Evaluation of Radiopharmaceutical Adverse Reaction Reports to the British Nuclear Medicine Society for the Period 2007 to 2016

Journal of Nuclear Medicine, published on May 18, 2017 as doi:10.2967/jnumed.117.194092

Evaluation of radiopharmaceutical adverse reaction reports to the British Nuclear Medicine Society for the period 2007 to 2016

Author Information

Tracia-gay Kennedy-Dixon, MSc Applied Pharmacology, BPharm (CORRESPONDING AUTHOR) International Atomic Energy Agency (IAEA) Fellow Radiopharmacy, Royal Liverpool and Broadgreen University Hospitals Trust Prescot Street, Liverpool, United Kingdom Email: [email protected] Tel no: +1 (876) 313-7519/ 493-8120 Fax no: +1 (876) 927-3823

Dr Maxine Gossell-Williams, PhD Researcher in Applied Pharmacology Head, Pharmacology Section Department of Basic Medical Sciences, Faculty of Medical Sciences University of the West Indies, Mona Campus Kingston 7, Jamaica Email: [email protected]

Dr Margaret Cooper, PhD Chief Radiopharmacist Radiopharmacy, Royal Liverpool and Broadgreen University Hospitals Trust Prescot Street, Liverpool, United Kingdom Email: [email protected] Moez Trabelsi, MSc Biochemistry Senior Pharmaceutical Scientist Radiopharmacy, Royal Liverpool and Broadgreen University Hospitals Trust Prescot Street, Liverpool, United Kingdom Email: [email protected]

Professor Sobhan Vinjamuri MD MSc FRCP Consultant Physician in Nuclear Medicine The Royal Liverpool and Broadgreen University Hospitals Trust Prescot Street, Liverpool, United Kingdom Email: [email protected]

Word Count: 2500

Funding: This study was not funded

Short Title: Adverse Reaction to Radiopharmaceuticals

Evaluation of radiopharmaceutical adverse reaction reports to the British Nuclear

Medicine Society for the period 2007 to 2016

T Kennedy-Dixon, M Gossell-Williams, M Cooper, M Trabelsi, S Vinjamuri

Abstract

Objective: This study sought to answer the calls for the restoration of reports of adverse reactions

from the European Association of Nuclear Medicine. It assessed reports of adverse reactions to radiopharmaceuticals (ARRPs) that were submitted to the British Nuclear Medicine Society’s

(BNMS) Radiopharmaceutical Adverse Reactions and Product Defects online database during the

period January 2007 to December 2016. Methodology: This investigation was a

pharmacovigilance based, non-experimental, cross-sectional study aimed at finding the prevalence

and association between radiopharmaceuticals and adverse reactions. Results: During the period

of the study, 204 reports were made of radiopharmaceutical adverse reactions, of which 13 were

considered invalid. This was due primarily to incomplete entries, while in other cases the causality

could not be determined. Tetrofosmin (34) and Oxidronate (32) had the highest prevalence, while

Medronate accounted for 21 reports and both Sestamibi and Nanocolloid had 14 reports each. Rash

(84), itching (46) and vomiting (30) were the three most frequently occurring adverse reactions.

The majority (96.8%) of the reports were for diagnostic radiopharmaceuticals. Conclusion: The prevalence of reported ARRPs remains low within the United Kingdom with a frequency of 3.1 reports per 100,000 administrations in 2013 and 2.5 per 100,000 administrations in 2015. In our review spanning 10 years, we did not find any particular concern with the usage of radiopharmaceuticals within this region.

Key Words: radiopharmaceuticals, adverse reactions, BNMS, pharmacovigilance

INTRODUCTION

According to the National Statistics released by the National Health Service in England,

approximately 560,000 imaging examinations with radio-isotopes were carried out in the country

during the period 1st of April 2015 to 31st of March 2016. The Diagnostic Imaging Dataset

collection which was first instituted in 2012/2013, states that approximately 520,000 similar

procedures were carried out in that year (1).

As nuclear medicine procedures have become more widespread, numerous studies have

been carried out to highlight the prevalence of ARRPs. In 2002, the European Association of

Nuclear Medicine published an annual report which outlined the nature and frequency of reports

that were submitted to the BNMS for the year 2000. In that calendar year there were sixty two

reports of adverse reactions to radiopharmaceuticals (2). Subsequently, there has not been any

further survey of the reports that have been submitted to the European database.

Notwithstanding, there have been reports generated from individual countries within the region. Laroche et al identified 304 reports of ARRPs to the French Pharmacovigilance Database from 1989 to 2013. The annual incidence of reported ARRPs for the period ranged from 1.2–3.4 per 100,000 diagnostic administrations. The frequency of ARRPs was 6.2*10-4 times that of reports from other classes of drugs made to the French pharmacovigilance network (3).

This study seeks to answer the calls for the restoration of reports from the European

Association of Nuclear Medicine database (4,5). Its objective is to assess, categorise and analyse

the reports of ARRPs that were submitted to the BNMS’s Radiopharmaceutical Adverse Reactions

and Product Defects online database. This is in an effort to provide additional information for

3 nuclear medicine practitioners globally, as well as to identify signals for uncommon and unexpected adverse reactions.

METHODS

This investigation was a non-experimental, cross-sectional study aimed at finding out the prevalence and association between radiopharmaceuticals and adverse reactions. It took a retrospective look at ARRPs experienced by patients during the ten-year period of January 2007 to December 2016 based on reports that were submitted for that time frame. Reports have been submitted primarily from the United Kingdom, with one report each from Italy and Germany.

The study protocol was registered as a clinical audit with the Audit Department of The

Royal Liverpool and Broadgreen University Hospitals NHS Trust prior to the commencement of the study. The Clinical Audit Committee ruled this retrospective study exempt from Institutional

Review Board review and from obtaining informed consent as it dealt with fully anonymised data.

The data, provided by the BNMS, provided age, gender and clinical information only.

The algorithm suggested by the Pharmacopoeia Committee of the Society of Nuclear

Medicine to categorize probabilities of causation was used for standardised case causality assessment (6). Causal relationship was classified as probable, possible or unlikely. Statistical analysis was performed with the Statistical Package for Social Sciences software program (version

24.0) and Microsoft Excel 2010. The results were expressed in terms of means, medians, standard deviation, interquartile ranges or percentage frequencies as appropriate.

All events were routinely reviewed by a senior medical practitioner, with a view of identifying any trends with the usage of radiopharmaceuticals in particular clinical settings, and to define the clinical context of any such trend.

RESULTS

From January 2007 to December 2016, a total of 204 reports of adverse reactions were

submitted to the BNMS’s Radiopharmaceutical Adverse Event and Product Defect website. Of

these reports, 13 were considered to be invalid. This assessment was due to incomplete entries as well as undeterminable causality. The distribution of annual reports for the remaining 191 cases reflect that in 2010 there were thirty one (31) reports of ARRPs, while the least reports, twelve

(12) were made in 2012 (see Fig 1) .

Of the 191 reports, 11 (5.8%) had no age of patient recorded. The mean age of the remaining 180 patients was 47 ± 23 years (range 1-93 years) and the median age was 52 years.

Patients in the age range 60 years and over made up the largest proportion of the study population

(31.9%), while the 12-19 age group made up the smallest (3.7%). The study population accounted for 128 (67.0%) females and 57 (29.8%) males, while 6 (3.2%) of the reports had unidentified gender.

Twenty nine (29) radiopharmaceuticals were isolated from the reports. Sixteen (55%) were

99mTc labelled products while thirteen (45%) were non-technetium products. 18F-FDG and 68Ga-

DOTA-NOC are the only photon emission tomography (PET) radiopharmaceuticals among the agents. All except Iodine-131 Sodium Iodide (131I-NaI) and Radium-223 (223Ra) Xofigo® were diagnostic agents.

With the use of the algorithm by Silberstein et al. (1996) (6) to determine the probability of causation of each report, 109 (57.1%) reports were classified as probable, 67 (35.1%) were possible and 15 (7.9%) were unlikely. No fatalities due to radiopharmaceutical administration were reported. However, 15 patients were hospitalised, 33 were admitted to the accident and emergency

department of their respective hospitals and 34 sought medical attention from their general

practitioners. Of the 15 patients that were hospitalized, 7 had experienced anaphylactic reactions.

Six (6) of these patients were treated with intravenous hydrocortisone, and 3 with intravenous chlorpheniramine. A total of 9 patients overall were reportedly treated with oxygen, 3 received adrenaline, 4 were nebulised with salbutamol and 4 received intravenous fluids. Eighty (80) patients reportedly did not receive pharmacological intervention for the relief of symptoms, while another 37 reports provided no information on the treatment options for the relief of symptoms.

DISCUSSION

An analysis of the Summary of Product Characteristics for each of the radiopharmaceuticals with reported adverse reactions revealed that the vast majority of the reactions are within those stated as undesirable effects. There were, however, a few exceptions.

To our knowledge, this study reports the first adverse reactions to Selenium-75 tauroselcholic acid

(SeHCAT). The use of SeHCAT capsules for the detection of bile acid malabsorption was first authorised in January 2002, with the Summary of Product Characteristics stating hypersensitivity reactions of an unknown frequency as the side effects (7). Although 2 of 7 reports were anaphylactic in nature (rash, itching, dyspnoea, throat constriction), there were also reports of dizziness, nausea, burning sensation and pain. The onset of hypersensitivity reaction (rash and itching) ranged from immediately after ingestion of the capsule to 24 hours post ingestion.

Silberstein (2014) reported flushing of the face and trunk occurring within minutes of 18F-FDG administration in submissions from 15 nuclear medicine facilities in the United States between

2007 and 2011 (8), while Laroche et al stated that the 27 cases of adverse reactions to 18F-FDG that were reported to the French Pharmacovigilance Database between 1989 to 2013 involved

mainly the skin (3). This study however highlights a report of sweating, nausea, vomiting and

uncontrollable diarrhoea within 90 minutes of injection, for which the patient was kept overnight

for observation.

Other ARRPs that are being reported for the first time, according to the authors’

knowledge, occurred with 111In-Octreotide, 51Cr-EDTA, 68Ga-DOTANOC, 99mTc-MAG3, 99mTc-

Tetrofosmin and 99mTc-labelled Carbon (Technegas) (See Table 1).

Consistent with the findings of previous studies on ARRP, the most common adverse

reactions found in this study were rash and itching (3,8). The use of intravenous and oral

antihistamines as well as corticosteroids continues to be mainstay for the treatment of these

reactions.

The co-administration of pharmacologic agents as a part of the nuclear medicine procedure,

e.g. the myocardial perfusion (stress) test, may create uncertainty of the causative agent for an

adverse reaction. A patient reported impaired function when attempting to drive home after a

myocardial perfusion stress test with 99mTc-Tetrofosmin. He reported a lack of appropriate

reactions to normal driving conditions which persisted on the following day. When the patient

returned for the rest scan, there was no adverse event, which led the reporting practitioner to

suspect that the reaction was possibly due to the administered stress agent, Rapiscan

(regadenoson). The Summary of Product Characteristics for Rapiscan states however, that it is

expected to have no or negligible influence on the ability to drive or use machines once treatment

has been completed. Another patient experienced swelling and redness of the face as well as

vomiting after the rest test and therefore the stress test was cancelled. The uncertainty experienced

in the former case is eliminated in the latter, as a pharmacologic agent was not administered in the

myocardial perfusion rest test.

The presence of co-morbidities in patients who presented for nuclear medicine imaging

also implicates the use of pharmacological agents. While the reporting system that is offered by

the BNMS makes provision for other known medications to be identified, 127 of the 191 reports

utilised this function, 46 of which stated that the patients were on no other medications. The

absence of information on co-administered medications is therefore a limitation to the findings of

this study.

A feedback mechanism, such as the reporting system currently offered by the BNMS is

beneficial to the nuclear medicine community i.e. patients, health care professionals in the field,

as well as the pharmaceutical companies that manufacture and distribute radiopharmaceuticals (9).

While the prevalence of ARRP remains stable (8), reports provide health care professionals with

knowledge of possible, probable as well as unlikely adverse reactions.

As was stated in an editorial by Hesse et al (2012), the unique growth and expansion of nuclear medicine procedures and the corresponding use of radiopharmaceuticals will undoubtedly lead to an increase in the frequency of adverse reactions (4). Although voluntary, it is therefore recommended that nuclear medicine departments report all suspected adverse reactions. While the first reported occurrence of an adverse reaction to a particular drug may be categorized as unlikely, continuous reporting provides an avenue for the identification of associated trends.

As part of our review, we did not identify any particular areas of concern with the usage of radiopharmaceuticals for certain clinical conditions. In conclusion, the reporting of ARRPs within the United Kingdom between 2007 and 2016 is well within the expected reporting levels.

DISCLOSURE/ COMPLIANCE WITH ETHICAL STANDARDS

Financial disclosure: This study was not funded

Conflict of interest: The authors declare that they have no conflict of interest.

Ethical Approval: All procedures performed in studies involving human participants were in

accordance with the ethical standards of the institutional and/or national research committee and

with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For

this type of study formal consent is not required.

ACKNOWLEDGEMENTS

The authors wish to thank the United Kingdom Radiopharmacy Group for its vision and

consistent effort in promoting pharmacovigilance in the field of Nuclear Medicine across

Europe. The efforts of Professor Marvin Reid from the University of the West Indies, Mona

Campus, Jamaica, the International Atomic Energy Agency and The Royal Liverpool and

Broadgreen University Hospitals Trust to enable the collaboration between these institutions in facilitating the training of nuclear medicine practitioners is also appreciated.

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FIGURE 1 Frequency of annual reports

35 # of reports 30

0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

TABLE 1 ARRPs that have not been previously reported and the associated causality assessment

Radiopharmaceutical Adverse Reaction Probability 111In-Pentetreotide (Octreoscan) Vaginal bleed possible 18F-FDG Nausea, vomiting, diarrhoea, sweating probable 51Cr-EDTA Discoloration of urine probable 68Ga-DOTA-NOC Maculo-papular rash probable 99mTc-MAG3 Vulvar inflammation and irritation, tremors unlikely 99mTc-Tetrofosmin Impaired function possible SeHCAT Anaphylactic (rash, itching, flushing, swelling, probable dyspnoea, throat constriction), nausea, indigestion, dizziness, burning sensation, pain Technegas Tingling probable

FDG = fluorodeoxyglucose; EDTA = ethylenediamine tetraacetic acid; DOTA-NOC = DOTA-1-NaI3-octreotide; MAG3 = mercaptoacetyltriglycine.