Contrast Media Safety Issues and ESUR Guidelines - 1st
Edition
Visit the link below to download the full version of this book:
https://medipdf.com/product/contrast-media-safety-issues-and-esur-guidelines-1st
-edition/
Click Download Now
Contents V
Foreword
For more than 10 years the ESUR contrast media safety committee has been providing
radiologists with the latest information and updates on the adverse effects and risks of
contrast media. The recommendations and guidelines from this committee have gen-
erated great interest and are now universally recognized for their high scientific value.
They are based on solid scientific research, objective data and comprehensive, inde-
pendent literature analysis. The long-standing and extensive personal clinical expertise
of each of the committee members constitute the base for authoritative statements on
many controversial issues regarding the correct use of contrast agents in clinical radi-
ology.
As a comprehensive work, this book covers not only the classic iodinated contrast
media and barium preparations, but also the more recent MR and US contrast agents.
Indeed, this work brings together an immense volume of data and invaluable specific
information, originally scattered throughout the literature but now available in one
publication.
I most sincerely congratulate H. S. Thomsen and all contributing authors for this
outstanding volume, which deserves to become the standard reference in the field.
I am confident that it will be of great interest for radiologists and referring physicians
in their daily practice.
Leuven Albert L. Baert
Contents VII
Preface
The European Society of Urogenital Radiology established its Contrast Media Safety
Committee in 1994. Over the years it has consisted of between 12 and 14 members, the
majority of whom are experts in the field of contrast media research. There is currently
one member from the scientific section of each of the pharmaceutical companies pro-
ducing contrast agents (Bracco, Italy; GE Healthcare Diagnostics, USA; Guerbet, France;
Schering, Germany). Although the members of the committee have diverse views the
Contrast Media Safety Committee works as one group for the good of patients. The
committee benefits from the wealth of knowledge on contrast agents brought to it by
the representatives of the pharmaceutical companies. However, the rules of the Contrast
Media Safety Committee forbid any commercial promotion and the committee deals
with all types of contrast agents based purely on objective analysis, sound scientific data,
well documented clinical experience and clinical common sense. Disagreement within
the committee is discussed rationally and without commercial influence. All contrast
media are referred to by their generic names, except when the generic name is confusing
(e.g. ultrasound contrast agents). After 11 years of work the committee has covered all
the topics of clinical importance regarding the safe use of contrast media. The current
book is mainly a collection of this work together with a few new chapters. The chap-
ters have been prepared by the individual authors based on their original papers (see
Appendix) when applicable and an up to date review of the literature. Some chapters
are new and have never been published as papers by the committee. The chapters have
not been circulated among or discussed by the members of the committee and have
been edited by myself. In the appendix the latest version of the ESUR guidelines agreed
at the meeting of the committee in Copenhagen, February 2005, is presented.
The ESUR guidelines have been well received by the radiological community. They
are frequently cited in the literature. They have been incorporated into the protocols
of many departments all over the world. They are also used by the health authorities in
many countries as a reference for good radiological practice. Several of the guidelines
have been translated into languages other than English, for example Spanish, Russian
and Japanese.
I am sure the readers will agree that this book offers an invaluable, unique, practical
and unparalleled resource dealing with safety issues related to radiographic, MR and
ultrasound contrast media, and that it will ultimately benefit patients.
It has been a great honor for me to serve as chairman of this prestigious commit-
tee for 9 years. Special mention goes to the secretary of committee, Dr. Sameh Morcos,
whose close cooperation has always been highly productive and inspirational. Without
his energy and enthusiasm we would never have accomplished what we have. Also, the
past and current members of the committee deserve sincere thanks for their continu-
VIII Contents
ing involvement and for the outstanding discussions at the annual committee meeting.
Despite disagreements we have always reached a consensus. A special thank you goes to
Dr. Judith Webb, who has not only participated actively in our work but has also ensured
that our manuscripts were published in correct English. Dr. Webb has revised the English
throughout this book and I am most grateful for her outstanding and continuous sup-
port. We also thank Professor Albert L. Baert, Editor-in-Chief of European Radiology
and Editor-in-Chief of this book series, as well as Springer-Verlag for their immediate
endorsement and support of the book.
Finally, I wish to thank my family, especially my wife Pia, for allowing me to invest so
many hours of family time in this project.
Herlev, Denmark Henrik S. Thomsen
Contents IX
Contents
1 Classification and Terminology
Peter Aspelin, Marie-France Bellin, Jarl Å. Jakobsen,
and Judith A. W. Webb. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Off-Label Use – Legal Aspects
June M. Raine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Section I: General Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 Prevention of Acute Reactions
Judith A. W. Webb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4 Management of Acute Adverse Reactions to Contrast Media
Henrik S. Thomsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5 Late Adverse Reactions to Intravascular Iodinated Contrast Media
Fulvio Stacul. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Section II: Renal Adverse Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
6 Reducing the Risk of Contrast Media Induced Nephrotoxicity
Henrik S. Thomsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
7 Dialysis and Contrast Media
Sameh K. Morcos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
8 Non-Insulin Dependent Diabetes and Contrast Media
Henrik S. Thomsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Section III: Other Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
9 Iodinated and Gadolinium Contrast Media During Pregnancy and Lactation
Judith A. W. Webb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
10 Effects on Blood and Endothelium
Peter Aspelin, Fulvio Stacul, and Sameh K. Morcos . . . . . . . . . . . . . . . . . . . . . . 65
11 Effects on Iodinated Contrast Media on Thyroid Function
Aart J. van der Molen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
X Contents
12 Pulmonary Effects of Radiographic Contrast Media
Sameh K. Morcos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
13 Phaeocromocytoma
Judith A. W. Webb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
14 Contrast Media: Interactions with Other Drugs and Clinical Tests
Sameh K. Morcos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
15 Contrast Medium Extravasation Injury
Jarl Å. Jakobsen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Section IV: MR Contrast Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
16 Non-tissue Specific Extra Cellular MR Contrast Media
Remy W. F. Geenen and Gabriel P. Krestin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
17 Gadolinium Contrast Media for Radiographic Examinations
Henrik S. Thomsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
18 Safety of MR Liver Specific Contrast Media
Marie-France Bellin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Section V: Ultrasonographic Contrast Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
19 Safety of Ultrasound Contrast Agents
Raymond Oyen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Section VI: Barium Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
20 Safety Issues
Sameh K. Morcos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Appendix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
21 ESUR Guidelines on Contrast Media prepared by the Contrast Media
Safety Committee of the European Society of Urogenital Radiology . . . . . . . . . . . . . 145
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
List of Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Classification and Terminology 1
1 Classification and Terminology
Peter Aspelin, Marie-France Bellin, Jarl Å. Jakobsen, and Judith A. W. Webb
CONTENTS several powers higher than audible sound which are
reflected back from tissue interfaces in the body to
1.1 Introduction 1 generate the image.
1.2 Radiographic Contrast Media 1
1.2.1 Iodine Agents 1
Contrast media may be used with all of these
1.2.2 Barium Contrast Media 2 imaging techniques to enhance the differences seen
1.3 MR Contrast Media 2 between the body tissues on the images. Contrast
1.3.1 Paramagnetic Contrast Agents 2 media alter the response of the tissues to the applied
1.3.2 Superparamagnetic Contrast Agents 3 electromagnetic or ultrasound energy by a variety
1.4 Ultrasound Contrast Media 3
1.4.1 Classification 4
of mechanisms. The ideal contrast medium would
achieve a very high concentration in the tissues with-
out producing any adverse effects. Unfortunately, so
far this has not been possible and all contrast media
1.1 have adverse effects.
Introduction This chapter deals with the classification of con-
trast agents and the terminology used to describe
Current radiological imaging uses either electro- them.
magnetic radiation (X-rays or radiowaves) or ultra-
sound. X-rays have a frequency and photon energy
several powers higher than visible light and can pen-
etrate the body. The radiation which emerges from 1.2
the body is detected either by analogue radiological Radiographic Contrast Media
film or by a variety of digital media. The radio-
waves used in magnetic resonance imaging have a Radiographic contrast media are divided into posi-
frequency and photon energy several powers lower tive and negative contrast agents. The positive con-
than visible light. The radiowaves cause deflec- trast media attenuate X-rays more than do the body
tion of protons in the body which have aligned in soft tissues and can be divided into water soluble
the magnetic field in the scanner and as the pro- iodine agents and non water soluble barium agents.
tons relax back to their resting position, they emit Negative contrast media attenuate X-rays less than
radiowaves which are used to generate the image. do the body soft tissues. No negative contrast media
Ultrasound imaging uses sound (pressure) waves are commercially available.
P. Aspelin, MD
Department of Radiology, Karolinska University Hospital, 1.2.1
14186 Stockholm, Sweden Iodine Agents
M.-F. Bellin, MD
Department of Radiology, University Paris-Sud 11, Paul
Brousse Hospital, AP-HP, 12–14 avenue. Paul Vaillant Couturier, Water soluble iodinated contrast agents which dif-
94804 Villejuif Cedex, France fuse throughout the extracellular space are prin-
J. Å. Jakobsen, MD cipally used for angiography, during computed
Department of Diagnostic Radiology, Rikshospitalet, 0017 tomography (CT) and conventional radiography.
Oslo, Norway
J. A. W. Webb, MD They can also be administered directly into the body
Department of Diagnostic Imaging, St. Bartholomew’s Hospi- cavities, for example the gastrointestinal tract and
tal, West Smithfield, London EC1A 7BE, UK urinary tract.
2 P. Aspelin et al.
All of these contrast media are based on a ben- 1.2.2
zene ring to which three iodine atoms are attached. Barium Contrast Media
A monomer contains one tri-iodinated benzene ring
and a dimer contains two tri-iodinated benzene Barium sulphate preparations used to visualize
rings. the gastrointestinal tract consist of a suspension of
Iodinated contrast media can be divided into two insoluble barium sulphate particles which are not
groups, ionic and nonionic based on their water solu- absorbed from the gut. Differences between the dif-
bility. The water in the body is polarised unevenly ferent commercially available agents are very minor
with positive poles around the hydrogen atoms and and relate to the additives in the different barium
negative poles around oxygen atoms. Ionic contrast sulphate preparations.
media are water soluble because they dissociate into
negative and positive ions which attract the negative
and positive poles of the water molecules. Nonionic
contrast media do not dissociate and are rendered 1.3
water soluble by their polar OH groups. Electrical MR Contrast Media
poles in the contrast medium OH groups are attracted
to the electrical poles in the water molecules. Magnetic resonance (MR) imaging contrast agents
The osmolality of contrast media affects the inci- contain paramagnetic or superparamagnetic metal
dence of side-effects. The early contrast media had ions which affect the MR signal properties of the sur-
very high osmolalities (1500–2000 mosm per kg) rounding tissues. They are used to enhance contrast,
and subsequently agents of lower osmolality have to characterize lesions and to evaluate perfusion and
been developed. Contrast media may be divided flow-related abnormalities. They can also provide
into high-, low- and iso-osmolar agents. An indica- functional and morphological information.
tion of the osmolality of an agent is given by the con-
trast medium ratio which is derived by dividing the
number of iodine atoms in solution by the number of 1.3.1
particles in solution: Paramagnetic Contrast Agents
Number of iodine atoms
Contrast medium Ratio = Paramagnetic contrast agents are mainly posi-
Number of particles in solution
tive enhancers which reduce the T1 and T2 relax-
The higher osmolality agents have more particles ation times and increase tissue signal intensity on
per iodine atom and therefore have lower ratios. T1-weighted MR images.
Thus the ionic monomers have a ratio of 1.5 (three
iodine atoms per two particles in solution), the non-
ionic monomers and the ionic dimers have a ratio
of 3 (three iodine atoms per particle in solution)
and the nonionic dimers have a ratio of 6 (six iodine
atoms per particle in solution) (Fig. 1.1). The non-
ionic dimers are iso-osmolar with blood (300 mosm
per kg) at all concentrations.
Using these properties four different classes of
iodinated contrast may be defined (Fig. 1.1):
1. Ionic monomeric contrast media (high-osmo-
lar contrast media, HOCM), e.g. amidotrizoate,
iothalamate, ioxithalamate
2. Ionic dimeric contrast media (low-osmolar con-
trast media, LOCM), e.g. ioxaglate
3. Nonionic monomeric contrast media (low-osmo-
lar contrast media, LOCM), e.g. iohexol, iopentol,
ioxitol, iomeprol, ioversol, iopromide, iobitridol,
iopamidol
4. Nonionic dimeric contrast media (iso-osmolar
contrast media, IOCM), e.g. iotrolan, iodixanol Fig. 1.1. Classification of iodinized contrast media
Classification and Terminology 3
The most widely used paramagnetic contrast Gd3+
agents are non-specific extracellular gadolinium COOH
HOOC
chelates. Their active constituent is gadolinium, a
N N N
paramagnetic metal in the lanthanide series, which
HOOC COOH
is characterized by a high magnetic moment and a
relatively slow electronic relaxation time. Non-spe- COOH
cific extracellular gadolinium chelates can be clas- Ionic and linear Gd-DTPA (gadopentetate dimeglumine)
sified by their chemical structure, macrocyclic or
linear, and by whether they are ionic or nonionic
Gd3+
(Fig. 1.2). They are excreted via the kidneys.
(CH3)NHCO CONH(CH3)
Paramagnetic contrast agents also include liver
N N N
specific gadolinium based agents (gadobenate
dimeglumine, Gd-BOPTA and gadoxetate, Gd-EOB- HOOC COOH
DTPA) and manganese-based preparations [man- COOH
ganese chelate (mangafodipir trisodium) and free Non-ionic and linear Gd-DTPA–BMA (gadodiamide)
manganese combined with vitamins and amino
acids (to promote the uptake) for oral intake]. These HOOC COOH
hepatobiliary contrast agents are taken up by hepa-
tocytes and then there is variable biliary excretion. N N
The gadolinium based liver specific contrast media Gd3+
are also excreted by the kidneys. N N
HOOC COOH
Ionic and cyclic Gd-DOTA (gadoterate meglumine)
1.3.2
Superparamagnetic Contrast Agents
HOOC COOH
Superparamagnetic contrast agents include super-
paramagnetic iron oxides (SPIOs) and ultra small N N
Gd +
superparamagnetic iron oxides (USPIOs). Two prep-
N N
arations of SPIOs are available: ferumoxides and fer-
ucarbotran. These particulate agents are composed HOOC CH(CH3)OH
of an iron oxide core, 3–5 mm in diameter, covered Non-ionic and cyclic Gd-HP-DO3A (gadoteridol)
by low molecular weight dextran for ferumoxides
and by carbodextran for ferucarbotran. SPIOs are O O
approved for liver imaging and USPIOs are under
consideration for MR lymphography. -O N N -O
3+
After injection, SPIO and USPIO particles are Gd
metabolised into a soluble, non superparamagnetic -O
N N H H OH
form of iron. Iron is incorporated into the body pool
of iron (e.g. ferritin, hemosiderin and hemoglobin)
O OH
within a few days.
OH
Non-ionic and cyclic gadobutrol CH3
H2N+
1.4 COO- COO- HO
Ultrasound Contrast Media 2 HO
N N COO- HO
O N
HO
Ultrasound contrast agents produce their effect by COO- COO-
increased back-scattering of sound compared to that BOPTA Gd3+ HO
from blood, other fluids and most tissues. On grey-
Ionic and linear Gd-BOPTA (gadobenate dimeglumine)
scale images microbubble contrast agents change
grey and dark areas to a brighter tone, when the con- Fig. 1.2. Structures of the organic ligands of Gadolinium
trast enters in fluid or blood. The spectral Doppler chelates approved for clinical use.
4 P. Aspelin et al.
intensity is also increased, with a brighter spectral sions [perfluorooctyl bromide (PFOB), phase-shift],
waveform displayed and a stronger sound heard. and (5) gastrointestinal (for ingestion). Products are
Using color Doppler technique, ultrasound contrast not commercially available from all classes.
agents enhance the frequency or the power intensity Ultrasound contrast agents (USCA) can also be
giving rise to stronger color encoding. The level of classified based on their pharmacokinetic properties
enhancement of the Doppler signals may be in the and efficacy: (1) Non-transpulmonary USCAs which
order of up to 30 dB. do not pass the capillary bed of the lungs following
Ultrasound contrast agents can be used to enhance a peripheral intravenous injection, show on B-mode
Doppler signals from most main arteries and veins. only in the right ventricle, and have a short dura-
They may be useful for imaging solid organs, e.g. tion effect, (2) transpulmonary blood pool USCAs
liver, kidney, breast, prostate and uterus. They can with a short half-life (< 5 min after an intravenous
also be used to enhance cavities e.g. bladder, ureters, bolus injection), which produce low signals using
Fallopian tubes, abscesses. harmonic imaging at low acoustic power, (3) trans-
pulmonary blood pool USCAs with a longer half-life
(> 5 min after an intravenous bolus injection), which
1.4.1 produce high signals using harmonic imaging at low
Classification acoustic power, (4) transpulmonary USCAs with a
specific liver and spleen phase which can be short-
Ultrasound contrast agents can be divided into five or long-lived. They lodge in the small vessels of the
different classes: (1) Nonencapsulated gas micro- liver or spleen, or are taken up by either the reticulo-
bubbles (e.g. agitated or sonicated), (2) stabilised gas endothelial system or by the hepatocytes.
microbubbles (e.g. with sugar particles), (3) encapsu- Agents which are currently available commer-
lated gas microbubbles (e.g. by protein, liposomes or cially or are close to being available commercially
in polymers), (4) microparticle suspensions or emul- are listed in Table 1.1.
Table 1.1. Some ultrasound contrast agents on or close to the market in various parts
of the world (officially available data per April, 2005)
Product name Some properties
TM
Definity (DMP 115) Fluorocarbon gas in liposomes
SonoVue® (BR1) Sulphur hexafluoride gas in polymer with phospholipid
OptisonTM (FS069) Octafluoropropane-filled albumin microspheres
SonazoidTM (NC100100) Perfluorinated gas-containing microbubbles
Levovist® (SHU 508A) Galactose-based, palmitic acid stabilised air-bubbles
Off-label Use of Medicines – Legal Aspects 5
2 Off-Label Use of Medicines – Legal Aspects
June M. Raine
CONTENTS 2.1
Definition of a Medicine
2.1 Definition of a Medicine 5
2.2 The European Regulatory System 6
2.3 Definition of Off-Label Use 6
As diagnostic agents, contrast media fall within the
2.4 Special Populations and Special Therapeutic definition of a medicine in European law, since the
Areas 6 definition includes:
2.5 Legal Position of the Prescriber 7 “Any substance or combination of substances
2.6 Guidance for Prescribers 8 which may be used in or administered to human
2.7 Conclusion 8
beings … with a view to … making a medical diag-
nosis”.
The legislation also encompasses radiopharmaceu-
ticals:
“Any medicinal product which, when ready for
In Europe, subject to certain exemptions explained use, contains one or more radionuclides (radioactive
below, no medicine can be marketed for human use isotopes) included for a medicinal purpose”.
without a Marketing Authorisation granted either Marketing authorisation is required for radio-
by a Member State competent authority or by the nuclide generators, kits, radionuclide precursor
European Commission. The regulatory system radiopharmaceuticals and industrially prepared
exists to protect patients by ensuring that marketed radiopharmaceuticals. A marketing authorisation
medicines meet acceptable standards of safety, qual- is not required for a radiopharmaceutical prepared
ity and efficacy in their indications. Nonetheless, at the time of use by a person or by an establish-
for a range of reasons use of medicines outside ment authorised, according to national legislation,
their authorised indications, commonly known as to use such medicinal products in an approved
off-label use, and use of unlicensed medicines (i.e. health case establishment exclusively from autho-
medicines without a marketing authorisation) are rised radionuclide generators, kits or radionuclide
common. This chapter outlines the definition of a precursors in accordance with the manufacturer’s
medicine and the current regulatory framework; instructions.
reviews the legal position of prescribers of off-label European medicines legislation does not apply to:
use and the use of unlicensed medicines; consid- Ο Medicines prepared in a pharmacy in accordance
ers special populations and therapeutic areas where with a medical prescription for an individual
off-label use or the use of unlicensed medicines is patient (the “magistral formula”).
common; and provides some general guidance for • Medicines prepared in a pharmacy in accordance
prescribers considering off-label use or the use of with the prescriptions of a pharmacopoeia and
unlicensed medicines. intended to be supplied directly to the patients
served by the pharmacy (the “officinal for-
mula”).
• Medicines for research and development trials
[covered by the Directive 2001/20/EC on good
clinical practice in the conduct of clinical trials
for human use (“the Clinical Trials Directive”)].
J. M. Raine, MD
• Intermediate products intended for further pro-
Medicines Control Agency, Market Towers, 1 Nine Elms Lane, cessing by an authorised manufacturer.
London, SW8 5NQ, UK • Any radionuclides in the form of sealed sources.
6 J. M. Raine
2.2 may legitimately decline to market a medicine for a
The European Regulatory System purpose they do not wish to support.
The European regulatory system governing the
marketing of medicines for human use is set out in 2.3
Directive 2001/83/EC as amended, Regulation (EC) Definition of Off-Label Use
No.726/2004 and associated legislation. The Regu-
lation lays down Community procedures for the The term “off-label use” applies to prescribing or
authorisation, supervision and pharmacovigilance administration outside any of the terms of the mar-
of medicines, establishes a European Medicines keting authorisation, generally in relation to indi-
Agency, and sets up a scientific committee attached cations, dosage, or contra-indications. The expres-
to the Agency, the Committee for Human Medici- sion relates to a term used in the US authorisation
nal Products. It makes provision for medicines to process: the Food and Drug Administration (FDA)
be approved by the European Commission via cen- approves product labelling. A medicine which is pre-
tralised authorisations valid in all member states. scribed off-label will be accompanied by informa-
The centralised procedure must be used for cer- tion which may not be consistent with its off-label
tain specified categories of medicines and can also use, creating the potential for concern or confusion
be used for medicines which contain a new active on the part of the patient, parent or carer.
substance or which constitute a significant thera- In the light of the regulatory framework, there are
peutic, scientific or technical innovation. It is there- a number of situations where off-label use or the use
fore unsurprising that a number of new diagnostic of unlicensed medicines occurs:
imaging agents have been authorised by the cen- • Products for which a marketing authorisation
tralised route. The Directive sets in place decen- application or variation has yet to be made. These
tralised and mutual recognition systems, enabling include drugs in development and undergoing
authorisations to be granted nationally by Member clinical trials.
States. For the foreseeable future, depending on the • Medicines for which a marketing authorisation
route by which a medicine has been authorised, application or variation has been refused.
differences may exist in Europe between member 앫 Medicines which no longer have a relevant market-
states’ authorisations for the same product, and in ing authorisation because it has been suspended,
availability of medicines. The result is that use may revoked, not renewed or compulsorily varied.
be within an authorisation in one country and off- • Products prepared in formulations specially
label in another. adapted to special populations such as lower
The terms in which a marketing authorisation is strengths for children or liquids for the elderly, or
granted are specified in the Summary of Product without particular excipients for patients allergic
Characteristics (SPC), with which all advertising to them.
must comply. The SPC contains detailed provisions
covering indications, recommended dosage, contra- The use of unlicensed medicines may also occur
indications, special warnings and precautions, and in clinical trials; i.e. where the drug is still under
adverse effects associated with the medicine. Copies development. The use of such medicines is subject
of SPCs are available from the marketing authorisa- to the provisions of the Clinical Trials Directive and
tion holder, from the European Medicines Agency, is not dealt with in this chapter.
from the some Member State competent authori-
ties and via the Electronic Medicines Compendium
on www.medicines.org.uk. The SPC also forms the 2.4
basis for the Patient Information Leaflet (PIL) which Special Populations and
accompanies the medicine and is written in terms Special Therapeutic Areas
which are understandable by patients. Clearly, a med-
icine which is unlicensed will not have an SPC or PIL. Off-label prescribing of medicines, and the prescrib-
Marketing authorisation holders are required to keep ing of unlicensed medicines, is common in the areas
their authorisations up to date as new information of oncology, obstetrics, and infectious disease (HIV/
accrues in clinical use, and there is naturally a par- AIDS) and is particularly common in the paediatric
ticular focus on safety data. New evidence on efficacy population. Hospital based studies have shown that
may not be so readily identified and manufacturers many drugs used in children are either not licensed
Off-label Use of Medicines – Legal Aspects 7
or are prescribed off-label. On general paediatric by an individual patient under his direct personal
surgical and medical wards 36% of children received responsibility”. This provision is the basis for what
at least one drug that was unlicensed or off-label is referred to as the “specials” regime. The exemp-
during their in-patient stay. In paediatric intensive tion helps preserve the clinical freedom to act in
care this figure was 70% and in neonatal intensive what is judged to be in the best interests of the indi-
case 90%. A study of children’s wards in five Euro- vidual patient.
pean countries found almost half of all prescriptions The way in which European legislation is framed
were either unlicensed or off label. This is consistent means that doctors can:
with the UK licensing position on contrast media • Prescribe medicines off-label.
– of around 90 licensed products; about 50% are • Prescribe unlicensed products for individual
indicated in children. patients, either under the “specials” regime (i.e.
This situation has resulted from practical, ethical when no suitable licensed alternative available)
and commercial considerations relating to conduct- or where they are specially prepared in a phar-
ing clinical trials in children. There are difficulties macy.
in developing formulations appropriate for children, • Supply another doctor with an unlicensed medi-
and funding for research into the paediatric use of cine, in accordance with the “specials” regime.
established medicines is lacking. Following initia- • Use unlicensed medicines in clinical trials.
tives taken by the FDA in 1997 and 1999 to create 앫 Use or advise the use of licensed medicines for
incentives and obligations to conduct trials in chil- indications or in doses or by routes of adminis-
dren, the position is changing. In 2004 the European tration outside the recommendations given in the
Commission published proposals for a Paediatric licence (i.e. off-label).
Regulation establishing a system of incentives and • Subject to the points made below, prescribe or
requirements, drawing on the experience of the US recommend the use of a medicine contrary to any
legislation. Importantly the European draft Regula- warnings or precautions given in the marketing
tion contains provisions for improved information authorisation.
on the use of medicines in children and publication
of information from clinical trials in children. It is While European legislation and the regulatory
not expected to be adopted before 2006. system permits the off-label use or, in certain circum-
stances, the use of unlicensed medicines, consider-
ation also needs to be given to potential civil liability
2.5 of the prescriber, in particular for negligence, in the
Legal Position of the Prescriber event that such use results in an injury to a patient.
Even in relation to an unlicensed product, manu-
The regulatory system aims to control the activi- facturers retain a responsibility for the efficacy and
ties of pharmaceutical companies manufacturing, safety of their product under Directive 85/374/EEC
selling or supplying medicines. It is not intended to on the liability for defective products (in the UK, see
impact on the practice of medicine. European legis- the Consumer Protection Act 1987), subject to the
lation does not require member states to prohibit the product being stored and administered correctly. A
prescription or administration of medicines outside manufacturer is however unlikely to be liable if injury
their authorised indications. Medicines prescribed results not from an inherent defect in the product or
outside the terms of the marketing authorisation its accompanying information, but from the decision
may be dispensed by pharmacists and administered of the doctor to use the product off-label, or to use an
by nurses or midwives. In addition, the legislation unlicensed product for a particular patient.
contains a specific exemption which enables Member The law relating to medical negligence differs in
States to permit the supply of unlicensed medicines different Member States, but generally provides for
for individual patients at the order of their doctor the imposition of liability on individual prescribers
– Article 5 of Directive 2001/83/EC provides that: “A in certain circumstances. In the UK, a doctor owes a
Member State may, in accordance with the legisla- duty of care to his individual patients; if he breaches
tion in force and to fulfil special needs, exclude from that duty by failing to take reasonable care and a
the provisions of this Directive medicinal products patient is injured as a result, he will be liable for neg-
supplied in response to a bona fide unsolicited order, ligence. A doctor will generally not be considered
formulated in accordance with the specifications of negligent if his actions would be accepted as proper
an authorised health-care professional and for use by a responsible body of medical professional opin-
8 J. M. Raine
ion. The courts will not however consider a body of ommended that, when obtaining consent to treat-
opinion as responsible if that opinion is not capable ment, the doctor should tell the patient of the drug’s
of withstanding logical analysis. licence status, and that for an unlicensed medicine
A doctor if also responsible for obtaining the con- its effects will be less well known and understood
sent of the patient to the treatment in question. Fail- than those of a licensed product. The provision of
ure to obtain fully informed consent may amount to information by the prescriber is particularly impor-
negligence. tant in relation to off-label use, where the patient
information leaflet may provide conflicting infor-
mation or information not relevant to such use,
2.6 and in relation to unlicensed medicines, where no
Guidance for Prescribers such leaflet is available. In relation to off-label use,
the prescriber should have access to the up-to-date
The responsibility for prescribing any medicine falls Summary of Product Characteristics, in order to
on the prescribing physician or health care profes- give appropriate information and advice.
sional. If the prescription is for an unlicensed medi- Providing a full verbal or written explana-
cine or for off-label use, these responsibilities are tion to the patient and recording that in writing,
enhanced. helps ensure that the patient understands the risks
First, when prescribing an unlicensed medicine or involved and gives genuine and informed consent.
a medicine for off-label use the prescriber is respon- This also reduces the risk of liability on the part of
sible for determining whether it is appropriate to use the prescriber in the event of injury to the patient.
the medicine as proposed for the individual patient. Thirdly, prescribers have a professional responsi-
Where the proposed use is not covered by the terms bility for monitoring the safety of medicines and for
of a marketing authorisation, the prescriber should submission of reports of any suspected adverse drug
consider the safety, and efficacy of the product in reactions to the competent authority of the Member
relation to the proposed use. The prescriber needs to State. This applies to unlicensed medicines no less
be satisfied that there is sufficient evidence and/or than authorised products. Some Member States have
experience of using the medicine in order to demon- introduced a legal requirement requiring health
strate its safety and efficacy. The prescriber should professionals to report suspected adverse drug reac-
consider any relevant published literature, clinical tions, but this does not appear to have resulted in
guidance, or clinical trial data made available by higher reporting rates.
regulatory authorities or companies themselves.
Prescribers can also rely on information and guid-
ance from a responsible body of medical opinion. 2.7
In the area of paediatrics for example, the UK pub- Conclusion
lication “Medicines for Children” produced by the
Royal College of Paediatrics and Child Health has The use of medicines according to the terms of the
been generally cited as representing the respected marketing authorisation is supported by evidence of
body of knowledge derived from a large number of safety, quality and efficacy which has satisfied regu-
UK paediatricians. A further example is the guide- latory authorities of Member States or the European
line on safe sedation of children undergoing diag- Commission. It is generally understood and accepted
nostic and therapeutic procedures published in 2004 that there are clinical situations where off-label use
by the Scottish Intercollegiate Guideline Network. or the use of unlicensed medicines may be judged by
In relation to unlicensed medicines, other than the prescriber to be in the patient’s best interests, on
a medicine prepared in a pharmacy in accordance the basis of the evidence available indicating a likely
with a prescription, the doctor must also be satis- favourable benefit:risk balance. In such cases, the
fied that an alternative licensed medicine would not onus is on the prescriber to be familiar with the avail-
meet the patient’s needs. able evidence of risk and benefit, to make appropriate
The second responsibility of prescribers under- information available to the patient, parent or carer,
taking off-label prescribing or the prescribing of and to monitor safety in use. If appropriate care is
unlicensed medicines is to ensure that the patient, taken, information provided and decisions related to
parent or carer is adequately informed about the off-label use or use of unlicensed medicines recorded,
risks and benefits of the medicine, in the absence the risk of a prescriber being found liable for any
of authorised product information. It has been rec- mishap should be minimised.
Prevention of Acute Reactions 9
Section I:
General Adverse Reactions
Prevention of Acute Reactions 11
3 Prevention of Acute Reactions
Judith A. W. Webb
CONTENTS 3.2
Iodinated Contrast Media
3.1 Introduction 11
3.2 Iodinated Contrast Media 11
3.2.1 Types and Frequency of Acute Reactions 11
3.2.1
3.2.2 Risk Factors for Acute Idiosyncratic Reactions 11 Types and Frequency of Acute Reactions
3.2.2.1 Type of Contrast Agent 11
3.2.2.2 Previous Contrast Medium Reaction 12 Acute idiosyncratic systemic reactions (also described
3.2.2.3 Asthma 12 as allergy-like or anaphylactoid) are defined as unpre-
3.2.2.4 Allergy 12
3.2.2.5 Drugs 12
dictable reactions which occur within 1 h of contrast
3.2.3 Prevention of Acute Idiosyncratic Reactions 13 medium administration, and which are unrelated to
3.2.3.1 Choice of Contrast Medium 13 the amount of contrast medium above a certain level.
3.2.3.2 Premedication 13 This definition aims to distinguish them from chemo-
3.2.3.3 Pretesting and Injection Rate 14 toxic reactions, which are dose-related and dependent
3.2.4 Summary: Iodinated Contrast Media 14
3.3 Gadolinium Contrast Media 15
on the physico-chemical properties of the contrast
3.3.1 Types of Reaction and Frequency 15 medium. However, in clinical practice, some reactions
3.3.2 Risk Factors for Reactions 15 such as cardiovascular collapse may be difficult to
3.3.2.1 Type of Contrast Medium 15 characterise definitely into one or other group.
3.3.2.2 Patient Risk Factors 15 The mechanisms by which idiosyncratic reactions
3.3.3 Prevention of Reactions 15
3.3.4 Summary: Gadolinium Contrast Media 15
occur are not fully understood. However, they do
References 16 appear to involve the release of active mediators, such
as histamine, bradykinin, leucotrienes, prostagland-
ins and complement factors. Available evidence sug-
gests that there are a variety of complex interactions
between the complement, contact, coagulation and
3.1 immune systems (Lasser 1985, 1987; Almen 1994).
Introduction Acute idiosyncratic reactions are usually charac-
terised as mild, moderate or severe. Mild or minor
Most of this chapter is concerned with acute idi- reactions include nausea, mild vomiting, urticaria and
osyncratic reactions to iodinated contrast media, itching. Moderate reactions include more severe vom-
particularly the factors predisposing to these reac- iting, marked urticaria, bronchospasm, facial or laryn-
tions and the measures that may be taken to prevent geal oedema, and vasovagal reactions. Severe reactions
them. At the end of the chapter acute reactions to include hypotensive shock, respiratory arrest, cardiac
gadolinium contrast media are also discussed. arrest and convulsions (Bush and Swanson 1991).
3.2.2
Risk Factors for Acute Idiosyncratic Reactions
3.2.2.1
Type of Contrast Agent
J. A. W. Webb
Department of Diagnostic Radiology, St Bartholomew’s Hos- With the older high osmolality ionic agents the rate of
pital, West Smithfield, London EC1A 7BE, UK reactions of all types is in the range 5%–12% (Ansell
12 J. A. W. Webb
et al. 1980; Witten et al. 1973; Shehadi 1975; with asthma, Katayama et al. (1990) described an
Katayama et al. 1990; Cochran et al. 2001). The 8.5 times increased risk with ionic agents and a 5.8
majority of reactions in these series were mild with times increased risk with nonionics. Other condi-
moderate reactions occurring in 1%–2% and severe tions, such as hayfever, eczema, etc. are associated
reactions in approximately 0.10%–0.15% (Ansell with an increased risk of reaction, but by a lesser
et al. 1980; Witten et al. 1973). Mortality with the amount than asthma (Ansell et al. 1980; Witten
ionic agents is in the range 1 in 14,000 to 1 in 169,000 et al. 1973; Shehadi 1975).
(Shehadi 1975; Katayama et al. 1990) with 1 in 75,000
an often quoted figure (Hartman et al. 1982).
With the newer low osmolality nonionic agents, 3.2.2.4
the reaction rates are lower, by a factor of approx- Allergy
imately four to five times (Katayama et al. 1990;
Palmer 1988; Wolf et al. 1991; Bettman et al. 1997). A history of allergy to foods, drugs or other sub-
Thus in Katayama’s series of over 300,000 patients stances is associated with an increased risk of con-
the reaction rates for ionic and nonionic agents were trast medium reaction, usually by a lesser amount
overall 12.66% and 3.13%, with severe reactions in than a history of asthma. Thus, Shehadi (1975) and
0.22% and 0.04%, respectively (Katayama et al. Katayama et al. (1990) found a two-fold increase
1990). Based on a meta-analysis of all data published in risk of a reaction and Ansell et al. (1980) a four
between 1980 and 1991, Caro et al. (1991) concluded times increase in risk of a reaction.
that 80% of contrast media reactions could be pre- Allergy to foodstuffs which contain iodine, e.g.,
vented by using low osmolality agents. The very seafood, often causes particular anxiety. However,
low mortality means that accurate mortality fig- the available data suggests that allergy to seafood is
ures are not yet available for the nonionic agents. In no more significant than allergy to other foodstuffs
Katayama et al.’s (1990) series there was no sig- (Witten et al. 1973; Shehadi 1975; Leder 1997).
nificant difference in mortality between the ionic Allergy to topical iodine skin preparations is
and nonionic agents, but other data suggests a lower a type of contact dermatitis and does not seem to
mortality with nonionic agents (Lasser et al. 1997). predispose to acute idiosyncratic contrast medium
reactions (Thomsen and Bush 1998).
3.2.2.2
Previous Contrast Medium Reaction 3.2.2.5
Drugs
A previous reaction to an iodinated contrast medium
is the most important patient factor predisposing Whether or not E blockers affect the incidence of idio-
to an acute idiosyncratic reaction (Bettman et al. syncratic contrast medium reactions is controversial.
1997). With ionic agents, the risk of a reaction in a Greenberger et al. (1987) reported that neither E
patient who reacted previously has been stated to be blockers nor calcium antagonists given separately or
16%–35% (Witten et al. 1973; Shehadi 1975) and to together increased the risk of reaction. Subsequently,
be eleven times greater than the risk in a non-reactor however, Lang et al. (1991) found that E blockers did
(Ansell et al. 1980). When a patient who previously increase the risk of reaction. It is however agreed that
reacted to an ionic agent is given a nonionic agent, the use of E blockers can impair the response to treat-
the risk of a repeat reaction is reduced to approxi- ment if a reaction does occur (Thomsen and Bush
mately 5% (Siegle et al. 1991). 1998; Greenberger et al. 1987; Lang et al. 1991).
Patients who are receiving or have received inter-
leukin-2 are at increased risk of adverse events fol-
3.2.2.3 lowing iodinated contrast media. Some of these
Asthma adverse events appear to recall the side-effects of
interleukin-2 (e.g., fever, nausea, vomiting, diar-
Asthma is another important risk factor. Shehadi rhoea, pruritus and rash) (Zukiwski et al. 1990;
(1975) found that 11% of asthmatics had a reaction Fishman et al. 1991; Oldham et al. 1991; Choyke
to ionic contrast media and Ansell et al. (1980) et al. 1992). Reactions are often late, occurring more
stated that the risk of reaction to ionic agents was than one hour after contrast medium, but can occur
increased five times in an asthmatic. In patients within the first hour (Choyke et al. 1992).
