms related to lesions or disorders of larynx and structures below larynx
 Terms related to lesions or disorders of nasal cavity
 Terms related to congenital, familial and genetic disorders
 Surgical, therapeutic and medical procedures of the oropharynx*
 Investigations related to the oropharynx (e.g. biopsy)* For sub-SMQ Oropharyngeal neoplasmso Terms for dental neoplasms* Some terms of these types were initially included and tested, but subsequently
excluded following discussions among the CIOMS WG team for this SMQ topic.
NOTE: In Version 16.0, Oropharyngeal lesions, non-neoplastic, non-infectious and nonallergic (SMQ) was renamed to Oropharyngeal conditions (excl neoplasms, infections
and allergies (SMQ).
NOTE: In Version 14.0, at the recommendation of the CIOMS SMQ Working Group,
approximately 50 salivary gland terms have been added to the sub-SMQs of SMQ
Oropharyngeal disorders, because it was determined that salivary gland disorders fall
into the definition and scope of this SMQ.
NOTE: In Version 13.0, the following sub-search SMQs under Oropharyngeal disorders(SMQ) have been changed in scope from broad terms only to narrow terms only:
Gingival disorders (SMQ), Oropharyngeal allergic conditions (SMQ), Oropharyngeal
infections (SMQ), Oropharyngeal lesions, non-neoplastic, non-infectious and nonallergic (SMQ) [please note that in Version 16.0, this SMQ name was changed toOropharyngeal conditions (excl neoplasms, infections and allergies(SMQ)], andOropharyngeal neoplasms (SMQ).

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2.70.3 Hierarchy Structure

Oropharyngeal disorders(20000109)

Oropharyngeal
neoplasms(20000110)

Oropharyngeal
infections(20000111)

Oropharyngeal
allergic
conditions(20000112)

Gingivaldisorders(20000113)

Oropharyngeal
conditions (excl
neoplasms,
infections andallergies)(20000114)

Figure 2-17. Hierarchy Structure of Oropharyngeal disorders (SMQ)•

Sub-SMQ Oropharyngeal conditions (excl neoplasms, infections and allergies) is
referred as SMQ Oropharyngeal lesions in the CIOMS Working Group original
documentation)

2.70.4 Notes on Implementation and/or Expectation of Query Results
Oropharyngeal disorders (SMQ) is a hierarchical SMQ with only narrow search terms.
Therefore, the narrow search and broad search return the same result. The detailed
notes are documented in section 1.5.2.1.
2.70.5 List of References for Oropharyngeal disorders (SMQ)•

Reporting Adverse Drug Reactions – Definitions of terms and criteria for theiruse. Council for International Organizations of Medical Sciences (CIOMS); 1999.

•

Dorland’s Illustrated Medical Dictionary – Saunders 2003, 30th Edition.

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2.71

Osteonecrosis (SMQ)(Production Release March 2010)
2.71.1 Definition•

Osteonecrosis occurs as a result of compromise to the blood supply to bone•

Hip (femoral head) is a common location, but other bones can also be affected•

Two main forms:
 Traumatico More common

o Due to direct injury and damage of blood supply Non-traumatico Associated with several risk factors/conditions including corticosteroid use,alcohol abuse, sickle cell anemia, Gaucher disease, systemic lupus
erythematosus, coagulopathies, hyperlipidemia, organ transplantation,
caisson disease, thyroid disorders and genetic factors
o Some cases are idiopathic•

Symptoms of osteonecrosis of the femoral head: Groin pain (occasionally buttock pain); deep, throbbing and worsens upon
walking May also be a “catching” or popping sensation with motion•

Physical examination:
 Pain with range of motion and walking
 Limitation of internal rotation
 Trendelenburg gait often present Plain radiographs of hip are often normal•

Osteonecrosis of jaw (ONJ):
 Associated with use of biphosphonates Typically occurs in the setting of recent dental surgery
 Signs and symptoms include pain, tooth mobility, mucosal swelling, erythemaand ulceration

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2.71.2 Inclusion/Exclusion criteria•

Included: PT Osteonecrosis and PT Osteoradionecrosis
 Terms for procedures for osteonecrosis (e.g., PT Hip arthroplasty)
 Terms for investigations for diagnosis of osteonecrosis (e.g., PT Face andmouth X-ray abnormal)
 Terms for signs and symptoms relatively specific for osteonecrosis (e.g., PT
Pain in jaw). Since osteonecrosis has a predilection for certain bones (e.g.,femoral head, jaw), terms selected tend to reflect those sites
 Terms for various infectious and non-infectious forms of osteomyelitis; this is
to account for the association of mandibular osteomyelitis and osteonecrosisin the setting of use of biphosphonate products
 Terms related to procedures and complications of osteomyelitis (e.g., PT
Primary sequestrum)•Excluded: PTs Necrosis, Necrosis ischaemic, Bone disorder, Jaw disorder and otherbroad concepts (e.g., PT Ulcer) as they are too non-specific

NOTE: For the broad search, PT Bone pain may create noise, depending on the
product, and users may consider removing this PT for their own purposes.
NOTE: In light of pharmacovigilance interest in osteonecrosis of the jaw, narrow PT
Osteonecrosis of jaw, broad PT Exposed bone in jaw, and other broad search terms in
Osteonecrosis (SMQ).will facilitate identification of cases of osteonecrosis of the jaw.
2.71.3 Notes on Implementation and/or Expectation of Query Results
Osteonecrosis (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.71.4 List of References for Osteonecrosis (SMQ)•

Osteonecrosis. Merck Manual Home Edition.
http://www.merck.com/mmhe/sec05/ch064/ch064a.html•

Levine, M., Rajadhyaksha, A., and Mont, M. Osteonecrosis, hip. eMedicine,
http://www.emedicine.com/orthoped/TOPIC430.HTM•

Tofferi, J. and Gilliland, W. Avascular necrosis.
http://www.emedicine.com/Med/topic2924.htm

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Purcell, PM and Boyd, IW. Biphosphonates and osteonecrosis of the jaw. Med J
Australia 2005; 182(8): 417 – 418.

•

Grbic, JT et al. Incidence of Osteonecrosis of the Jaw in Women With
Postmenopausal Osteoporosis in the Health Outcomes and Reduced IncidenceWith Zoledronic Acid Once Yearly Pivotal Fracture Trial. J Am Dent Assoc
2008;139;32-40.

•

Ruggiero, SL and Mehrotra, B. Biphosponate-related osteonecrosis of the jaw:
diagnosis, prevention, and management. Annu. Rev. Med 2009; 60: 85-96.

•

Cimatti L, Borderi M, Gibellini D, Re MC. Bone alterations during HIV infection.
New Microbiol. 2008 Apr; 31(2):155-64.

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2.72

Osteoporosis/osteopenia (SMQ)(Production Release September 2009)
2.72.1 Definition•

Osteoporosis = systemic skeletal disorder characterized by: Decreased bone mass (decreased mass per unit volume of normallymineralized bone) Deterioration of bone microarchitecture Osteopenia = milder form of bone loss•

Increased fracture risk even with minimal trauma; most common sites for suchbone loss and resultant fractures are thoracic and lumbar vertebrae, ribs, upper
femur, lower radius•

Usually causes no signs or symptoms except height loss and kyphosis until
fractures occur•

Pathogenesis
 Genetic factors (e.g., hereditary such as osteogenesis imperfecta)
 Medications (especially glucocorticoids)
 Diet Race Gender Lifestyle Physical activity•

Type 1 (postmenopausal)
 Most common type
 Results from sex hormone deficiency
 Increased recruitment/responsiveness of osteoclast precursors and increasedbone resorption outpace bone formation
 Decreased trabecular bone leads to an increased risk of Colles (distal radius)
and vertebral fractures
 Estrogen deficiency may cause bone to become more sensitive to parathyroid
hormone, leading to increased calcium release from bone, decreased renal
calcium excretion, and increased production of 1,25-dihydroxyvitamin D
 Increased production of 1,25(OH)2 D3 causesoIncreased gastrointestinal calcium absorptiono Increased calcium resorption from bone

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o Increased renal tubular calcium resorption
 Gonadal deficiency may also increase production of cytokines that have an
influence on osteoclasts•

Type 2 (senile) Occurs in both genders Decreased formation of bone and decreased renal production of 1,25(OH)2
D3 occurring late in life Loss of cortical and trabecular bone leads to increased fracture risk in hip,long bones, vertebrae•

Type 3
 Secondary to effects of medications (e.g., glucocorticoids) Or due to other conditions that cause increased bone loss by various
mechanisms•

Bone mineral density is frequently used as an approximate measure of bonestrength WHO defines osteoporosis as bone density that is 2.5 standard deviations
below mean for young adult white females•

Markers of bone turnover (bone specific alkaline phosphatase, osteocalcin, type I
procollagen peptides, and urinary deoxypyridinoline) sometimes used to monitor
response to therapy

2.72.2 Inclusion/Exclusion criteria•

Included: Terms for conditions of osteoporosis and osteopenia, including variants (e.g.,
PT Osteopenia, PT Osteoporosis postmenopausal)
 Terms for signs and symptoms (e.g., PT Body height below normal, PT
Kyphosis) including fracture types that are characteristic of osteoporosis (e.g.,
PT Hip fracture, PT Spinal compression fracture) Terms for investigations used in assessment of patients (e.g., PT Ntelopeptide urine increased, PT Bone density decreased); note that laboratory
terms qualified by “abnormal” are also included (e.g., PT Body height
abnormal) Terms for procedures associated with osteoporosis (e.g., PT Hip arthroplasty)
 PT Post-traumatic osteoporosis – although cause of this condition is related
to trauma, possibility that a drug may exacerbate it might need to beconsidered•

Excluded:

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 Congenital terms (e.g., PT Osteoporosis-pseudoglioma syndrome) PT Osteoporosis circumscripta cranii (a form of Paget’s disease) Terms for all fractures except those highly characteristic of osteoporosis, (i.e.,
hip, radius, proximal femur, and ribs [for drug-induced osteoporosis]) PT Kyphoscoliotic heart disease – although kypho(scolio)sis is a complicationof osteoporosis, it is decided to limit terms for complications toprimary/proximal ones and not to secondary complications
 PT Blood alkaline phosphatase increased – this was noted to be “noisy” onearly testing of this SMQ, retrieving cases related to liver disease. Users
should note that they may wish to consider searching cases coded to LLTs
related to bone form of alkaline phosphatase (e.g., LLT Blood alkaline
phosphatase bone increased) Terms from SOC Social circumstances such as PT Walking disability, PT
Wheelchair user, etc.
2.72.3 Notes on Implementation and/or Expectation of Query Results
Osteoporosis/osteopenia (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
2.72.4 List of References for Osteoporosis/osteopenia (SMQ)•

Hobar, C. Osteoporosis. eMedicine, 16 December 2005.
(http://www.emedicine.com/MED/topic1693.htm)•

WHO/Forum for Collaborative HIV Research Joint Meeting: ARV Drugs Adverse
Events, Case Definition, Grading, Laboratory Diagnosis and Treatment
Monitoring, Background Document (Draft), 28 – 29 February 2008.

•

Dorland’s Medical Dictionary.

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2.73

Ovarian neoplasms, malignant and unspecified (SMQ)(Production Release September 2008)

2.73.1 Definition•

Developed to detect all malignant and unspecified tumors related to ovary•

Covers all malignant and unspecified neoplasms related to ovary and in addition:
 Malignancy related conditions
 Malignancy related therapeutic and diagnostic procedures Tumor markers

2.73.2 Inclusion/Exclusion Criteria•

Included: Terms for malignant or unspecified neoplasms with a clear reference to ovary
 Terms for conditions related to malignant or unspecified neoplasms of theovary, including:o Procedureso Investigationso Tumor markers

o Signs and symptoms pointing to such disorders•

Excluded: Terms for malignant or unspecified neoplasms without a clear reference toovary Terms for unspecified site malignancy related therapeutic and diagnostic
procedures and tumor markers
 Terms for metastases to the ovary
 Terms related to vulva and vagina
 PT Ovarian operation as it is not a malignancy specific therapeutic procedure.
(This term may, however, be added if a very broad search is required).

NOTE: In Version 14.0, two new sub-SMQs have been added to Ovarian neoplasms,
malignant and unspecified (SMQ) to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.

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NOTE: For searches of non-specific malignancy related conditions and malignancy
related therapeutic and diagnostic procedures, it is recommended to use the respective
lower level sub-SMQ of SMQ Malignancies.
2.73.3 Hierarchy Structure
Ovarian neoplasms,
malignant andunspecified (SMQ)(20000151)

Ovarian malignant tumours(SMQ)(20000200)

Ovarian tumours ofunspecified malignancy(SMQ)(20000201)

Figure 2-18. Hierarchy Structure of Ovarian neoplasm, malignant andunspecified (SMQ)

2.73.4 Notes on Implementation and/or Expectation of Query Results
Ovarian neoplasms, malignant and unspecified (SMQ) has narrow and broad searchterms. The detailed notes are documented in section 1.5.2.1.
2.73.5 List of References for Ovarian neoplasms, malignant and unspecified(SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of
Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H,.Veronesi, U. Oxford Textbook of Oncology. 1995.

•

European Group on Tumour Markers (EGTM). http://www.egtm.eu/

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2.74

Periorbital and eyelid disorders (SMQ)(Production Release September 2009)

2.74.1 Definition•

Eyelids
 Maintain health of underlying eye by protecting cornea
 Assist in distribution and elimination of tears•

Eyelid structure Anterior layer of skin and orbicularis oculi muscle
 Posterior layer of tarsus and conjunctiva
 Orbicularis oculi muscles (innervated by CN VII) closes eyelid Upper eyelid is raised by levator muscle (innervated by CN III) and Müller'smuscle Orbital septum – originating from orbital rim – inserts into upper lid and lower
lido Septum limits spread of eyelid bleeding or infection to posterior orbital
structures
 Glands along eyelid margin contribute to lipid component of tears
o May become inflamedo Meibomian glands lie within tarsus

o Pilosebaceous glands of Zeiss and apocrine glands of Moll are anterior to
meibomian glands within distal eyelid margin•

Problems that can afflict eyelids
 Neoplasms
 Inflammation and infection
 Structural problems (e.g., ectropion)•

Most eyelid disorders do not threaten vision but may produce irritative symptoms(burning, foreign body sensation or pain)•

Blepharitis (eyelid inflammation) is characterized by erythematous eyelids withdebris accumulation along eyelid margin2.74.2 Inclusion/Exclusion criteria•

Included:

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 Terms for eyelid procedures (e.g., PT Blepharectomy)
 Eyelash terms
 Periorbital terms•

Excluded: Signs and symptoms of eyelid and periorbital disorders that could be sharedwith other eye disorders
 Common skin conditions that can affect the eyelid and periorbital region (e.g.,seborrheic keratosis) unless qualified with a word indicating eyelid is involved(e.g., PT Eyelids pruritus is included) Known causes of, or syndromes associated with, eyelid and periorbital
disorders (e.g., PT Myasthenia gravis, PT Horner's syndrome) Congenital terms (e.g., PT Congenital eyelid malformation)
 Infection terms
 Terms related to CN III and CN VII - although involved with motor control ofeyelid, they are not considered relevant for this SMQ
 Terms related to eyelid and periorbital injury

NOTE: Some “eyelid” terms at the LLT level have not been included in the term list forthis SMQ because their parent PTs may be too broad for inclusion. The SMQ user may
wish to review these LLTs and determine if they wish to capture cases coded with theseterms in addition to those retrieved by the included SMQ terms. These LLTs are:
Erythema circumocular-blepharal, Feeling of warmth blepharal, Hypertrichosis of eyelid,
Hypotrichosis of eyelid, Numbness of eyelid, Numbness of eyelids, Papular rashcircumocular-blepharal, and Xeroderma of eyelid.
2.74.3 Notes on Implementation and/or Expectation of Query Results
Periorbital and eyelid disorders (SMQ) has only narrow search terms. Therefore, thenarrow search and broad search return the same result. The detailed notes are
documented in section 1.5.2.1.
2.74.4 List of References for Periorbital and eyelid disorders (SMQ)•

Carter, S.R. Eyelid disorders: diagnosis and management. Amer. Fam. Phys.
57:(11), June 1998.
http://www.aafp.org/online/en/home/publications/journals/afp.html

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2.75

Peripheral neuropathy (SMQ)(Production Release November 2005)
2.75.1 Definition•

Impairment of the peripheral motor, sensory and autonomic nervous system•

Diagnosis is on clinical grounds, supplemented by electrophysiologicalinvestigation•

At least one of the following must be present: Muscular weakness with diminished tone, or flaccid paralysis (diminishedtendon reflexes and wasting) Sensory disturbances, including pain Impairment of autonomic function.

2.75.2 Inclusion/Exclusion Criteria•

Included: Terms for “peripheral neuropathy” and related concepts
 Terms for signs, symptoms and laboratory findings as described in the
CIOMS definition
 Autonomic terms (e.g., PT Autonomic neuropathy) and associated muscle
findings (e.g., PT Muscle atrophy) were also included.

•

Excluded: Terms related to peripheral nerve injury
 In general, demyelinating neuropathy terms (e.g. PT Chronic inflammatory
demyelinating polyneuropathy) are excluded because there is a separate
SMQ for demyelinating disorders under development.
 Terms for neuropathies associated with other medical conditions, such as PT
Diabetic neuropathy.

NOTE: PT Paralysis flaccid, a feature of neuropathy, was excluded from Peripheral
neuropathy (SMQ) through MedDRA Version 18.0, because it is an extreme anduncommon finding. In MedDRA Version 18.1, PT Paralysis flaccid was demoted to an
LLT under PT Paralysis. PT Paralysis is not included in Peripheral neuropathy (SMQ).
2.75.3 Notes on Implementation and/or Expectation of Query Results
Peripheral neuropathy (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
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2.75.4 List of References of Peripheral neuropathy (SMQ)•

Bankowski Z, Bruppacher R, Crusius I et al. Reporting adverse drug reactions,definition of terms and criteria for their use. Council for International
Organizations of Medical Sciences (CIOMS), 1999 p 32.

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2.76

Pregnancy and neonatal topics (SMQ)(Production Release March 2011)

2.76.1 Definition•

SMQ Pregnancy and neonatal topics was developed: To replace original SMQ Adverse pregnancy outcome/reproductive toxicity(incl neonatal disorders)­

Original SMQ had discrepancies in term inclusion resulting in maintenanceissues To make it more compatible with regulatory goals related to pregnancy andneonatal topics•

Fertility-related topics and developmental disorders are not part of this SMQ but
will be considered for separate, standalone SMQs•

CIOMS SMQ Working Group team referenced EMA’s Guideline on the Exposure
to Medicinal Products during Pregnancy: Need for Post-Authorisation Data as a
guide for term inclusion•

In the guideline, pregnancy outcomes are defined as: Live birth, normal
 Live birth, abnormal­

Pre-term, term, post-term birth­

Small for gestational age infants/ Intrauterine growth retardation­

Drug withdrawal syndrome in the neonate­

Malformations­

Morbidity

 Fetal death­

Ectopic­

Miscarriage­

Stillbirth Termination of pregnancy•

Lactation associated disorders (functional and related to neonatal exposuresthrough breast milk) are also in this SMQ

2.76.2 Inclusion/Exclusion criteria•

Included: Overall inclusion criteria for SMQ Pregnancy and neonatal topics:

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o Terms for pregnancy complications and outcomeso Terms for neonatal disorders and conditionso Terms for normal pregnancy and outcomeso Terms for abortion (induced and spontaneous) and stillbirtho Terms for conditions related to laboro Terms for lactation topics, both functional and related to exposures to thebaby via breast milko Terms for fetal disorders

o Terms for procedures related to congenital and fetal disorders
 For SMQ Congenital, familial and genetic disorders
o All PTs in SOC Congenital, familial and genetic disorders
 For SMQ Pregnancy, labour and delivery complications and risk factors (excl
abortions and stillbirth)o Terms for abnormal labor, pregnancy, delivery
o Terms for relevant investigationso Terms for relevant procedureso Terms related to ectopic pregnancy
o Terms for placenta issueso Uterine terms related to pregnancy, labour and delivery

o Terms for conditions that increase the risk of pregnancy complicationo Terms for malpresentation

 For SMQ Lactation related topics (incl neonatal exposure through breast milk)(includes additional sub-SMQs Functional lactation disorders and SMQ
Neonatal exposures via breast milko Terms related to lactation disorders and conditions occurring in thecontext of pregnancy
o Terms related to breast and nipple complications associated with lactation(e.g., PT Mastitis postpartum)o Terms for drug exposures and intoxications via breast milko Terms for feeding disorders
 For SMQ Foetal disorders

o All terms related to the condition of the fetus
 For SMQ Neonatal disorders
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o All terms related to the neonate/newborn

o All PTs related to procedures to correct/address congenital disorders in
the neonatal period (e.g., PT Systemic-pulmonary artery shunt) For SMQ Termination of pregnancy and risk of abortiono Terms for spontaneous and induced abortions and stillbirtho Terms for complications of abortion and termination of pregnancy
o Terms for relevant procedures and investigationso Terms for risk factors for abortionso Consists of all PTs linked to HLGT Abortions and stillbirth For SMQ Normal pregnancy conditions and outcomeso Terms related to normal pregnancy conditions and outcomes, including
terms from SOC Social circumstanceso Terms for unintended pregnancy

o Terms for investigation results indicative of pregnancy•

Excluded: Overall exclusion criteria for SMQ Pregnancy and neonatal topics
o Unqualified investigation terms

o Terms for fertility and sexual dysfunction (these are proposed to exist in a
separate, standalone [Level 1] SMQ)o Terms for developmental disorders (these are proposed to exist in a
separate, standalone [Level 1] SMQ)o PT Toxoplasmosis prophylaxis - unlikely to be drug-related
 For SMQ Congenital, familial and genetic disorders
o All terms that are not in SOC Congenital, familial and genetic disorders
 For SMQ Pregnancy, labour and delivery complications and risk factors (excl
abortions and stillbirth)o Terms for abortions and stillbirths
 For SMQ Lactation related topics (incl neonatal exposure through breast milk)(includes additional sub-SMQs Functional lactation disorders and SMQ
Neonatal exposures via breast milk)o Terms for non-pregnancy associated lactation conditions (e.g., PT
Galactorrhoea)
 For SMQ Foetal disorders

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o Terms related to fetal presentation (e.g., PT Foetal arm prolapse) and fetal
position (e.g., PT Unstable foetal lie)o Terms for risk factors for fetal disorders
 For SMQ Neonatal disorders
o Terms for developmental disorders (proposed for a separate, standalone
SMQ)o Congenital terms

o PT Distal intestinal obstruction syndrome (LLT Meconium ileus equivalent
syndrome links to PT Distal intestinal obstruction syndrome. However, thePT is a more general condition in patients of any age with cystic fibrosis)
 For SMQ Termination of pregnancy and risk of abortiono Terms indicative of a non-viable ectopic pregnancy
 For SMQ Normal pregnancy conditions and outcomeso Terms for conditions related to risk to the fetus/pregnancy
NOTE: In version 14.0, Pregnancy and neonatal topics (SMQ) is a new SMQ that wasadded to replace Adverse pregnancy outcome/reproductive toxicity (incl neonatal
disorders) (SMQ). Consequently, Adverse pregnancy outcome/reproductive toxicity (inclneonatal disorders) (SMQ) has been changed to inactive status.
NOTE: In version 14.0, all of the PTs under Congenital, familial and genetic disorders(SMQ) have been changed from broad to narrow scope.
NOTE: Because Neonatal disorders (SMQ) excludes congenital terms, users of
Neonatal disorders (SMQ) should consider whether the addition of Congenital, familial
and genetic disorders (SMQ) to the search is appropriate for the question in hand.

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2.76.3 Hierarchy Structure
Pregnancy andneonatal topics (SMQ)(20000185)

Congenital, familial
and genetic disorders(SMQ)(20000077)

Pregnancy, labour anddelivery complications
and risk factors (excl
abortions and stillbirth)(SMQ)(20000186)

Lactation related
topics (incl neonatal
exposure throughbreast milk) (SMQ)(20000187)

Functional lactation
disorders (SMQ)(20000188)

Foetaldisorders(SMQ)(20000190)

Neonataldisorders(SMQ)(20000191)

Termination ofpregnancy andrisk of abortion(SMQ)(20000192)

Normal pregnancy
conditions andoutcomes (SMQ)(20000193)

Neonatal exposures
via breast milk (SMQ)(20000189)

Figure 2-19. Hierarchy Structure of Pregnancy and neonatal topics (SMQ)

2.76.4 List of References for Pregnancy and neonatal topic (SMQ)•

Guideline on the Exposure to Medicinal Products during Pregnancy: Need for
Post-Authorisation Data. London, 14 November 2005,
EMEA/CHMP/313666/2005.

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2.77

Premalignant disorders (SMQ)(Production Release March 2007)
2.77.1 Definition•

Premalignant lesions: morphologically identifiable lesions that sometimes
precede the development of invasive cancer
 Also called precancers, preneoplastic lesions, incipient cancers, intraepithelial
neoplasias, and preinvasive cancers
 May lack constitutive properties of cancer
 May have certain attributes that are absent in cancers
 Need not progress to cancer Often have a high rate of regression
 When premalignant lesion progresses, cancer is the obligate outcome

2.77.2 Inclusion/Exclusion Criteria•

Included: Atypias, e.g., intraepithelial neoplasias found at LLT level, usually placed
under “dysplasia” PTs
 All terms in HLT Myelodysplastic syndromes All terms under HLT Myeloproliferative disorders (excl leukaemias) All terms under HLT Skin preneoplastic conditions NEC Selected terms in HLT Gastrointestinal mucosal dystrophies and secretion
disorders Terms from SOC Investigations and SOC Surgical and medical procedures
related to identifying and treating precancerous processes (see Excluded)•

Excluded: Terms already defined as malignant processes e.g., all carcinomata “in situ”
 Risk factors either leading to precancerous lesions or associated with ahigher incidence of a malignant process Cell markers and hormones or proteins that can be used as predictors ofmalignancy
 Terms referring to abnormal biopsy results (e.g., PT Biopsy colon abnormal)
because they are non-specific and did not yield significant data on testing

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NOTE: Terms for abnormal biopsy results are excluded from SMQ Premalignant
disorders. After retrieving data with SMQ Premalignant disorders or any of its subSMQs, the user may refer to SMQ Malignancies to identify “biopsy abnormal” terms if
additional data retrieval is deemed necessary.
NOTE: Because Premalignant disorders, general conditions and other site specificdisorders (SMQ) contains non site-specific terms such as PT Dysplasia, in order toretrieve all relevant cases for the site-specific sub-searches for Blood premalignant
disorders (SMQ),Gastrointestinal premalignant disorders (SMQ), Reproductive
premalignant disorders (SMQ), and Skin premalignant disorders, it may be necessary to
combine the subordinate SMQ with Premalignant disorders, general conditions andother site specific disorders (SMQ). Medical judgment may need to be applied.
NOTE: SMQ Premalignant disorders focuses on the premalignant conditions
themselves for safety analysis purposes. This SMQ specifically excludes terms formalignancy risk factors, such as:•

Genetic predispositions for malignancy (e.g., PT Li-Fraumeni syndrome)•

Lifestyle issues (e.g., PT Tobacco user)•

Certain inflammatory/infectious conditions that increase risk for malignancy (e.g.,
PT Hepatitis chronic active, PT Colitis ulcerative)

Some organizations may require a search for malignancy risk factors based on
MedDRA terms coded, for example, in a medical history field. An approach for this may
be to focus initially on whatever body system or cancer type is of concern. For
example, if skin malignancies are of interest, the user should consider searching the
medical history fields for terms related to sun exposure (e.g., PT Actinic elastosis, PT
Sunburn, etc.). For a more comprehensive search of all malignancy risk factors, acareful and broad search of related MedDRA terms would be needed, including terms
for genetic predispositions, lifestyle-associated terms, and certain
inflammatory/infectious terms as noted above.

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2.77.3 Hierarchy StructurePremalignant
disorders(20000085)

Blood
premalignant
disorders(20000086)

Gastrointestinal
premalignant
disorders(20000087)

Reproductive
premalignant
disorders(20000088)

Skin premalignant
disorders(20000089)

Premalignant
disorders, generalconditions andother site specificdisorders(20000169)

Figure 2-20. Hierarchy Structure of Premalignant disorders (SMQ)
NOTE: In Version 14.0, Premalignant disorders (SMQ) was modified in scope to include
narrow search terms only. This SMQ formerly included both narrow and broad searchterms.
NOTE: Also in Version 14.0, approximately 130 PTs in the five sub-SMQs of SMQ
Premalignant disorders have been made inactive per recommendation of the CIOMS
SMQ Working Group for the following reasons: “Biopsy abnormal” concepts (e.g., PT Biopsy lip abnormal) and othernonspecific procedure terms (e.g., PT Nasal polypectomy) are unlikely toretrieve events/cases of interest.
 Upon review, some terms were nonspecific, or were either already malignant(e.g., PT Chronic myelomonocytic leukaemia) or not truly premalignant (e.g.,
PT Seborrhoeic keratosis)
 Terms for risk factors (e.g., PT Coeliac disease) were made inactive because
most SMQs generally exclude terms for risk factors; instead, wording on
approaches to retrieving data related to malignancy risk factors have been
added to the SMQ Introductory Guide.
NOTE: In Version 12.0, per user’s request, Premalignant disorders, general conditions
and other site specific disorders (SMQ) was added at level 2 to group the PTs that had
been linked to Premalignant disorders (SMQ) but did not belong to any of the level 2
sub-SMQs. Unlike other level 2 sub-SMQ (e.g. Blood premalignant disorders (SMQ)),
Premalignant disorders, general conditions and other specific site disorders (SMQ) is
not a standalone SMQ topic. It should only be used as part of its superordinate SMQ
topic - Premalignant disorders (SMQ).

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Four sub-groups allow for more specific searches:
 Blood premalignant disorders (SMQ) Gastrointestinal premalignant disorders (SMQ) Reproductive premalignant disorders (SMQ) Skin premalignant disorders (SMQ)

Terms not pertaining to above four groups are gathered directly underneath thePremalignant disorders, general conditions and other site specific disorders (SMQ).
•

Users can refine searches by differentiating: “Obligate” lesions (definite or probable progression to malignancy)
 “Facultative” lesions (possible progression)

2.77.4 Notes on Implementation and/or Expectation of Query Results
Premalignant disorders (SMQ) is a hierarchical SMQ, and has only narrow terms.
Therefore, the narrow search and broad search return the same result. The detailed
notes are documented in section 1.5.2.1.
2.77.5 List of References for Premalignant disorders (SMQ)•

Classifying the precancers: A metadata approach (Jules J Berman and Donald E
Henson).

•Heenan PJ, Elder DJ, Sobin LH (1996) WHO International HistologicalClassification of Tumors. Berlin, Heidelberg, New York, Tokyo: Springer.

•

Berman JJ, Henson DE. A Comprehensive Classification and Data
Implementation for the Precancers.

•

http://www.pathinfo.com/jjb/preclass.htm , 2002 (This web site may not currently
be active).

•

Harrison's Principles of Internal Medicine, 16th Edition.

•

Dorland’s Medical Dictionary.

[NOTE: See CIOMS WG original documentation for additional web site references used]

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2.78

Prostate neoplasms, malignant and unspecified (SMQ)(Production Release September 2008)

2.78.1 Definition•

Developed to detect all malignant and unspecified tumors related to prostate•

Covers all malignant and unspecified neoplasms related to prostate and in
addition: Malignancy related conditions
 Malignancy related therapeutic and diagnostic procedures Tumor markers

2.78.2 Inclusion/Exclusion Criteria•

Included: Terms for malignant or unspecified neoplasms with a clear reference toprostate
 Terms for conditions related to malignant or unspecified neoplasms of theprostate, including:o Procedureso Investigationso Tumor markers

o Signs and symptoms pointing to such disorders•

Excluded: Terms for malignant or unspecified neoplasms without a clear reference toprostate
 Terms for unspecified site malignancy related therapeutic and diagnostic
procedures and tumor markers
 Terms for metastases to the prostate PT Prostatic operation as it is not a malignancy specific therapeutic
procedure. (This term may, however, be added if a very broad search is
required).

NOTE: In Version 14.0, two new sub-SMQs have been added to Prostate neoplasms,
malignant and unspecified (SMQ) to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.

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NOTE: For searches of non-specific malignancy related conditions, malignancy related
therapeutic and diagnostic procedures, it is recommended to use the respective lower
level sub-SMQ of SMQ Malignancies.
NOTE: PT Transurethral prostatectomy is omitted from this SMQ based on testing
results and because this is not a procedure that would normally be used for a malignant
neoplasm of the prostate.
2.78.3

Hierarchy Structure
Prostate neoplasms,
malignant andunspecified (SMQ)(20000152)

Prostate malignant
tumours (SMQ)(20000202)

Prostate tumours ofunspecified malignancy(SMQ)(20000203)

Figure 2-21. Hierarchy Structure of Prostate neoplasms, malignant andunspecified (SMQ)

2.78.4 Notes on Implementation and/or Expectation of Query Results
Prostate neoplasms, malignant and unspecified (SMQ) has narrow and broad searchterms. The detailed notes are documented in section 1.5.2.1.
2.78.5 List of References for Prostate neoplasms, malignant and unspecified(SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of
Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H,.Veronesi, U. Oxford Textbook of Oncology. 1995.

•

European Group on Tumour Markers (EGTM). http://www.egtm.eu/

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2.79

Proteinuria (SMQ)(Production Release September 2014)
2.79.1 Definition•

Proteinuria is the presence of an excess of serum proteins in the urine (>300
mg/24h)-Isolated proteinuria is urinary protein without other symptoms or urinary
abnormalities-

In many renal disorders, proteinuria occurs with other urinary abnormalities (e.g.,
hematuria)-

The presence of protein in the urine is toxic to the kidneys and causes renal
damage-Proteinuria caused by renal disorders usually is persistent (i.e., present on serial
testing) The upper limit of normal urinary protein excretion is considered to be 150
mg/day, which can be measured in a 24-h urine collection or estimated byrandom urine protein/creatinine ratio (values > 45 mg/mmol are abnormal); foralbumin it is about 30 mg/day
 Albumin excretion between 30 and 300 mg/day (20 to 200 µg/min) is considered
microalbuminuria, and higher levels are considered macroalbuminuria
 When in the nephrotic range, proteinuria can cause significant protein wasting May be associated with foamy urine•

Classification of proteinuria:

 Glomerular proteinuriao Results from glomerular disorders
o Increased glomerular permeability allows increased amounts of plasma
proteins (sometimes very large amounts) to pass into the filtrate Tubular proteinuriao Results from impaired reabsorption of protein by the proximal tubule
o Proteinuria mostly from smaller proteins such as immunoglobulin light chainsrather than albumin

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o Often accompanied by other defects of tubular function (e.g., HCO3 wasting,
glucosuria, aminoaciduria) and sometimes by glomerular pathology (which
also contributes to the proteinuria)
 Overflow proteinuria
o Excessive amounts of small plasma proteins (e.g., immunoglobulin lightchains produced in multiple myeloma) exceed the reabsorptive capacity of theproximal tubules
 Functional proteinuria
o Increased renal blood flow (e.g., due to exercise, fever, high-output heart
failure) delivers increased amounts of protein to the nephron, resulting inincreased protein in the urine (usually < 1 g/day)o Resolves when renal blood flow returns to normal
 Orthostatic proteinuriao A benign condition (most common among children and adolescents)
o Proteinuria occurs mainly when the patient is uprighto Urine typically contains more protein during waking hours (when people are
more often upright) than during sleepo Very good prognosiso Requires no special intervention
2.79.2 Inclusion/Exclusion Criteria•

Included:­Terms containing the word “proteinuria”-

Terms (investigational or not) referring to the levels of albumin in urine or blood,
including quantification of 24 h urine albumin excretion either by direct methods
or derived ones (albumin-to-creatinine ratio). Reduced losses of albumin(microalbuminuria) are also included.

-

Terms (investigational or not) referring to the levels of other proteins (other thanalbumin) which escape usual dipstick detection in urine or blood, such as Beta 2
microglobulin, immunoglobulin light chains (Bence-Jones protein), myoglobin,
etc.

-

Acquired nephrotic syndrome (PT Nephrotic syndrome) is included for its close
relationship with large urine protein loss, as well as the PT Protein deficiency andPT Oedema due to renal disease, which despite not being specific for nephrotic
syndrome, are both relevant downstream consequences of it.

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Excluded:-Potential causes of proteinuria, which include renal glomerular and tubulardiseases, with the exception of PT Nephrotic syndrome-

Other complications of nephrotic syndrome (except PT Protein deficiency and PT
Oedema due to renal disease) such as hypercoagulability, thromboembolism, or
hyperlipidemia, because of the likelihood of introducing noise in the search.

-

Urinalysis and renal function testing usually performed after or in the context ofproteinuria, such as measurement of serum electrolytes, BUN, creatinine, andglucose, determination of GFR, etc.

-

Congenital terms are excluded-

Non-qualified investigation terms are excluded, except for PT Protein urine which
returned significant counts in testing and was considered to represent a way ofreporting proteinuria using a non-qualified term

2.79.3 Notes on Implementation and/or Expectation of Query Results
Proteinuria (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.

2.79.4 List of References for Proteinuria (SMQ)•

Harrison’s Principles of Internal Medicine: Chapter 44. Azotemia and Urinary
Abnormalities•

Merck Manual for Health Care Professionals: Proteinuria•

Merck Manual for Health Care Professionals: Overview of Nephrotic Syndrome•

Current Diagnosis & Treatment: Nephrology & Hypertension: Chapter 1. Approach to
the Patient with Renal Disease

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2.80

Pseudomembranous colitis (SMQ)(Production Release March 2007)

2.80.1 Definition•

Pseudomembranous colitis is a severe, necrotizing process that involves thelarge intestine and occurs as a complication of antibiotic therapy•

It occasionally occurs in the absence of antibiotic exposure; a predisposing
condition is often present, e.g., recent bowel surgery, uraemia, intestinal
ischaemia, chemotherapy, bone marrow transplantation•

The responsible pathogen is “Clostridium difficile”, a member of the normal florathat overgrows in the presence of certain antibiotics or in the absence of normal
bacterial flora due to other factors•

Culture and toxin tests are available to identify C. difficile but a positive
microbiology test(s) in the absence of clinical findings does not support adefinitive diagnosis of pseudomembranous colitis•

Many reports of diarrhoea associated with antibiotic therapy may not havedefinitive diagnoses or specific tests for pseudomembranous colitis•

Uncomplicated antibiotic-induced diarrhoea usually subsides spontaneously
within two weeks of antibiotic discontinuation•

For persisting symptoms or frank colitis, aggressive therapy may be required torestore balance of the bacterial flora within the lumen of the intestinal tract

2.80.2 Inclusion/Exclusion Criteria•

Included: Terms for “Clostridium colitis” and related concepts
 Terms for signs, symptoms, and laboratory findings, as described in thedefinition
 Species-level microbial terms that specify “C. difficile”
 Nonspecific "clostridia" terms (e.g., PT Clostridial infection ) so that possible
C. difficile is not overlooked, but terms such as "C. perfringens" would not be
included Inclusion of PT Diarrhoea and PT Diarrhoea haemorrhagic in the narrowsearches for the antibiotic products were justified, as several cases wereretrieved that would not otherwise have been detected. However, careful
review of the case narratives is indicated to categorize such cases as being
relevant to the medical condition of interest. For the negative control
compounds, PT Diarrhoea within the broad search created a lot of noise.

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Thus, use of PT Diarrhoea and PT Diarrhoea haemorrhagic is recommended
for use only in narrow searches with antibiotics.
•

Excluded: Microbial terms that specify non-C. difficile species
 Terms for mucosal disorders that do not specify involvement of the large
intestine.

2.80.3 Notes on Implementation and/or Expectation of Query Results
Pseudomembranous colitis (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
2.80.4 List of References for Pseudomembranous colitis (SMQ)•

Merck Manual of Diagnosis and Therapy, 1999. 17th Edition.

•

Principles and Practices in Infectious Diseases, Mandell, Douglas, and Bennett,
2nd edition.

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2.81

Psychosis and psychotic disorders (SMQ)(Production Release September 2007)

2.81.1 Definition•

Psychosis refers to a mental disorder characterized by gross impairment inreality testing evidenced by: Delusions
 Hallucinations
 Markedly incoherent speech Disorganized and agitated behavior, usually without apparent awareness on
the patient’s part•

Psychosis is also used in a more general sense to refer to mental disorders inwhich mental functioning is sufficiently impaired as to interfere grossly withpatient's capacity to meet the ordinary demands of life•

Psychosis can be caused by many psychiatric disorders such as: Schizophrenia
 Schizoaffective disorder Delusional disorder Brief psychotic reaction
 Mania with psychosis Depression with psychosis
 Dementia
 Delirium•

Psychosis is also associated with:
 Certain illicit drugs (cocaine, amphetamine, etc.)
 Medications (dopamine agonists, l-dopa, psychostimulants, etc.)
 In Schizophrenia, Schizophreniform disorder, Schizoaffective disorder, andBrief Psychotic disorder, the term psychotic refers to delusions, any
prominent hallucinations, disorganized speech or disorganized or catatonic
behavior.

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2.81.2 Inclusion/Exclusion Criteria•

Included: Specific types of psychosis and those etiologies in which the PT mentions
psychosis (e.g., PT Psychotic disorder due to a general medical condition).
Considered narrow in scope.
 Symptoms commonly seen with psychosis or psychotic disorders or indicate
the presence of psychosis (e.g., PT Neologism, PT Paranoia). Considerednarrow in scope.
 Certain “broad” PTs (e.g., PT Major depression) in order to capture underlying
LLTs that mentioned psychosis (e.g., LLT Depression psychotic). Considered
broad in scope.
 Psychotic disorders that are not typically medication-induced (e.g.,
Schizophrenia) in order to capture the possibility that a medication may
exacerbate the underlying illness (e.g., dopamine agonists exacerbating
schizophrenic psychosis) and that a reporter may prematurely diagnose a
psychotic patient with schizophrenia before recognizing a medication-induced
psychosis•

Excluded: Antipsychotic drug level terms, such as PT Antipsychotic drug level above
therapeutic, PT Antipsychotic drug level below therapeutic, PT Antipsychotic
drug level increased, PT Antipsychotic drug level therapeutic because these
medications may be used for many symptoms other than psychosis
 PT Psychotic family member, PT Schizophrenic relative as they relate toanother person having psychosis
 PT Toxicity to various agents contains LLT Poisoning by psychodysleptics(hallucinogens) but also many other non-related LLTs that would create alarge amount of “noise”
 PT Drug abuser contains LLTs of Hallucinogen abuse but many others thatwould not consistently produce psychosis
 PT Drug use disorder contains LLTs of hallucinogen dependence but
many others that would not consistently produce psychosis
 PT Maternal drugs affecting foetus contains LLT Hallucinogenic agentsaffecting fetus or newborn via placenta or breast milk but it is impossible totell if a fetus or newborn is psychotic
 PTs that are potential etiologies of psychosis but do not mention psychosis(e.g., PT Porphyria, PT Delirium). PT Schizoid personality disorder as it is not
usually associated with psychosis and because a psychotic disorder must be
ruled out in order to make the diagnosis

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 Symptoms that may occur with psychosis or psychotic disorders but are very
common in the absence of psychosis (e.g., types of anxiety, confusion,
disorientation, etc.)
 Depression (with the exception of PT Major depression) and suicide related
terms as they are common in the absence of psychosis
 Non-specific investigation terms including PT Mental status changes, PT
Psychiatric evaluation abnormal, PT Neurological examination abnormal
2.81.3 Notes on Implementation and/or Expectation of Query Results
Psychosis and psychotic disorders (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.81.4 List of References for Psychosis and psychotic disorders (SMQ)•

Dorland’s Illustrated Medical Dictionary, 29th Edition, WB Saunders 2004.

•

American Psychiatric Association: Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition. Washington, DC, 1994.

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2.82

Pulmonary hypertension (SMQ)(Revised March 2016; Original Production Release September 2007)
2.82.1 Definition•

The Fifth World Symposium on Pulmonary Hypertension, 2013, established a
new classification of pulmonary hypertension, and a new definition of pulmonary
hypertension was released in 2015, which impacted the case identification
parameters for Pulmonary hypertension (SMQ).

•

A detailed review of the original terms included in this SMQ revealed thepresence of several conditions which are rarely associated with pulmonary
hypertension (e.g. PT Hepatic cirrhosis); excessively “noisy” signs andsymptoms; several sign and symptom term concepts typically associated withpulmonary hypertension were noted not to be included; and other terms were
found to be not fully consistent with selection criteria.

•

In light of the above, a decision was made to revise Pulmonary hypertension(SMQ). A new definition and new SMQ inclusion/exclusion criteria were
established based upon the conclusions of the Fifth World Symposium on
Pulmonary Hypertension, and of The Joint Task Force for the Diagnosis andTreatment of Pulmonary Hypertension of the European Society of Cardiology(ESC) and the European Respiratory Society (ERS). The term list for this SMQ
was updated accordingly, and the terms were subjected to testing.

•PH has been defined in the past as a resting mean pulmonary arterial pressure(mPAP) >25 mm Hg, or an mPAP with exercise >30 mm Hg. The subgroup of PH
known as pulmonary arterial hypertension (PAH) adds the criterion that thepulmonary arterial wedge pressure must be ≤ 15 mm Hg. Some definitions havealso included pulmonary vascular resistance (PVR), requiring that it be ≥2 or 3
Wood units.
Potential weaknesses of the previous definition relate to the fact that the level,
type, and posture of exercise had not been specified. Furthermore, the normal
exercise pulmonary arterial pressure (PAP) varies with age.

•

Clarification of the definition based on available evidence was an important
objective of the 2015 ESC/ERS guideline:
The new definition of PH is a resting mean pulmonary artery pressure(mPAP) ≥ 25 mm Hg. Further studies are needed to better determine the natural
history of patients with mPAP 21 to 24 mm Hg.
 The exercise and pulmonary vascular resistance (PVR) criteria should be
eliminated.
 A resting mPAP of 8 to 20 mm Hg should be considered normal, based on
available evidence.

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2.82.2 Inclusion/Exclusion Criteria•

Included: Terms directly related to pulmonary hypertension (PT Portopulmonary
hypertension; PT Pulmonary arterial hypertension) Acute forms of pulmonary hypertension (PT Pulmonary hypertensive crisis;
PT Acute right ventricular failure; PT Cor pulmonale acute), were firstconsidered for exclusion, but were finally included in view that some drugs
may cause acute pulmonary hypertension.
 Specific consequences of pulmonary hypertension (PT Cor pulmonale
chronic; PT Right ventricular hypertrophy; PT Tricuspid valve incompetence) Highly specific etiologic conditions which often result in pulmonary
hypertension (PT Pulmonary vascular resistance abnormality; PT Pulmonaryvein stenosis ; PT Pulmonary veno-occlusive disease) Investigations and therapeutic procedures specifically used in pulmonary
hypertension (PT Pulmonary endarterectomy; PT Pulmonary arterial pressure
increased; PT Vascular resistance pulmonary increased) Signs and symptoms highly related to pulmonary hypertension (PT Right
ventricular heave; PT Hepatojugular reflux)•

Excluded: Etiologic conditions which are only occasionally associated with pulmonary
hypertension (PT Cirrhosis alcoholic; PT Cryptogenic cirrhosis; PT Chronic
obstructive pulmonary disease) Nonspecific investigations or therapeutic procedures which are only weakly
related to pulmonary hypertension (PT Catheterisation cardiac abnormal; PT
Carbon dioxide decreased; PT Chest X-ray abnormal)
 Signs and symptoms not specific to pulmonary hypertension, which often
appear in other conditions or syndromes and can cause noise in a search (PTDizziness)
 Nonqualified investigation terms
 Congenital terms

2.82.3 Notes on Implementation and/or Expectation of Query Results
Pulmonary hypertension (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
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2.82.4 List of References for Pulmonary hypertension (SMQ)•

Diagnosis and Assessment of Pulmonary Arterial Hypertension. Journal of theAmerican College of Cardiology Vol. 54, No. 1, Suppl S.

•

Updated Clinical Classification of Pulmonary Hypertension. Journal of theAmerican College of Cardiology Vol. 54, No. 1, Suppl S.

•

Guidelines for the diagnosis and treatment of pulmonary hypertension. European
Heart Journal (2009) 30, 2493–2537.

•

Assessment of right ventricular volumes and ejection fraction byechocardiography: from geometric approximations to realistic shapes. Ellen
Ostenfeld and Frank A Flachskampf•

Department of Clinical Physiology, Ska°nes Universitetssjukhus, Lund University,
22185 Lund, Sweden.

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2.83

Renovascular disorders (SMQ)(Production Release March 2010)
2.83.1 Definition•

Renovascular disorders include: Atherosclerotic renal artery stenosis (most common primary disease of therenal arteries) Fibromuscular dysplasia of the renal arteries
 Embolic renal artery occlusion
 Renovascular microvascular disorders•

All can result in renal dysfunction, usually evidenced by high plasma renin levels•

Usually present in one of three forms:
 Asymptomatic renal artery stenosis
 Renovascular hypertension
 Ischemic nephropathy•

Primarily due to constriction of afferent renal artery resulting in decreased
perfusion pressure of larger circulation and/or microcirculation
 Disorder of larger circulation commonly due to unilateral or bilateral renalartery stenosis
 Microcirculation disorders commonly due to small vessel thrombosis:
o From proximal upstream thrombi (e.g., in the stenosed renal artery)o From distal sites (e.g., intracardiac thrombi)•

Mechanisms of chemotherapy-induced renal dysfunction include: Damage to kidney vasculature or structures
 Hemolytic uremic syndrome Prerenal perfusion deficits•

Renovascular disorders may result in progressive severe hypertension with theusual sequelae of this condition

2.83.2 Inclusion/Exclusion criteria• Included: Narrow search: All terms in HLT Renal vascular and ischaemic conditions
except PT Thrombotic microangiopathy and terms containing “necrosis”(broad search)
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 Narrow search: Terms relating to renal hypertension
 Broad search: PT Haemolytic uraemic syndrome and related terms, e.g., PT
Thrombotic microangiopathy and PT Thrombotic thrombocytopenic purpura
 Broad search: Terms in HLT Renal vascular and ischaemic conditions
containing the word “necrosis”
 Broad search: Relevant investigation terms, e.g., PT Arteriogram renal
abnormal•Excluded: Congenital terms

2.83.3 Notes on Implementation and/or Expectation of Query Results
Renovascular disorders (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.83.4 List of References for Renovascular disorders (SMQ)•

Bloch MJ, Basile J. Clinical insights into the diagnosis and management ofrenovascular disease. An evidence-based review. Minerva Med 2004
Oct;95(5):357-73.

•

Kendrick J and Chonchol M. Renal artery stenosis and chronic ischemic
nephropathy: epidemiology and diagnosis. Adv Chronic Kidney Dis 2008
Oct;15(4):355-62.

•

Kintzel PE. Anticancer drug-induced kidney disorders. Drug Saf 2001
Jan;24(1):19-38.

•

Nally JV. Acute renal failure in hospitalized patients. Cleveland Clinic J Med
2002; 69: 569-574.

•

Thatte L, and Vaamonde CA. Drug-induced nephrotoxicity-The crucial role of risk
factors. Postgraduate Medicine1996;100: 1-15.

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2.84

Respiratory failure (SMQ)(Production Release March 2015)
2.84.1 Definition•

Respiratory failure is a life-threatening impairment of oxygenation or carbon
dioxide elimination that affects breathing function or the lungs themselves, andcan result in failure of the lungs to function properly.

•

Two main pathophysiological etiologies (may occur singly, or in combination):­ Inadequate oxygenation (impaired gas exchange)­ Inadequate carbon dioxide elimination (decreased ventilation resulting in arise in PaCO2)•

Common precipitating conditions: Acute exacerbations of asthma and chronic obstructive pulmonary disease Overdoses of drugs that suppress ventilatory drive Conditions that cause respiratory muscle weakness (e.g., Guillain-Barré
syndrome, myasthenia gravis, botulism)•

Typical signs and symptoms:
 Dyspnea
 Tachypnea
 Use of accessory muscles of respiration
 Tachycardia
 Diaphoresis
 Cyanosis
 Altered consciousness
 Without treatment, eventually obtundation, respiratory arrest, and death•

Diagnostic measures:
 Patient observation and clinical evaluation
 Arterial blood gases
 Chest x-ray•

Treatment includes:
 Correction of underlying cause Supplemental oxygen Control of secretions
 Ventilatory assistance

2.84.2 Inclusion/Exclusion Criteria•

Included:

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 Terms indicating respiratory failure/depression/arrest, including terms forneonatal respiratory events
 Terms for signs and symptoms associated with respiratory failure, e.g. PT
Use of accessory respiratory muscles, PT Xyphoid retraction
 Breathing abnormalities indicating respiratory failure, e.g. PT Orthopnoea, PT
Tachypnoea
 Relevant treatment terms for respiratory failure, e.g. PT Continuous positive
airway pressure
 Laboratory terms indicating respiratory failure, e.g. PT Venous oxygen
saturation abnormal
 Relevant imaging investigations, e.g. PT Ventilation/perfusion scan abnormal•

Excluded: Terms for conditions predisposing to respiratory failure, e.g. PT Pickwickian
syndrome, PT Sleep apnoea syndrome Toxic causes, e.g. PT Carbon monoxide poisoning Non-respiratory causes for low PO2 pressure, such as anaemia

2.84.3 Notes on Implementation and/or Expectation of Query Results
Respiratory failure (SMQ) has narrow and broad search terms. The detailed notes are
documented in Section 1.5.2.1.
Initial testing of this SMQ was based on the term list of the existing Acute central
respiratory depression (SMQ) and a term list from a company “home grown” search.
During the test period additional PTs for inclusion were identified and were tested aswell. However, the initial aim to broaden the scope of the existing Acute central
respiratory depression (SMQ) to include terms for chronic and peripheral causes forrespiratory failure was abandoned as it would have weakened the specificity andproduced excessive “noise” for the retrieval of cases specific to centrally acting drugs
associated with acute central respiratory depression. Consequently, the Respiratory
failure (SMQ) was developed as a stand alone SMQ.

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2.84.4 List of References for Respiratory failure (SMQ)•

The Merck Manual. Professional edition. Critical care medicine. Respiratory
failure and Mechanical Ventilation•

Harrison's Principles of Internal Medicine, 18e. Part 11. Disorders of the
Respiratory System. Chapter 251. Approach to the Patient with Disease of the
Respiratory System•

Harrison's Principles of Internal Medicine, 18e. Chapter 35. Hypoxia andCyanosis•

Medscape. Family Medicine. Respiratory Failure

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2.85

Retinal disorders (SMQ)(Production Release March 2009)
2.85.1 Definition•

Retinal disorders are manifested by a variety of signs and symptoms; no overall
definition possible•

SMQ focuses on retinal disorders with damage of retina due to: Blockage of its blood supply Nutritional deficiencies
 Toxins
 Diseases affecting retina

2.85.2 Inclusion/Exclusion Criteria•

Included: Narrow search:o All terms that contain “retin,” except those which represent retinal
infections (see Exclusion criteria)o Terms relating to the maculao Terms for visual disturbances related to the retina, such as tunnel visiono Investigational terms specific for retinal disorders
 Broad search:o Terms for signs and symptoms of visual disturbanceo Investigational terms that are not necessarily specific for retinal disorders•

Excluded: Terms for other diseases which might impact the retina as a clinicalconsequence but that do not necessarily affect it and where no specific terms
exist in MedDRA, respectively
 Congenital terms
 Terms pertaining to retinal infections

2.85.3 Notes on Implementation and/or Expectation of Query Results
Retinal disorders (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.

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2.85.4 List of References for Retinal disorders (SMQ)•

The Merck Manual – Online Medical Library.

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2.86

Retroperitoneal fibrosis (SMQ)(Production Release September 2006)
2.86.1 Definition•

Retroperitoneal fibrosis (RPF; also known as Ormond’s disease) is a rare
disorder that is idiopathic in most cases (68%).

•

Evidence suggests autoimmunity.
 Response to ceroid leaking from arteries thinned by atheromatous plaque•

Many diverse causes for the 34% non-idiopathic cases
 Drugs:o Methysergide, ergotamine, some beta-adrenergic blocking agents,
hydralazine, and methyldopa
 Other associations (immune-mediated):o E.g., primary biliary cirrhosis, systemic lupus erythematosus
 Malignant form (poor prognosis):o Occurs in response to metastatic tumor cells in the retroperitoneum Other implicated causes:
o Abdominal aortic aneurysm, ureteric injury, infection, retroperitoneal
malignancy, radiation therapy, and chemotherapy•

Characterized by extensive deposition of fibrous tissue in retroperitoneal spacecompressing ureters bile ducts, blood vessels, and other structures•

Symptoms generally vague; clinical picture nonspecific Radiologic and other imaging modalities needed to confirm diagnosis•

Insidious symptomatology:
 Flank pain, back pain, lower abdomen pain, malaise, anorexia, weight loss,
pyrexia, nausea, vomiting, lower extremity edema and/or thrombophlebitis,and symptoms of arterial compromise of abdomen or lower extremities (e.g.,intermittent claudication)

2.86.2 Inclusion/Exclusion Criteria•

Included: PT Retroperitoneal fibrosis and terms representing associated conditions thatdevelop as a consequence such as “hydroureter,” “hydronephrosis,” etc.
 Relatively few signs/symptom terms chosen for query because they arevague; diagnosis is often based on supporting imaging studies

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 PT Flank pain chosen as this is one of the few consistent symptoms
 PT Abdominal adhesions was included Related investigations (e.g., PT Urine output decreased) Based on the testing results, it was decided in the CIOMS working group to
include both PT Abdominal pain and PT Abdominal pain lower.
•

Excluded: Terms that do not fit within definition of RPF or which are so non-specific as
to be deemed not useful Terms for associated immune-mediated disorders (e.g., rheumatoid arthritis) Terms related to malignant form of RPF (e.g., metastases to retroperitoneum)2.86.3 Notes on Implementation and/or Expectation of Query Results
Retroperitoneal fibrosis (SMQ) has narrow and broad search terms. The detailed notes
are documented in section 1.5.2.1.
2.86.4 List of References for Retroperitoneal fibrosis (SMQ)•CIOMS, Reporting Adverse Drug Reactions, 1999, p 20 – 21.

•

Khan, AN. Retroperitoneal fibrosis. 13 September 2002.
http://www.emedicine.com/radio/topic605.htm•

Diamond, JR. Clinical manifestations and diagnosis of retroperitoneal fibrosis.
UpToDate®, 27 February 2005 http://www.utdol.com/

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2.87

Rhabdomyolysis/myopathy (SMQ)(Production Release December 2004)
2.87.1 Definition•

Myopathy is a disorder of striated muscle, with or without changes in muscle
mass, and may be accompanied by muscle pain or tenderness.

•

Rhabdomyolysis is a syndrome resulting from extensive necrosis of skeletal
muscle with release of muscle contents, particularly creatine kinase (CK) andother muscle enzymes (such as aminotransferases and lactic dehydrogenase),creatinine, potassium, uric acid, myoglobin, calcium, and phosphorus into thesystemic circulation. Some cases are related to hereditary metabolic or
structural abnormalities effecting skeletal muscle cells, such as disorders ofglycogen and lipid metabolism. However, the majority of cases occur in healthy
individuals due to a variety of non-hereditary causes such as trauma (due tocrushing injuries or excessive exercise), bacterial and/or viral infections (such as
Staphylococcus or influenza), medications (such as HMG-CoA reductase
inhibitors and antipsychotics), recreational drugs (such as cocaine,
amphetamines, and alcohol), toxins (such as tetanus and some snake venoms),
and ischemia. Rhabdomyolysis varies from mild and self-limiting to severe andpossibly life-threatening.

•Muscle signs and symptoms usually include muscle pain, weakness, tenderness,and contractures, usually involving large muscles such as those of the calves,
thighs, and lower back, but can also involve the chest, abdomen, palate andthroat, and masticatory muscles.

•

Other non-specific symptoms can include weight gain, fatigue, malaise, fever,nausea, tachycardia, and dark red or cola-colored urine. Potentially serious
systemic sequelae include acute renal failure, compartment syndrome,disseminated intravascular coagulation, cardiomyopathy, and respiratory failure.

•

Laboratory abnormalities usually indicative of rhabdomyolysis include elevatedcreatine kinase (CK, particularly CK-MM, often markedly elevated),
myoglobinuria, and increased serum myoglobin. Other laboratory findings may
include elevated serum creatinine, lactic dehydrogenase, and aminotransferases.
Hypocalcemia and potentially life-threatening hyperkalemia (in patients withacute renal failure) may also occur. Diagnosis can be confirmed by muscle
biopsy.

2.87.2 Inclusion/Exclusion Criteria•

Narrow scope: diagnoses and laboratory test results that are unique or directly
lead to rhabdomyolysis/myopathy. For example, PT Muscle necrosis (diagnosis)
and PT Myoglobin urine present (test result).

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Broad scope: terms not specifically reported as rhabdomyolysis or myopathy but
reporting other musculoskeletal, renal, metabolic, or laboratory PTs that might
involve rhabdomyolysis or myopathy. These terms have the potential ofidentifying positive cases. For example, PT Muscle fatigue (symptom) and PT
Blood creatinine increased (test result).

•

Because of the variety of clinical manifestations associated with rhabdomyolysis
or myopathy, it is possible that cases may not have been initially classified andcoded as such. In an attempt to provide sufficient sensitivity to the SMQ, it
encompassed events such as compartment syndrome and other, non-myopathyrelated muscle events (myalgia, muscle fatigue or weakness, musculoskeletal
pain or discomfort, or abnormal muscle biopsy) or other non-musculoskeletal
events suggestive of possible rhabdomyolysis or myopathy (renal failure andrelated events, increased CK or other muscle enzymes, hypocalcaemia, or
chromaturia).

•

In an effort to make the query relatively specific, not all possibly rhabdomyolysisor myopathy-related events were included (for example, not all PTs listed underthe HLT Myopathies are included).

•

No specific exclusions are defined for this SMQ.

NOTE: Due to MedDRA rules and conventions, LLT Rhabdomyolysis-induced renal
failure is placed under PT Acute kidney injury. Therefore, LLT Rhabdomyolysis-induced
renal failure is included as a broad search term even though it would logically be anarrow term because its PT Acute kidney injury is a broad term.
2.87.3 Notes on Implementation and/or Expectation of Query Results
Rhabdomyolysis/myopathy (SMQ) has narrow and broad search terms. The detailed
notes are documented in section 1.5.2.1.
2.87.4 List of References for Rhabdomyolysis/myopathy (SMQ)•

Basic requirements for the use of terms for reporting adverse drug reactions (IV).
Pharmacoepidemiology and Drug Safety 1993; 2:149-153.

•

Reporting Adverse Drug Reactions. Definitions and criteria for their use. CIOMS
publication, Geneva, 1999.

•

Poels PJE and Gabreëls FJM. Rhabdomyolysis: a review of the literature. Clin
Neurol Neurosurg 1993; 95:175-192.

•

Omar MA, Wilson JP, and Cox, TS. Rhabdomyolysis and HMG-CoA reductase
inhibitors. Annals Pharmacother 2001; 35:1096-1107.

•

Prendergast BD and George CF. Drug-induced rhabdomyolysis – mechanisms
and management. Postgrad Med J 1993; 69:333-336.

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2.88

Scleral disorders (SMQ)(Production Release March 2010)
2.88.1 Definition•

Sclera Dense, white fibrous outer protective layer of eye
 Consists largely of collagen Histologic structure similar to cornea
 Varies in thickness from 0.3 mm to about 0.6 mm
 Continuous with cornea (anterior) and dural sheath of optic nerve (posterior) Lamina fusca – layer of brown pigment on scleral inner surface
 Optic nerve axons pass through lamina cribrosa (collagen and elastic tissue
bands at posterior scleral foramen) Posterior ciliary arteries and nerves reach ciliary body through shallow groove
on inner surface of sclera•

Episclera Thin layer of elastic tissue on outer surface of anterior sclera Contains blood vessels that feed sclera•

Signs and symptoms of sclera disorders Lacrimation
 Hyperemic patches Globe perforation
 Discoloration
 Plaque deposits
 Redness
 Eye pain
 Photophobia
 Loss of vision•

Conditions affecting sclera Blue sclerao Occurs in certain connective tissue disorders (e.g., osteogenesis
imperfecta, Ehlers-Danlos syndrome, etc.)

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o Also may be in normal newborns and patients with keratoconus or
keratoglobus
 Scleral ectasiao Occurs with prolonged elevation of intraocular pressure early in infancy(e.g., congenital glaucoma)o May also be congenital or following injury, inflammation of sclera Staphylomao Result of bulging of uvea into ectatic sclera

o Generally have poor vision and high myopia (posterior staphyloma)o Posterior staphyloma may be associated with subretinal
neovascularization, choroidal atrophy Episcleritis
o Localized inflammation of vascularized connective tissue overlying sclerao Affects patients mainly in third or fourth decade of life, females three times
more frequently than maleso About one-third of patients have an associated disorder (e.g., ocularrosacea, atopy, gout, infection, or collagen-vascular disease)o Signs and symptoms include redness, mild irritation/discomfort, episcleralinjectiono Course is generally self-limited (1–2 weeks)
 Scleritis
o Cellular infiltration, destruction of collagen, and vascular remodelingo May be immunologically mediated, result of infection or initiated by local
traumao Occurs in women more commonly than men, typically in fifth or sixth
decades of lifeo Bilateral in one-third of caseso Pain, tender globe, slightly reduced visual acuity, mildly elevatedintraocular pressureo One-third of patients may have concurrent keratitis or uveitiso Occlusive vasculitis indicates a poor prognosiso Scleral thinning and perforation may occur

 Scleromalacia perforanso Scleral necrosis (without inflammation)o Seen almost exclusively in patients with rheumatoid arthritis
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 Hyaline degenerationo Seen in people over age 60

o Small, round, translucent gray areas, about 2–3 mm, located anterior toinsertion of rectus muscleso Asymptomatic and is not associated with complications
2.88.2 Inclusion/Exclusion criteria•

Included: Terms for specific scleral disorders (e.g., PT Scleromalacia)
 Terms for signs and symptoms characteristic of scleral disorders (e.g., PT
Scleral discolouration)
 Terms for episcleral conditions (e.g., PT Episcleral hyperaemia)
 Terms for results of investigations related to sclera disorders (e.g., PT Biopsy
sclera abnormal)
 Terms for procedures related to sclera (PT Scleral buckling surgery)•Excluded: Congenital terms
 Terms for nonspecific signs and symptoms of scleral disorders that could beshared with other eye disorders (they will be in a separate SMQ) e.g., PT
Visual impairment
 Terms for conditions that represent complications of scleral disorders (e.g.,glaucoma, uveitis, etc.)
 Infectious terms (e.g., LLT Syphilitic episcleritis is linked to PT Eye infection
syphilitic)
 Unqualified investigation terms (e.g., PT Biopsy sclera)

2.88.3 Notes on Implementation and/or Expectation of Query Results
Scleral disorders (SMQ) has only narrow search terms. Therefore, the narrow searchand broad search return the same result. The detailed notes are documented in section
1.5.2.1.
2.88.4 List of References for Scleral disorders (SMQ)•

Riordan-Eva, P. Vaughan & Asbury's General Ophthalmology, Chapter 1:
Anatomy & Embryology of the Eye.

•Cunningham, ET and Shetlar, DJ. Vaughan & Asbury's General Ophthalmology,
Chapter 7: Uveal Tract & Sclera.

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Gaeta, TJ. Scleritis. eMedicine, 14 April 2008,
http://www.emedicine.com/EMERG/topic521.htm•

Hampton, R. Episcleritis. eMedicine, 18 March 2008.
http://www.emedicine.com/oph/topic641.htm•

Merck Manual, 17th edition, p 717.

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2.89

Severe cutaneous adverse reactions (SMQ)(Production Release April 2005)

2.89.1 Definition
This SMQ was developed to identify cases of severe, sometimes life-threatening skinreactions that are often drug-induced.
Severe cutaneous adverse reactions (SCARs) include•

Erythema multiforme
 EM is an acute disease characterized by symmetrically distributed papularlesions affecting mainly the extremities, often with mucosal erosions.
 The typical lesion is target-shaped; it is concentrically organized with threedifferent colored zones, often with a blister in the center, and it is clearly
demarcated from the surrounding skin.
 There may be general symptoms such as fever and malaise.

•

Stevens-Johnson syndrome SJS is characterized by widespread skin lesions which may either be targetshaped or consist of erythematous macules with epidermal detachment,
together with severe mucosal erosions.
 SJS includes erosions of the skin up to 10% of body surface area. The
general symptoms are more marked than in erythema multiforme.

•

Toxic epidermal necrolysis
 TEN is characterized by widespread erythematous areas with epithelial
necrosis and epidermal detachment exceeding 10% body surface area,leaving bare dermis.
 There are often also small erythematous or purpuric lesions with or without
blisters.
 Extensive mucosal erosions are frequent. General symptoms, usually
severe, include high fever, malaise, and painful skin.

•

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)(Please note that DRESS syndrome has also has been referenced in theliterature as “Drug rash with eosinophilia and systemic symptoms”)
 DRESS syndrome is characterized by an extensive rash, fever,lymphadenopathy, hematologic abnormalities, hepatitis, and involvement of
the kidneys, lungs, heart, or pancreas

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 Characteristic hematologic abnormalities seen with this condition are
eosinophilia, thrombocytopenia, and atypical lymphocytosis.
 The onset of symptoms is often delayed, occurring 2–6 weeks after drug
initiation•

Acute generalized exanthematous pustulosis (AGEP) AGEP is a rare, acute pustular eruption characterized by the development of
numerous nonfollicular sterile pustules on a background of edematous
erythema The eruption develops within hours or days of drug exposure and resolves
spontaneously in one to two weeks after drug discontinuation.
 Fever and peripheral blood leukocytosis are usually present
 It predominantly affects the main body folds and upper trunk, but facial
involvement is possible.

These conditions are characterised by cutaneous eruptions that may be
exanthematous, urticarial, vesicular, or pustular, with variable extension.
2.89.2 Inclusion/Exclusion Criteria•

Included: Narrow scope: diagnosis terms that represent the above five conditions (EM,SJS, TEN, DRESS and AGEP) are included.
 Broad scope: MedDRA PTs that represent the signs/symptoms included in
the criteria for the diagnoses of each of the above five conditions (EM, SJS,TEN, DRESS and AGEP) are included.

•

Excluded: MedDRA PTs that are signs or symptoms of a skin condition but not includedin the criteria for the diagnosis of EM, SJS, TEN, DRESS and AGEP areexcluded, e.g., PT Dermatitis herpetiformis and PT Keratolysis exfoliativa
acquired.
 General, non-specific, and often mild skin reactions (e.g., rash) are excluded,e.g., PT Ulcer and PT Vascular skin disorder.

2.89.3 Notes on Implementation and/or Expectation of Query Results
Severe cutaneous adverse reactions (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.

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2.89.4 List of References for Severe cutaneous adverse reactions (SMQ)•

Roujeau JC and Stern RS. Severe adverse cutaneous reactions to drugs. New
England Journal of Medicine 1994; 331: 1272-1285.

•

Reporting Adverse Drug Reactions. Definitions of terms and criteria for their use.
CIOMS publication, Geneva 1999.

•

RegiSCAR group (http://regiscar.uni-freiburg.de).

•

Severe Cutaneous Adverse Reactions to Drugs (SCAR): Definitions, Diagnostic
Criteria, Genetic Predisposition, Jean-Claude Roujeau, Laurence Allanore,
Yvonne Liss, Maja Mockenhaupt (http://www.dermatolsinica.com/web/data/20091130043801.pdf)

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2.90

Shock (SMQ)(Production Release September 2006)
2.90.1 Definition•

A condition of profound and generally acute hemodynamic and metabolic
disturbance characterized by failure of the circulatory system to maintainadequate perfusion of vital organs•

Clinical indicators:
 Reduced mean arterial pressure, tachycardia, tachypnea, cool skin andextremities, acutely altered mental status, oliguria, hypotension (usually, but
not always, present), narrow differential pressure (difference between systolicand diastolic blood pressure), low cardiac output leading to a delayed
capillary refill End result is tissue hypoxia, often manifested by lactic acidosis•

Clinical manifestations of hypovolemic or cardiogenic shock: Hypotension, hyperventilation, cold, clammy, cyanotic skin, a weak and rapid
pulse, oliguria, mental confusion, and combativeness or anxiety•

Clinical manifestations of septic shock: Chills and fever, warm flushed skin, a lower degree of hypotension, and anincrease in cardiac output
 If unresponsive to therapy, septic shock progresses to the clinical patterndescribed for hypovolemic and cardiogenic shock•

Forms of shock: Hypovolemico Most common formo Results either from loss of blood (hemorrhagic shock) or from loss ofplasma aloneo Drug-related hypovolemic shock cannot represent a credible drug-related
event unless a drug has a marked effect on blood volume
 Traumatico Almost always produces the clinical pattern of hemorrhagic hypovolemia Cardiogenico Caused by failure, often sudden, of heart as an effective pump (e.g., acute
myocardial infarction, severe cardiomyopathy, etc.)o Acute aggravation of chronic conditions of cardiac impairment canrepresent a challenge in evaluation of pharmacological causality
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 Septico Caused by the systemic reaction to severe infection with participation of
biologically active soluble mediators
 Neurogenico Produces extreme vasodilatation with acute drop of arterial pressureo Inducers of neurogenic shock: cerebral trauma, profuse hemorrhage,spinal cord injuries, deep general or spinal anesthesia, or toxic central
nervous depression

 Anaphylactico Manifestation of immune-mediated acute hypersensitivity

o Exposure of a sensitized individual to a specific antigen, including drugs(e.g., penicillin) results in angioedema, followed by vascular collapse often
accompanied by life-threatening respiratory distresso Anaphylactoid shock defines a pseudoanaphylactic reaction mimicking thesame clinical picture described above Hypoglycemico Often caused by inappropriate treatment of unbalanced or unstablediabetes with excess insulin (often in combination with oral antidiabetic
medications)o Also observed in severe adrenocortical insufficiency
2.90.2 Inclusion/Exclusion Criteria•

Included: Narrow: All PTs containing “shock“ with the potential of representing anadverse drug reaction
 Broad:o Organ failure terms

o Terms containing the word “anuria”

o Terms containing the word “hypoperfusion”•

Excluded: Conditions occurring prior to manifestation of shock (e.g., myocardial
infarction, thromboembolic events)
 Terms not consistent with conditions as described above
 Electrical shock and traumatic shock terms
 Terms representing minor organ dysfunction, not necessarily due tocirculatory failure, were considered too broad and were generally excluded

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 Terms lacking specificity (e.g., tachycardia, tachypnea, oliguria)o Some were excluded after review of phase I testing results
 Terms representing chronic conditions were generally excluded
The CIOMS WG for SMQs reviewed phase II feedback on this SMQ at their May 2006
meeting. Some terms were recommended to be added, and the WG agreed that somewould be of value. One such recommended term was “acute cardiac failure”. It wasrecommended by the CIOMS WG that users use Cardiac failure (SMQ) if there is aneed for such terms in one’s query. Terms for hemorrhage and left ventricular failure
were also considered too broad for inclusion. Again, users should consider using theexisting Haemorrhages (SMQ) if necessary to assist in performing a specific query.
NOTE: There are two SMQs related to anaphylaxis: Anaphylactic reaction (SMQ) andAnaphylactic/anaphylactoid shock conditions (SMQ). The two SMQs have different
focuses. Anaphylactic/anaphylactoid shock (SMQ) is specific for more severe
anaphylactic manifestations, i.e. those that result in shock, and not less severe ones
such as rash. Anaphylactic reaction (SMQ) widens the search beyond shock conditions
by including such terms as PT Type I hypersensitivity.
2.90.3 Hierarchy StructureThis is a hierarchical SMQ with one overall (Level 1) SMQ (SMQ Shock) and six (Level2) sub-SMQs.
•

Each sub-SMQ has narrow and broad search terms.

•

Broad terms are the same for all six sub-SMQs; narrow term set for each subSMQ is distinct.

Shock(20000066)

Shockassociatedcirculatory or
cardiacconditions (excl
Torsade depointes)(20000067)

Torsade depointes, shockassociatedconditions(20000068)

Hypovolaemic
shock
conditions(20000069)

Toxic-septic
shock
conditions(20000070)

Anaphylactic/
anaphylactoid
shock
conditions(20000071)

Hypoglycaemic
and neurogenicshock
conditions(20000072)

Figure 2-22. Hierarchy Structure of Shock (SMQ).
NOTE: The names of the sub-SMQs in the CIOMS WG documentation differs from thisbulleted summary as follows:

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CIOMS WG Document

This Document

SMQ Cardiac/circulatory conditions

Shock-associated circulatory or cardiac
conditions (excl Torsade de pointes)(SMQ)

SMQ Torsade de pointes

Torsade de pointes, shock-associatedconditions (SMQ)SMQ Hypovolaemic conditions

Hypovolaemic shock conditions (SMQ)

SMQ Toxic/septic conditions

Toxic/septic shock conditions (SMQ)

SMQ Anaphylactic/anaphylactoid
conditions

Anaphylactic/anaphylactoid shockconditions (SMQ)

SMQ Other shock conditions

Renamed to Hypoglycaemic andneurogenic shock conditions (SMQ)

Table 2-8. Link Table between CIOMS WG Document and SMQ Introductory
Guide for Shock (SMQ)
2.90.4 Notes on Implementation and/or Expectation of Query Results
Shock (SMQ) is a hierarchical SMQ with narrow and broad search terms. Other thanthe hierarchy structure, the implementation for this SMQ is similar to the nonhierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.
2.90.5 List of References for Shock (SMQ)•

Harrison’s Principles of Internal Medicine 16th ed, Mc Graw Hill, 2005, pp 1581,
1600-1605.

•

Dorland’s Illustrated Medical Dictionary, 28th ed, Philadelphia WB Saunders Co.

•

Reporting Adverse Drug Reactions, Definitions and Criteria for Their Use,CIOMS, Geneva, 1999.

•

Harrison’s Principles of Internal Medicine 16th ed, Mc Graw Hill, 2005, pp 136771.

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2.91

Skin neoplasms, malignant and unspecified (SMQ)(Production Release March 2009)

2.91.1 Definition•

SMQ developed to detect all types of malignant and unspecified tumors related
to the skin•

SMQ covers all types of malignant and unspecified neoplasms related to skin;also: Malignancy related conditions (specific for skin) Malignancy related therapeutic procedures (specific for skin) Malignancy related diagnostic procedures (specific for skin)2.91.2 Inclusion/Exclusion Criteria•

Included: Terms for:o Malignancy related conditions (specific for skin)o Malignancy related therapeutic procedures (specific for skin)o Malignancy related diagnostic procedures (specific for skin) Terms for malignant and unspecified neoplasms with a clear reference to theskin Terms related to malignant and unspecified neoplasms of the skin, including:o Terms for conditionso Terms for procedureso Terms for investigationso Terms for tumor markers

o Terms for signs and symptoms of such disorders

o Terms for potential skin related terms of penis or vulva•

Excluded: Terms for malignant and unspecified neoplasms unrelated to skin Terms for non-site specific malignancy related therapeutic procedures
 Terms for non-site specific malignancy related diagnostic procedures
 Terms for non-site specific tumor markers
 Terms related to the cervix

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 Terms for metastases to skin PT Skin operation because it is not a malignancy specific therapeutic
procedure (see NOTE below)
NOTE: In Version 14.0, two new sub-SMQs have been added to Skin neoplasms,
malignant and unspecified (SMQ) to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.
NOTE: PT Skin operation may be added if a very broad search is required.
NOTE: For searches of non-specific malignancy related conditions, malignancy related
therapeutic procedures, and malignancy related diagnostic procedures, it isrecommended to use sub-SMQs of SMQ Malignancies.
2.91.3 Hierarchy Structure
Skin neoplasms,
malignant andunspecified (SMQ)(20000173)

Skin malignant tumours(SMQ)(20000204)

Skin tumours ofunspecified malignancy(SMQ)(20000205)

Figure 2-23. Hierarchy Structure of Skin neoplasms, malignant andunspecified (SMQ)
2.91.4 Notes on Implementation and/or Expectation of Query Results
Skin neoplasms, malignant and unspecified (SMQ) has narrow and broad search terms.
The detailed notes are documented in section 1.5.2.1.
2.91.5 List of References for Skin neoplasms, malignant and unspecified (SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of
Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H,Veronesi, U. Oxford Textbook of Oncology. 1995.

•

European Group on Tumour Markers (EGTM). http://www.egtm.eu

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2.92

Systemic lupus erythematosus (SMQ)(Production Release March 2006)

2.92.1 Definition•

Chronic inflammatory autoimmune disorder affecting many body systems withvariable severity•

Thought to be caused by interactions between susceptible genes andenvironmental factors such as estrogen containing hormones, ultraviolet light,
and Epstein-Barr Virus (EBV) resulting in production of autoantibodies against
nuclear antigens (particularly DNA), cytoplasmic antigens, and blood cell
antigens
 Antibodies to double-stranded DNA and Sm polypeptides occur in 30-60% of
patients.
 Antiphospholipid antibodies may also occur, including lupus anticoagulant,
anticardiolipin antibodies, and those that cause false-positive tests for
syphilis.
 Complement activation leads to immune complex deposition in blood vessels.

•

Drugs may trigger systemic lupus erythematosus (SLE) symptoms de novo or
exacerbate existing symptoms.
 Drug-induced SLE only rarely affects the kidney.
 Antinuclear antibodies in drug-induced SLE are directed mostly against
histones and rarely against double stranded DNA.

•Clinical presentations vary in severity and onset.
 Systemic symptoms: anorexia, weight loss, malaise, myalgia, arthralgias, andfever Cutaneous manifestationso Common is a macular “butterfly” erythema (across the face).

o Discoid lesions and maculopapular lesions on the face, neck, chest, andelbowso Erythema on sides of the palms; red or purple macular lesions on volar
finger surfaceso Other cutaneous symptoms: alopecia, periungual erythema, mucus
membrane lesions, purpura, and photosensitivity
 Polyarthritis (90% of patients) of wrists, hands, and kneeso Joint deformities in 10% of patients
 Nephritis is a serious manifestation.
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o May be asymptomatico May have proteinuria, diffuse membranoproliferative glomerulonephritis,
abnormal urinalysis (hematuria, pyruia, urinary casts), or increased serum
creatinineo May develop hypertension and nephrotic syndrome (increased risk for end
stage renal disease) Central nervous system manifestationso Headaches, epilepsy, psychoses, organic brain syndrome, and personalitychangeso Stroke or transient ischemic attacks due to vascular occlusion
 Other manifestations/complicationso Cardiovascular: pericarditis, myocarditis, fibrinous (Libman-Sachs)
endocarditis, and valve insufficiencies
o Pulmonary: pleurisy with or without effusiono Hematologic: anemia, leucopenia, and thrombocytopenia due tohemolysiso Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea

o Ocular: sicca syndrome, nonspecific conjunctivitis, retinal vasculitis, andoptic neuritis
2.92.2 Inclusion/Exclusion Criteria•

Included: Terms that fit within the definition of SLE (including symptoms, signs, andlaboratory findings)

 Words/roots searched: “lup-,” “erythemato-,” “SLE –“ and “LE-“ HLT Lupus erythematosus and associated conditionso

All PTs in both primary and secondary locations in this HLT are included
except PT Lupoid hepatic cirrhosis, which is excluded.

 Additional terms representing the diagnostic criteria of the American Collegeof Rheumatology (ACR), e.g., Malar rash, Arthritis, Renal disorder, etc.

 PT Antinuclear antibody positive is placed in narrow search based on the Pre-

Phase II Working Group discussion.

•

Excluded: PT Lupoid hepatic cirrhosis (not a true lupus condition), PT Pancytopenia, PT

Cardiac tamponade, PT Nasal septum ulceration, PT Nasal ulcer, PT Lip
ulceration, PT Anaemia, PT Arthralgia, PT Rheumatoid arthritis, PT Alopecia,
PT Pyrexia, and Coombs test terms

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2.92.3 Algorithm
Nine categories are defined as follows:
Category

Definition

Term WeightA

Narrow terms

Not applicable

B

Photosensitivity

1

C

Oral ulcers

2D

Arthritis

3

E

Serositis

3

F

Renal disorder

1

G

Neurologic disorder2

H

Haematologic disorder

3

I

Immunologic disorder

3

Table 2-9. Categories of Systemic lupus erythematosus (SMQ)

The “weight” system for broad terms was developed empirically and relates to thefrequency of the terms and the probability that these relate to the well-known
occurrence of SLE in patients receiving these drugs.
The algorithm was applied as follows:•

The PTs mentioned in the case report are grouped according to the predetermined categories. Occurrence of multiple PTs within a category is counted
only once.

•

The category that the term is attributed to is then multiplied by its empirically predetermined “weight” (for example – three for categories Hematologic disorder,
Serositis, and Immunologic disorder) and summed for all the categories.

•

If this sum is greater than six, it is proposed that the case report qualifies as asuspected SLE case report. For example, a case report which has PTs in the
categories of Hematologic disorder (3), Immunologic disorder (3), and Renal
disorder (1) will classify as a SLE broad search case report (3 + 3 + 1 = 7).

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2.92.4 Notes on Implementation and/or Expectation of Query Results
In addition to narrow and broad searches, Systemic lupus erythematosus (SMQ) is analgorithmic SMQ. The algorithm is a combination of broad search terms among various
categories to further refine the identification of cases of interest. The algorithm can be
implemented in a post-retrieval process as noted below:•

First, retrieve relevant cases by applying the SMQ query as a narrow/broad SMQ(see section 1.5.2.1).

•

Post-retrieval process, software applies the algorithmic combination to screen thecases retrieved above. For small data sets of retrieved cases, the algorithm may
be applied on manual review of cases. The algorithm for Systemic lupus
erythematosus (SMQ) is A or the sum of category weights > 6. Cases filtered by
the algorithm can be listed for output.

2.92.5 List of References for Systemic lupus erythematosus (SMQ)•

Guidelines for referral and management of systemic lupus erythematosus inadults. American College of Rheumatology Ad Hoc Committee on Systemic
Lupus Erythematosus Guidelines. Arthritis Rheum 1999;42:1785-96.

•

Hellman DB, Stone JH. Arthritis and musculoskeletal disorders. In: Tierney, Jr.
LM, McPhee SJ, Papadakis MA, editors. Current medical diagnosis andtreatment. 43rd ed. New York: McGraw-Hill Companies, Inc.; 2004. Available
via intranet at STAT!Ref Online Medical Database. Teton Data Systems,
Jackson, Wyo. (Version 3.3.6, 2004).

•

Hahn BH. Disorders of the immune system, connective tissues, and joints. In:
Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, editors.
Harrison’s principles of internal medicine. 16th ed. New York: McGraw-Hill
Companies; 2005. Available via intranet at STAT!Ref Online Medical
Database. Teton Data Systems, Jackson, Wyo. (Version 3.3.6, 2004).

•

Diffuse connective tissue disease. In: Beers MH, Berkow R, editors. The merck
manual of diagnosis and therapy. 11th ed. Whitehouse Station: Merck ResearchLaboratories; 1999. Available via intranet at STAT!Ref Online Medical
Database. Teton Data Systems, Jackson, Wyo. (Version 3.3.6, 2004).

•

Trethewey P. Systemic Lupus Erythematosus. Dimens Crit Care Nurs
2004;23:111-5.

•

CIOMS Publication, “Reporting Adverse Drug Reactions: Definitions of Terms
and Criteria for their Use,” pp 19 – 20, 1999.

•

The Merck Manual, Seventeenth Edition, pp 426 – 430, 1999.

•“Harrison’s Principles of Internal Medicine,” 14th edition, pp 1874 – 1880, 1998.

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2.93

Taste and smell disorders (SMQ)(Production Release March 2006)
2.93.1 Definition•

Causes of disorders of smell and taste include psychiatric disorders, nasal andsinus disease, poor dental hygiene, and intracranial disorders.
 Often occur concurrently in a patient Medicinal products associated with disturbances of taste and smell
 Chemotherapy products
 Antihypertensive products Hyperlipidemic products•

Key terms and definitions: Ageusia = absence of the sense of taste Dysgeusia = perversion of the sense of taste; a bad taste in the mouth Hypogeusia = a parageusia involving diminished sensitivity of taste Anosmia = absence of the sense of smell
 Hyposmia = a parosmia involving diminished sensitivity of smell
 Parosmia = any disease or perversion of olfaction

2.93.2 Inclusion/Exclusion Criteria•

Included: Terms related to disturbances of taste or smell, regardless of the direction(e.g., PT Hypogeusia), degree (e.g., PT Anosmia), or nature of impairment(PT Parosmia)

 Terms related to hallucinatory perceptions
 Terms related to the clinical evaluation of these types of sensory disorders(e.g., PT Olfactory test abnormal)

 All included PTs in both primary and secondary placements in HLT Taste

disorders and HLT Olfactory nerve disorders are included in SMQ

 Two PTs in HLT Perception disturbances (PT Hallucination, gustatory and PT

Hallucination, olfactory) are included Terms containing the roots “taste,” “tasti-,” “geus-,” “smell,” “gustat-,” “-osmia,”and “olfact-“•

Excluded: Due to the limited scope of this SMQ, no specific exclusions were applied

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NOTE: In the company database phase I testing, the cases of unpleasant taste andsmell of the medical substance were also coded using the same terms. Medical review
is required to distinguish between reports of the medical disorder and the physicalproperties of the treatment compound.
NOTE: In Version 12.1, Taste and smell disorders (SMQ) was modified in scope toinclude only narrow search terms, from formerly only broad terms.
2.93.3 Notes on Implementation and/or Expectation of Query Results
Taste and smell disorders (SMQ) has only narrow search terms. Therefore, the narrowsearch and broad search return the same result. The detailed notes are documented in
section 1.5.2.1.
2.93.4 List of References for Taste and smell disorders (SMQ)•

The Merck Manual, 17th ed., 1999, p 687.

•

Harrison’s Principles of Internal Medicine, 14th ed., 1998, pp 173 – 175.

•

Doty, RL et al. Influences of antihypertensive and antihyperlipidemic drugs on thesenses of taste and smell: a review. J Hypertens 21: 1805 –1813.

•

Dorland’s Medical Dictionary, 28th ed., 2001.

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2.94

Tendinopathies and ligament disorders (SMQ)(Production Release March 2015)

2.94.1 Definition•

Chronic tendinopathies and ligament disorders are pathological conditions oftendons and ligaments, resulting mainly from repeated minor strain.

•

Formerly called “tendonitis” or “ligamentitis•

Etiologic factors:
 Degenerative processes are thought to be the principal underlying pathology
 Repeated minor strain is considered to be the main precipitating factor
 Drug-associated forms of the disorder have also been described An understanding of the pathophysiology continues to evolve•

The most commonly injured tendons and ligaments include: The supraspinatus tendon and long head of the biceps muscle
 Medial and lateral extensors of the elbow
 Patellar tendon
 Achilles tendon
 Posterior tibialis tendon•

Risk factors for tendinopathies and ligament disorders include both intrinsic andextrinsic factors, such as: Overuse (sports activities, training errors, fatigue) Cold environment during outdoor training Faulty footwear/equipment
 Drugso Fluoroquinolone antibiotics in particularo Associations with oral contraceptives, injected corticosteroids andstatins have also been suggested•

Commonly described presenting symptoms:
 Pain at the site of the affected tendon or ligament Morning stiffness, local tenderness, swelling and reduced articular range of
motion may also be observed•

Therapeutic approaches: Exercise
 Shock wave therapy
 Growth factors
 Nitric oxide

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 Sclerosant therapy
 Gene therapy
 Tissue engineering
2.94.2 Inclusion/Exclusion Criteria•

Included: Terms for disorders of tendons and ligaments (e.g., PT Ligament disorder, PT
Ligament rupture, PT Tendon rupture, PT Tendonitis) Terms for therapeutic procedures for tendon/ligament disorders (e.g., PT
Ligament operation, PT Tendon graft, PT Tenolysis)
 Terms related to abnormal results of investigations for tendon/ligamentdisorders (e.g., PT Biopsy ligament abnormal, PT Biopsy tendon abnormal)
 Terms for signs and symptoms specific to tendon/ligament disorders (e.g., PT
Ligament pain, PT Tendon pain) Non-infective, non-traumatic fascia disorders and fasciitis are included as
broad scope terms, since fascia are either adjacent to or contiguous withtendons and tendon sheaths.

•

Excluded: Terms for congenital tendinopathies or ligament disorders
 Terms for hernial conditions
 Terms for infectious tendinopathies or ligament disorders (e.g., PT Infective
tenosynovitis) Terms for non-specific signs and symptoms (e.g., PT Pain, PT Swelling) thatwould likely create excessive “noise”

NOTE: In v20.0, the following inclusion criterion was added to Tendinopathies andligament disorders (SMQ): Non-infective, non-traumatic fascia disorders and fasciitis
are included as broad scope terms since fascia are either adjacent to or contiguous withtendons and tendon sheaths.
2.94.3 Notes on Implementation and/or Expectation of Query Results
Tendinopathies and ligament disorders (SMQ) has narrow and broad search terms.
The detailed notes are documented in Section 1.5.2.1.

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2.94.4 List of References for Tendinopathies and ligament disorders (SMQ)•

Riley, G. Tendinopathy – from basic science to treatment.
http://www.medscape.org/viewarticle/569113•

Abate M, Silbernagel KG, Siljeholm C, Di Iorio A, De Amicis D, Salini V, Werner
S, Paganelli R. Pathogenesis of tendinopathies: inflammation or degeneration?
Arthritis Res Ther 2009; 11(3): 235•

Kaleagasioglu, F and Olcay, E. Fluoroquinolone-induced tendinopathy: etiology
and preventive measures. Tohoku J Exp Med 2012: 226: 251 – 258•

Marie I, Delafenêtre H, Massy N, Thuillez C, Noblet C, Network of the French
Pharmacovigilance Centers. Tendinous disorders attributed to statins: a study
on ninety-six spontaneous reports in the period 1990-2005 and review of theliterature. Arthritis Rheum. 2008 Mar 15;59(3):367 – 37

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2.95

Thrombophlebitis (SMQ)(Production Release September 2007)
2.95.1 Definition•

Thrombophlebitis is an inflammation of a vein (phlebitis), associated withthrombus formation (thrombosis) (definition based on Dorland's Illustrated
Medical Dictionary).

2.95.2 Inclusion/Exclusion Criteria•

Included: Terms related to phlebitis / venous inflammationo With thrombus formation included narrow scopeo Without thrombus formation included broad scope Prophylaxis terms
o With thrombus formation included narrow scopeo Without thrombus formation included broad scope Laboratory test terms with indication of test resulto With thrombus formation included narrow scopeo Without thrombus formation included broad scope•

Excluded: Risk factor terms (e.g., hereditary, infective or autoimmune causes) Laboratory test terms without indication of test result(i.e., the unqualified test term or "normal" test results)
 PT Haemorrhoids due to too much “noise”

User comments on the utility of including site-specific thrombosis terms would beappreciated.
NOTE: In order to get all relevant terms of thrombophlebitis, it may be necessary to
combine this SMQ with the Embolic and thrombotic events (SMQ).
2.95.3 Notes on Implementation and/or Expectation of Query Results
Thrombophlebitis (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.

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2.95.4 List of References for Thrombophlebitis (SMQ)•

Dorland's Illustrated Medical Dictionary. William Alexander Newman Dorland.
30th Edition, June 2003, Saunders, an Elsevier imprint.

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2.96

Thyroid dysfunction (SMQ)(Production Release March 2009)
2.96.1 Definition•

Thyroid dysfunction can present as hypo- or hyperactive thyroidal function•

Hypothyroidism is thyroid hormone deficiency
 Primary hypothyroidism is due to thyroid disease; TSH is increasedo Most common cause is autoimmuneo Other common causes are post-therapeutic, occurring after radioactive
iodine therapy, surgery, radiation or lithium therapy
 Secondary hypothyroidism occurs when:o Hypothalamus produces insufficient TRH or pituitary produces insufficientTSH Signs and symptoms of hypothyroidism include:o Cold intolerance, constipation, personality changes, dementia or frank
psychosis
o Hoarse voice, facial puffiness, coarse hair and skin, fluid retention,
decreased metabolism, paresthesias, decreased libido, menstrualirregularities, bradycardia, pericardial effusions•

Hyperthyroidism is excessive production of iodinated thyroid hormones, T3 andT4 Graves’ disease (toxic diffuse goiter) is most common causeo Characterized by hyperthyroidism, goiter, exophthalmos, pretibial
myxedema Inflammatory thyroid disease (thyroiditis) includes subacute granulomatous
thyroiditis, Hashimoto's thyroiditis, and silent lymphocytic thyroiditis
 Drug-induced hyperthyroidism can result from lithium or interferon-alpha Signs and symptoms of hyperthyroidism include:o Hyperactivity, increased sweating, increased appetite, weight loss,
insomnia, weakness, frequent bowel movements, hypomenorrhea, tremor;tachycardia, and atrial fibrillationo Eye signs include stare and eyelid retraction. Infiltrative ophthalmopathy is
specific to Graves’ disease.
o Thyroid storm is life-threatening emergency; patients may present withfever, psychosis, coma, cardiovascular collapse

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2.96.2 Inclusion/Exclusion Criteria•

Included: Terms relevant for hypothyroidism and hyperthyroidism
 Terms for specific signs and symptoms such as PT Exophthalmos
 Thyroid investigation terms including PTs containing the word “abnormal”(e.g., PT Thyroxine abnormal).
 Thyroid-related terms in SOC Investigations are included in the broad
searches for both sub-SMQs as these terms are not indicative ofhyperthyroidism or hypothyroidism specifically•Excluded: Terms for non specific signs and symptoms such as PT Nervousness, PT
Palpitations, and PT Constipation
 Terms containing the word “normal” (e.g., PT Iodine uptake normal) Neonatal terms
 PTs indicating an inherited disorder Terms for tumors or malignancies of thyroid

2.96.3 Hierarchy Structure
Thyroid dysfunction (SMQ)(20000159)

Hyperthyroidism(SMQ)(20000161)

Hypothyroidism(SMQ)(200000160)

Figure 2-24. Hierarchy Structure of Thyroid dysfunction (SMQ)

2.96.4 Notes on Implementation and/or Expectation of Query Results
Thyroid dysfunction (SMQ) is a hierarchical SMQ with narrow and broad search terms.
Other than the hierarchy structure, the implementation for this SMQ is similar to thenon-hierarchical SMQs with narrow and broad search terms (see section 1.5.2.1). The
superordinate SMQ can be applied by combining the terms in the subordinate SMQs.

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2.96.5 List of References forThyroid dysfunction (SMQ)•

Dorland’s Medical dictionary accessed online on as
http://www.dorlands.com/def.jsp?id=100051907•

The Merck Manual accessed online as
http://www.merck.com/mmpe/sec19/ch282/ch282c.html•

Harrisons Principles of Internal Medicine, Mc Graw Hill accessed online as
http://accessmedicine.com/public/about_am.aspx•

http://www.dorlands.com/def.jsp?id=100051347•

http://www.merck.com/mmpe/sec12/ch152/ch152e.html#sec12-ch152-ch152e239

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2.97

Torsade de pointes/QT prolongation (SMQ)(Production Release December 2004)

Torsade de pointes/QT prolongation (SMQ) was released as a stand alone SMQ in
December 2004. In MedDRA release 9.1, it was moved under Cardiac arrhythmias(SMQ) as a level 2 sub-SMQ. In MedDRA Version 10.1, it has again become astandalone level 1 SMQ.
2.97.1 Definition•

Torsade de pointes (TdP) is a form of rapid ventricular tachycardia whose
underlying cause appears to be related to delayed ventricular repolarization,
primarily resulting from blockade of potassium conductance.

•

Electrocardiogram (ECG) findings: TdP is associated with or may be preceded bypolymorphic QRS complexes that change in amplitude and cycle length,
prolonged QT or QTc interval, prominent U waves, T wave alternans or bizarre T
wave aberrations, or “long-short sequences.”•

Signs and symptoms: The arrhythmia can resolve spontaneously, but acquired
forms often recur until the underlying cause is corrected, and can progress toventricular fibrillation. Clinical manifestations during prolonged episodes can
include episodes of palpitations, dizziness, syncope, and, rarely, sudden death;
however, patients are often unaware of palpitations.

2.97.2 Inclusion/Exclusion Criteria•

Included: Narrow scope: diagnoses and laboratory test results that are unique or
directly lead to torsade de pointes/QT prolongation. For example, PT Long
QT syndrome (diagnosis) and PT Electrocardiogram QT prolonged (testresult).
 Broad scope: signs, symptoms, diagnoses, and test results that are closely
related to Torsade de pointes/QT prolongation. These terms have thepotential in identifying positive cases. For example, PT Cardiac death(outcome) and PT Electrocardiogram U-wave abnormality (test result).
 To make this search reasonably sensitive, the types of PTs identified included
concepts of TdP, QT/QTc prolongation, ventriculararrhythmia/fibrillation/flutter/tachycardia, U- or T-wave abnormalities,
syncope, and sudden death.
 PT Syncope (symptom) produced some “noise” (i.e., many non-relevantcases retrieved) during phase I testing. However, a decision was made toretain it in the SMQ as it is a significant symptom of this condition.

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 PT Ventricular tachycardia is included in narrow search to obtain LLT TdP
ventricular tachycardia and LLT Polymorphic ventricular tachycardia. LLT
TdP ventricular tachycardia has been moved to PT Torsade de pointes since
this SMQ was developed.
•

Excluded: Non-serious events as well as general signs, symptoms, and ECG results are
excluded, such as palpitations, dizziness. During Phase I testing, it was
decided that these terms are uninformative and not likely to contain sufficient
information to contribute meaningful information.

2.97.3 Notes on Implementation and/or Expectation of Query Results
Torsade de pointes/QT prolongation (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.97.4 List of References for Torsade de pointes/QT prolongation (SMQ)•

Zipes DP. Specific arrhythmias: diagnosis and treatment. Heart Disease: A
Textbook of Cardiovascular Medicine (5th Ed). Braunwald E (Ed). WB Saunders:Philadelphia, 1997, pg. 640-704.

•

Marriott HJL and Conover MB. Polymorphic ventricular tachycardia. Advanced
Concepts in Arrhythmias (3rd Ed). Mosby: New York, 1998, pg. 293-310.

•

Definitions and basic requirements for the use of terms for reporting adverse
drug reactions (XI): cardiovascular system disorders. Pharmacoepidemiology
and Drug Safety 1998; 7:351-357.

•

Reporting Adverse Drug Reactions. Definitions and criteria for their use. CIOMS
publication, Geneva, 1999.

•

Josephson ME and Zimetbaum P. The tachyarrhythmias. Harrison’s Principles
of Internal Medicine (15th Ed). Braunwald E, Fauci AS, Kasper DL et al (Eds).
McGraw-Hill: New York, 2001, pg. 1292-1309.

•

Bauman JL and Schoen MD. Arrhythmias. Pharmacotherapy: A
Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert RL, Yee GC et al (Eds).
McGraw-Hill: New York, 2002, pg. 273-303.

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2.98

Tubulointerstitial diseases (SMQ)(Production Release September 2014)
2.98.1 Definition
Renal tubulointerstitial diseases is a group of kidney diseases, specificallyinvolving the interstitium and tubules, that develop as a result of primary injury
or inflammation and which progress to decreased renal function. The
glomeruli may be affected only late in the disease course or not at all.
•Two classes of tubulointerstitial disease: Acute tubulointerstitial disease:o Develops over days to monthso Characterized by inflammatory infiltrate and edema that affect therenal interstitiumo Leads to acute renal insufficiency or failureo In severe cases can lead chronic renal failure and/or permanent
renal injury
o Principal etiologies: infections; drugs
 Chronic tubulointerstitial disease:o Can gradually develop over years
o Involves interstitial infiltrate, fibrosis, tubular atrophy anddysfunction, and eventually renal dysfunctiono Interstitial inflammation and scarring of the renal parenchyma is
associated with gross changes, including papillary blunting andmarked calyceal deformities; can be detected by imagingo Systemic insults, such as genetic disorders, hypertension, toxins,
etc., feature symmetric and bilateral diseaseo Other causes of chronic disease may result in unequal renal
scarring, and may involve one or both kidneyso Principal etiologies include: toxins; drugs; autoimmune, genetic,
and neoplastic disorders; obstructive uropathy

2.98.2 Inclusion/Exclusion Criteria•

Included: Terms related to the definition or representing renal tubular disorders
strongly associated with tubulointerstitial diseases (e.g., PT
Tubulointerstitial nephritis; PT Renal tubular disorder)

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 Nephropathies and renal disorders resulting from the impairment of
tubular function or derangement of the tubulointerstitial region of thekidney (e.g., PT Fanconi syndrome acquired; PT Kidney fibrosis) Urinalysis and urinary abnormalities closely associated to renal tubular
dysfunction (e.g., PT Eosinophils urine present; PT Isosthenuria)
 Acid-base disorders and electrolyte and fluid balance conditions andinvestigations which are consequences of renal tubular dysfunction (e.g.,
PT Urine phosphorus increased; PT Acidosis hyperchloraemic).
 Etiologic terms frequently resulting in tubulointerstitial diseases (e.g., PT
Nephritis allergic; PT Nephropathy toxic)•

Excluded: Congenital terms, with the exception of PT Aminoaciduria (which may be
used to code acquired forms of aminoaciduria, especially before the PT
Acquired aminoaciduria was added in MedDRA Version 16.0)
 Nonspecific renal disorders, urinary tract signs and symptoms or urinary
investigations which may be downstream effects of tubulointerstitialdisease, but are not specific to it, and may appear in many other forms ofrenal and non-renal dysfunctions, because they are likely to returnconsiderable “noise” (e.g., PT Flank pain; PT Oliguria; PT Costovertebral
angle tenderness)
 Some initially considered image and histopathology investigations
occasionally associated with tubulointerstitial diseases, were finally
excluded due to lack of specificity (e.g., PT Biopsy kidney abnormal; PT
Kidney enlargement; PT Renal scan abnormal); however, this does notpreclude that new, more specific concepts of these types of investigations
may be added in the future Other non-renal disorders, signs, symptoms or investigations which may
be downstream effects of tubulointerstitial disease, but are not specific toit, and are likely to return considerable “noise” (e.g., PT Eosinophilia; PT
Eosinophil count increased; PT Blood immunoglobulin E increased) Etiologies for the development of tubulointerstitial disease that are notgenerally drug related (e.g., PT Myeloma cast nephropathy; PT
Obstructive uropathy).
 All forms of urolithiases

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 Nonqualified investigation terms (exception: relevant "abnormal"
investigation terms are included)
NOTE: Severe forms of acute tubulointerstitial nephritis may lead to acute renal
failure. For this reason, searches combining both Tubulointerstitial diseases(SMQ) and Acute renal failure (SMQ) may be of interest in some cases.
2.98.3 Notes on Implementation and/or Expectation of Query Results
Tubulointerstitial diseases (SMQ) has narrow and broad search terms. The
detailed notes are documented in section 1.5.2.1.
2.98.4 List of References for Tubulointerstitial diseases (SMQ)•

Harrison’s Principles of Internal Medicine: Chapter 285. Tubulointerstitial
Diseases of the Kidney•

Merck Manual for Health Care Professionals: Tubulointerstitial Diseases•

Current Diagnosis & Treatment: Nephrology & Hypertension: Chapter 36. Acute
Tubulointerstitial Nephritis•

Current Diagnosis & Treatment: Nephrology & Hypertension: Chapter 37.
Chronic Tubulointerstitial Nephritis•

Coltran RS, Rennke H, and Kumar V. : Robbins Basic Pathology. 7th ed.
Philadelphia: Saunders, 2003. Chapter 14:526-527.

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2.99

Tumour lysis syndrome (SMQ)(Production Release September 2013)
2.99.1 Definition
•
•

•

•
•
•

•
•

•

Tumor lysis syndrome (TLS): caused by release of tumor cell contents either
from spontaneous cell lysis or in response to therapy
Characteristic findings:
 Hyperuricemia
 Hyperkalemia Hyperphosphatemia Hypocalcemia
Can lead to downstream effects:
 Renal insufficiency
 Cardiac arrhythmia
 Seizures
 Death (due to multiorgan failure)
Dying cells also release cytokines which may cause a systemic inflammatory
response syndrome and multiorgan failure
Occurs most frequently in patients with high grade non-Hodgkin lymphoma andacute leukemia
 Other tumors can also be implicatedPatients at highest risk having pre-existing: Chronic renal insufficiency
 Oliguria
 Dehydration
 Hypotension
 Acidic urineManagement of TLS is directed toward, the metabolic and renal complications
through supportive care
Distinction between “laboratory” TLS and “clinical” TLS
 “Laboratory” TLS requires two or more of the following abnormalities within 3days before and 7 days after starting therapy:o Hyperuricemiao Hyperkalemiao Hyperphosphatemiao Hypocalcemia
 “Clinical” TLS occurs when “laboratory” TLS has been established and is also
accompanied by:o Increased creatinine levelo Seizures
o Cardiac dysrhythmia, oro DeathRenal injury in TLS is an important aspect of the disorder

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 Occurs when calcium phosphate, xanthine and uric acid precipitate in renal
tubules leading to obstruction and inflammation
2.99.2 Inclusion/Exclusion criteria•

Included: The “diagnostic” term for TLS – i.e., PT Tumour lysis syndrome Terms for the metabolic conditions that are manifestations of TLS (e.g., PT
Hyperuricaemia, PT Hypocalcaemia)
 Terms for investigation results that represent the metabolic manifestations ofTLS (e.g., PT Blood uric acid increased, PT Blood calcium decreased) Terms for the renal manifestations of TLS, since these are so significantly
connected to the other metabolic manifestations and are highly characteristicof the syndrome (e.g., PT Acute kidney injury)
 Terms for the investigation results corresponding to the renal manifestationsof TLS (e.g., PT Blood creatinine increased)•

Excluded: Terms for the underlying etiologies and precipitating factors for TLS (e.g., PT
Burkitt's lymphoma, PT Chemotherapy)
 Terms for “downstream” clinical effects of the metabolic manifestations of TLS(e.g., PT Seizure; PT Arrhythmia)

NOTE: During discussions between the development team for SMQ Tumour lysis
syndrome and the CIOMS SMQ Working Group, it was pointed out that PT Urate
nephropathy is fairly characteristic of TLS, and a proposal was made to move this termfrom the broad scope terms in Category C to a narrow scope, Category A. However, it
was decided to keep the term in the broad scope Category C with other clinicalmanifestations, but to alert the user of the SMQ that PT Urate nephropathy is somewhat“borderline” between a narrow and broad scope term in this SMQ.
2.99.3 List of References for Tumour lysis syndrome (SMQ)
Howard, HC, Jones, DP and Pui, C-H. The tumor lysis syndrome. New Engl J
Med 2011; 364:19, 1844 – 54
Krishnan, K, Jaishankar, D and Ikeda, A. Tumor lysis syndrome. eMedicine(October 2012) http://emedicine.medscape.com/article/282171-overview•

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2.100 Uterine and fallopian tube neoplasms, malignant and unspecified (SMQ)(Production Release September 2008)
2.100.1

Definition•

Developed to detect all malignant and unspecified tumors related to uterus andfallopian tube•

Covers all malignant and unspecified neoplasms related to uterus and fallopian
tube and in addition:
 Malignancy related conditions
 Malignancy related therapeutic and diagnostic procedures
 Premalignant conditions

2.100.2•

Inclusion/Exclusion Criteria

Included: Terms for malignant or unspecified neoplasms with a clear reference touterus and fallopian tube
 Terms for conditions related to malignant or unspecified neoplasms of theuterus and fallopian tube, including:o Procedureso Investigationso Tumor markers

o Signs and symptoms pointing to such disorders•

Excluded: Terms for malignant or unspecified neoplasms without a clear reference touterus and fallopian tube
 Terms for unspecified site malignancy related therapeutic and diagnostic
procedures and tumor markers
 Terms related to placenta
 Terms for metastases to uterus and fallopian tube, including PT Metastases
to reproductive organ PT Uterine operation and PT Fallopian tube operation as they are notmalignancy specific therapeutic procedures. (These terms may, however, beadded if a very broad search is required).

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NOTE: In Version 14.0, two new sub-SMQs were added to Uterine and fallopian tube
neoplasms, malignant and unspecified (SMQ) to allow users to retrieve malignant-only
events/cases; events/cases of neoplasms of unspecified malignancy; or a combinationof malignant and unspecified neoplasm events/cases.
NOTE: For searches of non-specific malignancy related conditions and malignancy
related therapeutic and diagnostic procedures, it is recommended to use the respective
lower level sub-SMQ of SMQ Malignancies.
2.100.3

Hierarchy Structure
Uterine and fallopian tube
neoplasms, malignant andunspecified (SMQ)(20000153)

Uterine and fallopian tube
malignant tumours (SMQ)(20000206)

Uterine and fallopian tube
tumours of unspecified
malignancy (SMQ)(20000207)

Figure 2-25. Hierarchy Structure of Uterine and fallopian tube neoplasms,
malignant and unspecified (SMQ)
2.100.4

Notes on Implementation and/or Expectation of Query Results

Uterine and fallopian tube neoplasms, malignant and unspecified (SMQ) has narrowand broad search terms. The detailed notes are documented in section 1.5.2.1.
2.100.5
List of References for Uterine and fallopian tube neoplasms,
malignant and unspecified (SMQ)•

DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of
Oncology. 7th Edition, 2005.

•

Peckham, M; Pinedo, H,.Veronesi, U. Oxford Textbook of Oncology. 1995.

•

European Group on Tumour Markers (EGTM). http://www.egtm.eu/

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2.101 Vasculitis (SMQ)(Production Release March 2009)
2.101.1

Definition•

Vasculitis: inflammation of blood vessel walls•

Clinical and pathological features vary depending on site and type of bloodvessels affected•

Primary vasculitis: vasculitis is the primary process. Examples are:
 Temporal arteritis
 Polyarteritis nodosa Wegener’s granulomatosis•

Vasculitis can be a secondary feature as with:
 Systemic lupus erythematosus
 Rheumatoid arthritis•

Characterized by inflammation of and damage to blood vessels
 Vessel lumen is usually compromised Associated with ischemia of tissues supplied by the involved vessel•

Broad and heterogeneous group of syndromes may result from this process•

Any type, size, and location of blood vessel may be involved•

May be confined to a single organ, such as skin, or may simultaneously involve
several organ systems

2.101.2•

Inclusion/Exclusion Criteria

Included: Terms for primary vasculitides (e.g., PT Henoch-Schonlein purpura, PT
Behcet's syndrome, or PT Granulomatosis with polyangiitis [which includes
LLT Wegener's granulomatosis])
 Terms containing “vasculitis” (e.g., PT Cutaneous vasculitis, PT Lupus
vasculitis, or PT Rheumatoid vasculitis) Terms containing “arteritis” (e.g., PT Arteritis coronary or PT Polyarteritis
nodosa) Terms containing “angiitis” (e.g., PT Microscopic polyangiitis or PT
Thromboangiitis obliterans)

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 Terms for forms of purpura indicative of a vascular condition such as PT
Henoch-Schonlein purpura and PT Chronic pigmented purpura (narrow,
which includes LLTMajocchi's purpura) and PT Palpable purpura (broad) Terms for laboratory test results that may indicate vasculitis (e.g., PT
Antineutrophil cytoplasmic antibody increased)•

Excluded: Terms for symptoms of vasculitis as they are dependent on particular bloodvessels involved by inflammatory process
 Terms for secondary vasculitis associated with an infective or allergic process
and malignancy (e.g., PT Arthritis allergic and PT Phlebitis infective)
 Congenital terms (e.g., PT Infantile septic granulomatosis)
 Terms for conditions relating exclusively to inflammation of veins (e.g., PT
Thrombophlebitis and PT Phlebitis (user may wish to refer to SMQ
Thrombophlebitis) All general and specific purpura terms that are not specifically indicative of avasculitic condition (e.g., PT Purpura, PT Purpura senile, PT Thrombotic
thrombocytopenic purpura, and PT Purpura non-thrombocytopenic, etc)
 Terms for conditions for which patients are at risk for vasculitis, such as
rheumatoid arthritis and other autoimmune diseases
 Terms for systemic lupus erythematosus (user may wish to refer to SMQ
Systemic lupus erythematosus)
 Terms for eosinophilic conditions (user may wish to refer to SMQ Eosinophilic
pneumonia)
 Terms for laboratory tests that may be increased in vasculitis, but are highly
non-specific (e.g., PT Antinuclear antibody positive, PT C-reactive proteinincreased, and PT Red blood cell sedimentation rate increased)

NOTE: In initial testing by the CIOMS Working Group, broad terms retrieved too few
cases to adequately evaluate differentiation between positive and negative control
compounds tested. The terms chosen for the broad search, however, are felt to be
medically appropriate and may prove useful in some databases.
2.101.3

Notes on Implementation and/or Expectation of Query Results

Vasculitis (SMQ) has narrow and broad search terms. The detailed notes are
documented in section 1.5.2.1.
2.101.4•

List of References for Vasculitis (SMQ)

Savage COS et al. ABC of Arterial and Vascular Disease, Vasculitis. BMJ 2000
May; 320 1325-1328.

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The Vasculitis Syndromes. In: Harrison’s Internal Medicine16th Edition [bookonline]. The McGraw-Hill Companies, 2007. http://www.accessmedicine.com.
Accessed may 8, 2007.

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Appendix I -- List of Abbreviations Used in This Document

APPENDIX I – LIST OF ABBREVIATIONS USED IN THIS DOCUMENT
Abbreviation

Definition

CIOMS

Council for International Organizations of Medical Sciences

JMO

Japanese Maintenance Organization

LLT

Lowest level term

MAG

MedDRA Analytical Grouping

MedDRA

Medical Dictionary for Regulatory Activities

MSSO(MedDRA) Maintenance and Support Services OrganizationNEC

Not elsewhere classified

PT

Preferred term

SMQ

Standardised MedDRA Query

SOC

System organ class

SSC

Special search category

SSQ

Standardised Search Queries

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Appendix II – CIOMS SMQ Working Group Membership

APPENDIX II – CIOMS SMQ WORKING GROUP MEMBERSHIP (as of 6 July
2016)
Name

Affiliation

Lembit Rägo
(Observer)

Council for International Organizations of Medical
Sciences (CIOMS)
Geneva, Switzerland

Norbert Paeschke(Member)

BfArM
Bonn, Germany

Sabine Brosch(Member)

European Medicines Agency (EMA)
London, UK

Victoria Newbould(Member)

European Medicines Agency (EMA)
London, UK

Aniello Santoro(Member)

European Medicines Agency (EMA)
London, UK

Sonja Brajovic(Member)

FDA
White Oak, MD, USA

Lynn Macdonald(Member)

Health Canada
Ottawa, Ontario, Canada

Marielle McMorran(Alternate)

Health Canada
Ottawa, Ontario, Canada

Miki Ohta(Observer)

Pharmaceuticals and Medical Devices Agencies (PMDA)
Tokyo, Japan

Christiane Michel(Member)

Novartis Pharma AG
Basel, Switzerland

Constantin Mirea(Member)

Boehringer-Ingelheim
Ingelheim am Rhein, Germany

Christina W. Winter(Member)

GlaxoSmithKline R&D
Middlesex, UK

William W. Gregory(Member)

Pfizer, Inc.
New York, NY, USA

Silvia Bader-Weder(Member)F. Hoffmann-LaRoche
Basle, Switzerland

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Name

Affiliation

Ilona GrosseMichaelis(Member)

Bayer-Schering Pharma AG
Berlin, Germany

Thomas Bold
(Member)Merck & Co.
North Wales, PA, USA

Anne Kehely(Member)

Eli Lilly & Co.
UK

Judith Jones(Member)

The Degge Group Ltd.
Arlington, VA, USA

Odette Morin(Observer)

ICH Secretariat
Geneva, Switzerland

Dawn Ronan(Observer)

ICH Secretariat
Geneva, Switzerland

Tomás Moraleda(Member)

MedDRA MSSO
Madrid, Spain

Eva-Beate Rump
(Member)

MedDRA MSSO
Düsseldorf, Germany

Cecilia Biriell(Observer)

The Uppsala Monitoring Centre
Uppsala, Sweden
Medicine and Healthcare Products Regulatory Agency(MHRA)
London, UK

Sarah Vaughan(Member)
Brigitte KellerStanislawski(Vaccine WG
interface)

Paul Ehrlich InstituteGermany

Yutaka Nagao(Observer)

JMO, Pharmaceutical and Medical Device Regulatory
Science Society of Japan (PMRJ)Tokyo, JapanYu Wada(Observer)

Pharmaceuticals and Medical Devices Agencies (PMDA)
Tokyo, Japan

Hitomi Takeshita(Observer)

Japan Pharmaceutical Manufacturers Association (JPMA).
United Kingdom

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Appendix II – CIOMS SMQ Working Group MembershipName
Yo Tanaka(Observer)

Affiliation
Japan Pharmaceutical Manufacturers Association (JPMA).
Japan

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APPENDIX III – COMPREHENSIVE LISTING OF SMQs AND SUB-SMQs

APPENDIX III – COMPREHENSIVE LISTING OF ACTIVE SMQs AND SUB-SMQs
Following is a comprehensive alphabetical listing of all active SMQs with respective
sub-SMQs. Algorithmic SMQs are identified with an asterisk*. The original production
release dates are also indicated:
Accidents and injuries (SMQ) [September 2007]
Acute central respiratory depression (SMQ) [September 2007]
Acute pancreatitis (SMQ)* [November 2005]
Acute renal failure (SMQ) [April 2005]
Agranulocytosis (SMQ) [November 2005]
Anaphylactic reaction (SMQ)* [November 2005]
Angioedema (SMQ) [November 2005]
Anticholinergic syndrome (SMQ)* [September 2006]
Arthritis (SMQ) [September 2013]
Asthma/bronchospasm (SMQ) [November 2005]
Biliary disorders (SMQ) [September 2007]
o Biliary neoplasms (SMQ)• Biliary neoplasms benign (incl cysts and polyps) (SMQ)• Biliary neoplasms malignant and unspecified (SMQ)− Biliary malignant tumours (SMQ) [March 2011]− Biliary tumours of unspecified malignancy (SMQ) [March 2011]o Congenital biliary disorders (SMQ)o Functional, inflammatory and gallstone related biliary disorders (SMQ)• Biliary tract disorders (SMQ)• Biliary system related investigations, signs and symptoms (SMQ)• Gallbladder related disorders (SMQ)• Gallstone related disorders (SMQ)o Infectious biliary disorders (SMQ)
Breast neoplasms, malignant and unspecified (SMQ) [September 2008]o Breast malignant tumours (SMQ) [March 2011]o Breast tumours of unspecified malignancy (SMQ) [March 2011]
Cardiac arrhythmias (SMQ) [September 2006]
o Arrhythmia related investigations, signs and symptoms (SMQ)o Cardiac arrhythmia terms (incl bradyarrhythmias and tachyarrhythmias) (SMQ)• Bradyarrhythmias (incl conduction defects and disorders of sinus nodefunction) (SMQ)- Bradyarrhythmia terms, nonspecific (SMQ)- Conduction defects (SMQ)- Disorders of sinus node function (SMQ)• Cardiac arrhythmia terms, nonspecific (SMQ)• Tachyarrhythmias (incl supraventricular and ventricular tachyarrhythmias)(SMQ)- Supraventricular tachyarrhythmias (SMQ)
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APPENDIX III – COMPREHENSIVE LISTING OF SMQs AND SUB-SMQs- Tachyarrhythmia terms, nonspecific (SMQ)- Ventricular tachyarrhythmias (SMQ)o Congenital and neonatal arrhythmias (SMQ)
Cardiac failure (SMQ) [March 2007]
Cardiomyopathy (SMQ) [September 2008]
Central nervous system vascular disorders (SMQ) [September 2006]
o Central nervous system haemorrhages and cerebrovascular conditions (SMQ)• Conditions associated with central nervous system haemorrhages andcerebrovascular accidents (SMQ)• Haemorrhagic central nervous system vascular conditions (SMQ)• Ischaemic central nervous system vascular conditions (SMQ)o Central nervous system vascular disorders, not specified as haemorrhagic or
ischaemic (SMQ)
Chronic kidney disease (SMQ) [March 2013]
Conjunctival disorders (SMQ) [September 2009]
Convulsions (SMQ) [March 2007]
Corneal disorders (SMQ) [March 2009]
Dementia (SMQ) [March 2007]
Demyelination (SMQ) [September 2008]
Depression and suicide/self-injury (SMQ) [March 2006]
o Depression (excl suicide and self injury) (SMQ)o Suicide/self-injury (SMQ)
Drug reaction with eosinophilia and systemic symptoms syndrome (SMQ)*[March 2016]

Drug abuse, dependence and withdrawal (SMQ) [September 2007]
o Drug abuse and dependence (SMQ)o Drug withdrawal (SMQ)
Dyslipidaemia (SMQ) [November 2005]
Embolic and thrombotic events (SMQ) [March 2007]
o Embolic and thrombotic events, arterial (SMQ)o Embolic and thrombotic events, venous (SMQ)o Embolic and thrombotic events, vessel type unspecified and mixed arterial andvenous (SMQ)
Eosinophilic pneumonia (SMQ)* [March 2009]
Extrapyramidal syndrome (SMQ) [March 2007]
o Akathisia (SMQ)o Dyskinesia (SMQ)o Dystonia (SMQ)o Parkinson-like events (SMQ)
Extravasation events (injections, infusions and implants) (SMQ) m ,m[September
2007]

Fertility disorders (SMQ) [September 2011]
Gastrointestinal nonspecific inflammation and dysfunctional conditions (SMQ)[September 2007]

o Gastrointestinal nonspecific dysfunction (SMQ)o Gastrointestinal nonspecific inflammation (SMQ)
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o Gastrointestinal nonspecific symptoms and therapeutic procedures (SMQ)
Gastrointestinal perforation, ulceration, haemorrhage or obstruction (SMQ)oooo[September 2007]

Gastrointestinal haemorrhage (SMQ)
Gastrointestinal obstruction (SMQ)
Gastrointestinal perforation (SMQ)
Gastrointestinal perforation, ulcer, haemorrhage, obstruction non-specificfindings/procedures (SMQ)o Gastrointestinal ulceration (SMQ)
Generalised convulsive seizures following immunisation (SMQ)* [September 2012]
Glaucoma (SMQ) [March 2008]
Guillain-Barre syndrome (SMQ) [September 2007]
Haematopoietic cytopenias (SMQ) [November 2005]
o Haematopoietic cytopenias affecting more than one type of blood cell (SMQ)o Haematopoietic erythropenia (SMQ)o Haematopoietic leukopenia (SMQ)o Haematopoietic thrombocytopenia (SMQ)
Haemodynamic oedema, effusions and fluid overload (SMQ) [March 2008]
Haemolytic disorders (SMQ) [April 2005]
Haemorrhages (SMQ) [March 2006]
o Haemorrhage laboratory terms (SMQ)o Haemorrhage terms (excl laboratory terms) (SMQ
Hearing and vestibular disorders (SMQ) [March 2009]o Hearing impairment (SMQ)o Vestibular disorders (SMQ)
Hepatic disorders (SMQ) [April 2005]
o Congenital, familial, neonatal and genetic disorders of the liver (SMQ)o Drug related hepatic disorders - comprehensive search (SMQ)• Cholestasis and jaundice of hepatic origin (SMQ)• Drug related hepatic disorders - severe events only (SMQ)- Hepatic failure, fibrosis and cirrhosis and other liver damage-related
conditions (SMQ)- Hepatitis, non-infectious (SMQ)- Liver neoplasms, benign (incl cysts and polyps) (SMQ)- Liver neoplasms, malignant and unspecified (SMQ) Liver malignant tumours (SMQ) [March 2011]
 Liver tumours of unspecified malignancy (SMQ) [March2011]• Liver related investigations, signs and symptoms (SMQ)• Liver-related coagulation and bleeding disturbances (SMQ)o Hepatic disorders specifically reported as alcohol-related (SMQ)o Liver infections (SMQ)o Pregnancy-related hepatic disorders (SMQ)
Hostility/aggression (SMQ) [September 2007]
Hyperglycaemia/new onset diabetes mellitus (SMQ) [March 2006]
Hypersensitivity (SMQ) [March 2013]
Hypertension (SMQ) [September 2008]
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Hypoglycaemia (SMQ) [March 2016]
Hyponatraemia/SIADH (SMQ) [September 2007]
Hypotonic-hyporesponsive episode (SMQ)* [September 2011]
Interstitial lung disease (SMQ) [March 2006]
Ischaemic colitis (SMQ) [March 2008]
Ischaemic heart disease (SMQ) [March 2006]
o Myocardial infarction (SMQ)o Other ischaemic heart disease (SMQ)
Lack of efficacy/effect (SMQ) [November 2005]
Lacrimal disorders (SMQ) [September 2009]
Lactic acidosis (SMQ) [November 2005]
Lens disorders (SMQ) [September 2008]
Lipodystrophy (SMQ) [September 2009]
Malignancies (SMQ) [March 2007]
o Malignancy related conditions (SMQ)o Malignancy related therapeutic and diagnostic procedures (SMQ)o Malignant or unspecified tumours (SMQ)• Malignant tumours (SMQ) [March 2011]­ Haematological malignant tumours (SMQ) [March 2017]­ Non-haematological malignant tumours (SMQ) [March 2017]• Tumours of unspecified malignancy (SMQ) [March 2011]- Haematological tumours of unspecified malignancy (SMQ) [March
-

2017]

Non-haematological tumours of unspecified malignancy (SMQ)[March 2017]o Tumour markers (SMQ)
Malignant lymphomas (SMQ) [March 2013]
Medication errors (SMQ) [March 2016]
Myelodysplastic syndrome (SMQ) [September 2013]
Neuroleptic malignant syndrome (SMQ)* [March 2006]
Noninfectious diarrhoea (SMQ) [September 2013]
Noninfectious encephalitis (SMQ) [September 2007]
Noninfectious encephalopathy/delirium (SMQ) [September 2007]
Noninfectious meningitis (SMQ) [September 2007]
Ocular infections (SMQ) [September 2010]
Ocular motility disorders SMQ) [September 2010]
Optic nerve disorders (SMQ) [September 2008]
Oropharyngeal disorders (SMQ) [September 2007]
o Gingival disorders (SMQ)o Oropharyngeal allergic conditions (SMQ)o Oropharyngeal infections (SMQ)o Oropharyngeal conditions (excl neoplasms, infections and allergies) (SMQ)o Oropharyngeal neoplasms (SMQ)
Osteonecrosis (SMQ) [March 2010]
Osteoporosis/osteopenia (SMQ) [September 2009]
Ovarian neoplasms, malignant and unspecified (SMQ) [September 2008]
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o Ovarian malignant tumours (SMQ) [March 2011]
o Ovarian tumours of unspecified malignancy (SMQ) [March 2011]
Periorbital and eyelid disorders (SMQ) [September 2009]
Peripheral neuropathy (SMQ) [November 2005]
Pregnancy and neonatal topics (SMQ) [March 2011]o Pregnancy, labour and delivery complications and risk factors (excl abortions andstillbirth) (SMQ)o Congenital, familial and genetic disorders (SMQ)o Lactation related topics (incl neonatal exposure through breast milk) (SMQ)• Functional lactation disorders (SMQ)• Neonatal exposures via breast milk (SMQ)o Foetal disorders (SMQ)o Neonatal disorders (SMQ)o Termination of pregnancy and risk of abortion (SMQ)o Normal pregnancy conditions and outcomes (SMQ)
Premalignant disorders (SMQ) [March 2007]
o Blood premalignant disorders (SMQ)o Gastrointestinal premalignant disorders (SMQ)o Premalignant disorders, general conditions and other site specific disorders(SMQ)
o Reproductive premalignant disorders (SMQ)o Skin premalignant disorders (SMQ)
Prostate neoplasms, malignant and unspecified (SMQ) [September 2008]
o Prostate malignant tumours (SMQ) [March 2011]o Prostate tumours of unspecified malignancy (SMQ) [March 2011]
Proteinuria (SMQ) [September 2014]
Pseudomembranous colitis (SMQ) [March 2007]
Psychosis and psychotic disorders (SMQ) [September 2007]
Pulmonary hypertension (SMQ) [September 2007; Revised March 2016]]
Renovascular disorders (SMQ) [March 2010]
Respiratory failure (SMQ) [March 2015]
Retinal disorders (SMQ) [March 2009]
Retroperitoneal fibrosis (SMQ) [September 2006]
Rhabdomyolysis/myopathy (SMQ) [December 2004]
Scleral disorders (SMQ) [March 2010]
Severe cutaneous adverse reactions (SMQ) [April 2005]
Shock (SMQ) [September 2006]
o Anaphylactic/anaphylactoid shock conditions (SMQ)o Hypoglycaemic and neurogenic shock conditions (SMQ)o Hypovolaemic shock conditions (SMQ)o Shock-associated circulatory or cardiac conditions (excl torsade de pointes)(SMQ)
o Torsade de pointes, shock-associated conditions (SMQ)o Toxic-septic shock conditions (SMQ)
Skin neoplasms, malignant and unspecified (SMQ) [March 2009]o Skin malignant tumours (SMQ) [March 2011]
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o Skin tumours of unspecified malignancy (SMQ) [March 2011]
Systemic lupus erythematosus (SMQ)* [March 2006]
Taste and smell disorders (SMQ) [March 2006]
Tendinopathies and ligament disorders (SMQ) [March 2015]
Thrombophlebitis (SMQ) [September 2007]
Thyroid dysfunction (SMQ) [March 2009]o Hyperthyroidism (SMQ)o Hypothyroidism (SMQ)
Torsade de pointes/QT prolongation (SMQ) [December 2004]
Tubulointerstitial diseases (SMQ) [September 2014]
Tumour lysis syndrome (SMQ) [September 2013]
Uterine and fallopian tube neoplasms, malignant and unspecified (SMQ)[September 2008]o Uterine and fallopian tube malignant tumours (SMQ) [March 2011]o Uterine and fallopian tube tumours of unspecified malignancy (SMQ) [March2011]
Vasculitis (SMQ) [March 2009]

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