Drug Safety (2021) 44:211–222

https://doi.org/10.1007/s40264-020-01006-2

ORIGINAL RESEARCH ARTICLE

Patient‑Reported Adverse Events of Radiopharmaceuticals:

A Prospective Study of 1002 Patients
Nanno Schreuder1,2   · Niels A. Jacobs1 · Pieter L. Jager3 · Jos G. W. Kosterink1,4 · Eugène P. van Puijenbroek1,5

Accepted: 22 September 2020 / Published online: 22 October 2020

© The Author(s) 2020

Abstract
Introduction  Adverse events of radiopharmaceuticals may be underreported or remain undetected. Patients can provide infor-
mation about these adverse events to enable healthcare professionals to detect, understand, and manage them more efficiently.
Objective  In this study, we aimed to (a) determine the type, causality, and frequency of patient-reported adverse events
of radiopharmaceuticals and to (b) assess the onset, outcome, and follow-up of these adverse events from the patient’s
perspective.
Methods  We performed a prospective cohort study of 1002 patients who underwent a nuclear medicine examination. Using a
validated questionnaire, we collected patient-reported information on adverse events that occurred immediately after admin-
istration of the radiopharmaceutical as well as those that occurred later. Adverse events were analysed, coded and assessed
for causality by two independent researchers.
Results  A total of 187 (18.7%) patients reported 379 adverse events. Most patient-reported adverse events of radiophar-
maceuticals belonged to the ‘general disorder and administration site conditions’ (42.0%) and ‘nervous system disorders’
(16.9%) system organ classes. Of the patient-reported adverse events, 43.0% were possibly or probably causally related to
radiopharmaceuticals. We found the frequency of patient-reported adverse drug reactions to diagnostic radiopharmaceuti-
cals to be 2.8%. No important medical events were related to the administrations of diagnostic radiopharmaceuticals. Most
adverse events (80.0%) occurred shortly after administration of the radiopharmaceutical and were resolved within a few
hours. Some events (20.0%) emerged after patients had left the nuclear medicine department, took longer to resolve, and
sometimes prompted the patient to consult a healthcare professional.
Conclusion  Adverse reactions to diagnostic radiopharmaceuticals can occur, and the frequency reported by patients was
found to be 2.8%, which is higher than reported in the existing literature. We hope that the results of this study increase
awareness of these adverse reactions among patients and healthcare professionals.

Electronic supplementary material  The online version of this

article (https​://doi.org/10.1007/s4026​4-020-01006​-2) contains Key Points 
supplementary material, which is available to authorized users.

* Nanno Schreuder The frequency of patient-reported adverse reactions to

[email protected] diagnostic radiopharmaceuticals was found to be 2.8%,
which is higher than reported in the existing literature.
1
Groningen Research Institute of Pharmacy, Unit
of PharmacoTherapy, ‑Epidemiology & ‑Economics, Most patient-reported adverse events related to radiop-
University of Groningen, Groningen, The Netherlands harmaceuticals were ‘general disorder and administra-
2
GE Healthcare Radiopharmacy Zwolle, Zwolle, tion site conditions’ and ‘nervous system disorders’.
The Netherlands
3
Most adverse events (80.0%) occurred shortly after
Department of Nuclear Medicine, Isala Hospital, Zwolle,
The Netherlands
administration of the radiopharmaceutical and were
4
resolved within a few hours.
Department of Clinical Pharmacy and Pharmacology,
University of Groningen, University Medical Center
Groningen, Groningen, The Netherlands
5
Netherlands Pharmacovigilance Centre Lareb,
’s‑Hertogenbosch, The Netherlands

Vol.:(0123456789)

212 N. Schreuder et al.

1 Introduction Knowledge about the true frequency of the occurrence of

adverse events associated with the use of radiopharmaceuti-
Radiopharmaceuticals are essential for medical imaging and cals is limited but is needed to enable healthcare profession-
therapy in nuclear medicine. Adverse events with the use of als to detect, understand, and manage the adverse events of
radiopharmaceuticals can occur, although it is assumed in radiopharmaceuticals efficiently. The current way of collect-
literature that they are rare in comparison with other phar- ing safety data may provide us with information on possible
maceuticals. This can be attributed to a low dose—mostly in safety signals but cannot provide more detailed knowledge
the order of micrograms—and the absence of pharmacologic of the frequency and impact on the patient of the adverse
effects for most radiopharmaceuticals. Furthermore, radiop- events of radiopharmaceuticals. For this reason, we recently
harmaceuticals are used infrequently in individual patients developed, validated, and tested a questionnaire specifically
with a short duration of use, often only being administered designed to assess the adverse events of radiopharmaceuti-
once or a small number of times in a lifetime [1–3]. Several cals from the perspective of the patient [17]. This validated
studies have been performed to determine the frequency questionnaire was used to perform a study on a large group
of adverse events in radiopharmaceuticals. Recently, in a of patients who underwent a nuclear medicine examination,
systematic review, we reported a median frequency of 1.63 focusing especially on adverse events from the perspective
adverse events per 100,000 administrations based on 22 of the patients.
studies of diagnostic radiopharmaceuticals [4]. However, The aim of this study was to (a) determine the type, cau-
most of these studies retrieved their data from voluntary sality, and frequency of patient-reported adverse events of
reports of adverse events from hospitals or pharmacovigi- radiopharmaceuticals and to (b) assess the onset, outcome,
lance centres. and follow-up of these adverse events from the patient’s per-
Due to underreporting, which is inherent to voluntary spective. Additionally, we compared the characteristics of
reporting, an underestimation of the true frequency of the group that did not report adverse events with the group
adverse events in radiopharmaceuticals may occur [4–6]. that did.
Reasons for the underreporting of adverse events have been
well described for other drugs and include aspects such as
the reporter’s lack of time, unclear causal relationship with 2 Methods
the drug, uncertainty about the way to report, and inadequate
awareness of the benefits of reporting [7, 8]. Adverse events 2.1 Study Design
that occur after the use of radiopharmaceuticals may also
remain undetected because such events may occur after the We performed a prospective cohort study in patients under-
patient has left the nuclear medicine department and there going a nuclear medicine examination at the Isala Hospital
is usually no follow-up contact between this department and in Zwolle, a 1103-bed regional hospital in the Netherlands.
the patient. Data were collected from November 2016 to November
Besides reports by healthcare professionals, patients 2018. We obtained ethical exemption in writing from the
themselves are a valuable source of information and there Medical Ethics Committee of the Isala Hospital in Zwolle in
is a growing interest in patient-reported data concerning the Netherlands (Reference number 16.08138), as this study
adverse events [9, 10]. In comparison with healthcare pro- did not require formal approval according to Dutch law. All
fessionals, patients tend to report different adverse events, patients gave their approval for the use of their data for this
including those that were previously unknown, and they also evaluation in agreement with Dutch privacy laws.
provide detailed accounts of known adverse events, includ-
ing adverse changes in quality of life [11–15]. Furthermore, 2.2 Patients
patients are able to disclose adverse events that occur with
a later onset, which is useful to detect adverse events that We invited patients who were scheduled for a nuclear
occur after the patient has left the nuclear medicine depart- medicine examination at the Isala Hospital to participate
ment. Nevertheless, studies on the adverse events of radiop- in this study. Patients received information by letter about
harmaceuticals from the perspective of the patient are scarce. the study 2 weeks before their visit to the nuclear medicine
To the best of our knowledge, only one study has assessed department. We informed patients in general terms that we
adverse events in radiopharmaceuticals from the perspective intended to study their experience with the nuclear medi-
of the patient and described one patient who reported mild cine examination, and we did not explicitly state the aim of
adverse events among 55 patients who received [­ 99mTc]Tc- the questionnaire. This approach will limit a social desir-
medronic acid [16]. ability bias, whereby patients would report adverse events
in the direction of the perceived aim of the study. Patients
could volunteer to participate on the day of their visit to the
Patient-Reported Adverse Events of Radiopharmaceuticals 213

nuclear medicine department before their examination, and aspects when patients reported an adverse event (Table 1).
we did not ask patients about their reasons for not partici- We did not collect specific patient identifiers (such as their
pating to avoid placing an additional burden on patients and name and contact details) and there was also no need to
staff. There were no non-participating patients who still par- contact patients for further clarification of the data collected.
ticipated after their examination. Patients who underwent a For each patient we added to the data the name of the radiop-
nuclear medicine examination and gave their signed approval harmaceutical used and the radioactivity (in megabecquerel)
for the use of their data for this study were included. Patients obtained from the medical record system (Eridanos version
were excluded when data were missing that were required to 7.78, IC2it).
initiate the web-based questionnaire, such as email address
or date of birth, or when no radiopharmaceutical was used. 2.4 Data Classification

2.3 Data Collection After obtaining the data with the questionnaire, we stand-
ardised the names of the radiopharmaceuticals according
We used the questionnaire that we had developed, validated, to the Anatomical Therapeutic Chemical (ATC) classifica-
and tested in our previous work [17]. The questionnaire in tion system [21] and applying the International Consensus
Dutch and an English translation can be found as supple- Radiochemistry Nomenclature Guidelines [22]. Adverse
mentary material in the Electronic Supplement Material events reported by patients were manually coded using
(ESM). Participants in the present study received a link terminology from the Medical Dictionary for Regulatory
to the web-based questionnaire ­(Researchmanager®; [18]) Activities ­(MedDRA®) version 21.1 [23]. ­MedDRA® is the
7 days after their nuclear medicine examination. We sent a international medical terminology developed under the aus-
reminder after another 7 days in case patients had not com- pices of the International Conference on Harmonisation of
pleted the questionnaire, but access to the questionnaire was Technical Requirements for Registration of Pharmaceuticals
limited to 21 days after the nuclear medicine examination. for Human Use (ICH). This terminology contains terms on
These timespans were chosen for two reasons. First, we five hierarchical levels: lowest level terms, preferred terms,
would expect possible adverse events to occur within a few high-level terms, high-level group terms, and system organ
days after the nuclear medicine examination. Second, longer classes. The lowest level terms are connected in meaning to
recall periods may introduce bias due to patients forgetting preferred terms, which represent unique medical concepts
information or patients bringing up information from other and can, therefore, be used for data representation. Although
sequential doctor visits or examinations [4, 17]. In the ques- the preferred terms can be connected in meaning to mul-
tionnaire, we collected data from the patients about several tiple system organ classes, a primary system organ class
aspects of their characteristics, health status, and occurrence is always allocated to the preferred term in the ­MedDRA®
of adverse events at several moments, as well as additional terminology. In our study, we used both the preferred terms

Table 1  Aspects on which data were collected using the questionnaire

Category Aspects

Patient characteristics Gender

Age
Weight (kg)
Height (cm)
Use of over-the-counter medicines
Health status Health status using the EuroQol–5 dimensions-3 levels (EQ-5D-3L) ques-
tionnaire [19, 20]
Occurrence of adverse events Adverse events during past nuclear examinations
Adverse events after administration of the radiopharmaceutical
Adverse events within 1 week after leaving the nuclear medicine department
Additional data when patients reported adverse events Symptoms
Time of onset
Recovery status of the patient
Time of recovery
Contact with a healthcare professional
Treatment of the adverse events

214 N. Schreuder et al.

and the corresponding primary system organ classes in our test in combination with the normal Q–Q plots. When
coding. With respect to the type of adverse events, we also normally distributed, data were compared using the inde-
screened for important medical events using the important pendent t test, or when they were not normally distrib-
medical event terms list drafted by the EudraVigilance uted, the Mann–Whitney U test was used. For the nominal
Expert Working Group [24]. This list contains the preferred data of the characteristics, we used the Chi square test or
terms that are considered to be important by the European Fisher’s exact test when the numbers were small. For all
Medicines Agency, which comprise occurrences that may analyses, p values of < 0.05 were considered to be statisti-
result in death, that are life-threating, require hospitalisation, cally significant. The other results were analysed descrip-
result in disability, or are congenital defects. In other words, tively using Microsoft Excel version 1808.
important medical events are those that may jeopardise the
patient or require intervention to prevent a serious adverse
event [25]. 3 Results
To assess the causal relationship between the radiophar-
maceuticals and the adverse events, we used the algorithm 3.1 Patient Characteristics
of Silberstein [3], which was specifically developed to deter-
mine the likelihood of whether an adverse event is related Out of the total 5497 patients invited, 1535 (27.9%)
to a radiopharmaceutical. Silberstein’s algorithm comprises patients were considered for inclusion in this study. After
four categories of causality: not related, unlikely, possible, excluding patients with no email address (n = 74), patients
and probable. Each category has several criteria based who were not retrieved from the medical record system
on aspects such as time sequence, response pattern to the (n = 3), and patients with a missing date of birth (n = 1), we
suspected test material, and rechallenge. For the causality sent out questionnaires to 1457 patients. Of these patients,
assessment, we used data obtained through the question- 1147 (78.7%) completed the questionnaire. We excluded
naire on adverse events’ time of onset, the occurrence of 145 patients as they did not use a radiopharmaceutical;
adverse events during previous nuclear medicine examina- some scans at the nuclear medicine department only made
tions, the recovery status of the patient, and other possible use of the computed tomography (CT) modality of the
causes of adverse events, such as the administration of inter- scanning equipment. This resulted in 1002 patients with
ventional agents or as indicated by the patient. To determine questionnaires that were included (Fig. 1). The median age
whether previous conclusive reports had been made about of the group of patients was 66 years (IQR 57–72), with
the reported event or whether it was a known response pat- men (52.7%) and women (47.3%) almost equally repre-
tern, we used data from our previously published systematic sented (Table 2). The most commonly used radiopharma-
review of the literature [4] and the summaries of product ceuticals were ­[99mTc]Tc-oxidronic acid (n = 307, 30.6%),
characteristics (SmPCs). ­[ 99mTc]Tc-tetrofosmin (n = 253, 25.3%), ­[ 18F]fludeoxy-
To ensure clarity, adverse events with a possible or prob- glucose (n = 159, 15.9%) and [­ 82Rb]Rb-chloride (n = 119,
able proven relationship (as determined with the algorithm 11.9%; Table 3).
of Silberstein) were further defined as adverse drug reac-
tions (ADRs) as specified by the World Health Organization 3.2 Patient‑Reported Adverse Events
(WHO): “a response to a drug which is noxious and unin-
tended, and which occurs at doses normally used in man for Of the 1002 patients surveyed, 187 (18.7%) reported 379
the prophylaxis, diagnosis, or therapy of disease, or for the adverse events, with an average of 2.0 adverse events per
modification of physiological function” [26, 27]. patient. In the group that reported adverse events, there
Two researchers (N.J. and N.S.) independently conducted were significantly more women (55.1% versus 45.5%;
extraction, coding into M ­ edDRA® terms, screening for p = 0.018), patients were younger (62  years old versus
important medical events, and causality assessment. When 66 years old; p = 0.005), had a higher BMI (27.1 kg/m2
the syntheses of the results were not in agreement, the results versus 26.5 kg/m2; p = 0.042), and indicated more often
were discussed with a third researcher (E.v.P.) to resolve that they had not had a nuclear medicine examination in
discrepancies. the past (62.2% versus 46.9%; p = 0.001) than in the group
that did not report adverse events. None of the other char-
2.5 Data Analysis acteristics of the patients differed between the two groups
(Table 2).
We used SPSS Statistics version 26 (IBM) to compare the Of the patients who reported adverse events, 153 reported
characteristics of the group that did not report adverse that 303 (80.0%) adverse events occurred shortly after the
events with those of the group that did. We determined the administration of the radiopharmaceutical and 51 patients
normality of the continuous data using the Shapiro–Wilk reported that 76 (20.0%) adverse events occurred within
Patient-Reported Adverse Events of Radiopharmaceuticals 215

Fig. 1  Inclusion process of
patients Patients invited to participate
(n = 5,497)

Patients excluded:
No email address = 74
Patients considered for inclusion Not retrieved from the medical
(n = 1,535) record system = 3
Missing date of birth = 1
(n = 78)

Questionnaires sent Questionaires not filled in

(n = 1,457) (n = 310)

Questionnaires completed No radiopharmaceutical used

(n = 1,147) (n = 145)

Patients included
(n = 1,002)

Table 2  Characteristics of patients in the study (n = 1002)

Total (n = 1002) Did not report adverse Reported adverse p-Value
event (n = 815) event (n = 187)

Gender
 Women, n (%) 474 (47.3) 371 (45.5) 103 (55.1) 0.018
 Men, n (%) 528 (52.7) 444 (54.5) 84 (44.9)
Age (years), median (25th–75th percentile) 66 (57–72) 66 (57–72) 62 (53–70) 0.005
Body mass index (kg/m2), median (25th–75th percentile) 26.6 (24.2–29.8) 26.5 (24.1–29.6) 27.1 (24.7–31.0) 0.042
Use of over-the-counter medicines
 Yes, n (%) 622 (62.1) 502 (61.6) 120 (64.2) 0.513
 No, n (%) 380 (37.9) 313 (38.4) 67 (35.8)
EQ-5D
  EQ-5D index value, median (25th–75th percentile)* 0.811 (0.737–1) 0.811 (0.737–1) 0.811 (0.773–1) 0.839
  EQ VAS, median (25th–75th percentile) 70 (50–81) 70 (50–81) 71 (52–80) 0.818
Past nuclear medicine examination
 Yes, n (%) 497 (49.6) 427 (52.4) 70 (37.4) 0.001
 No, n (%) 499 (49.8) 382 (46.9) 117 (62.6)
  Do not know, n (%) 6 (0.6) 6 (0.7) 0 (0)

EQ-5D EuroQol–5 dimensions, VAS visual analog scale

*Based on the Dutch algorithm for the EQ-5D scores; utility scores range from 0 (death) to 1 (full health) [19, 20]

216 N. Schreuder et al.

Table 3  Frequency of adverse drug reactions to radiopharmaceuticals as reported by patients

Diagnostic Radiopharmaceutical Dose, median in Patients, n Adverse events per Silberstein category, n
Patients Frequency, %
or thera- MBq (range) with
peutic Not related Unlikely Possible Probable ADR, n

Diagnostic [99mTc]Tc-oxidronic acid 700 (189–749) 307 17 6 5 9 12 3.9

[99mTc]Tc-tetrofosmin 186 (135–700) 253 72 16 114 13 8* 3.2*
[18F]fludeoxyglucose 342 (185–500) 159 10 5 2 2 4 2.5
[82Rb]Rb-chloride 1480 (1138–1480) 119 65 8 0 0 0 0.0
[99mTc]Tc-pertechnetate 800 40 1 0 0 0 0 0.0
[99mTc]Tc-mertiatide 100 26 4 1 0 0 0 0.0
[123I]sodium iodine 19 (18–22) 22 0 1 0 4 2 9.1
(capsule)
[99mTc]Tc-nanocolloid 40 (20–120) 13 0 1 0 0 0 0.0
[123I]ioflupane 185 (185–252) 12 0 0 0 0 0 0.0
[99mTc]Tc-macrosalb 150 12 0 0 0 0 0 0.0
[18F]fluorocholine 250 (118–250) 9 0 0 0 0 0 0.0
[68Ga]Ga-edotreotide 150 (100–150) 8 2 0 0 0 0 0.0
(DOTA-TOC)
[99mTc]Tc-sestamibi 550 4 0 0 0 1 1 25.0
[18F]fluciclovine 307 (242–371) 2 0 0 0 0 0 0.0
[124I]sodium iodine 74 2 0 1 0 2 1 50.0
[99mTc]Tc-exametazime 500 2 0 0 0 0 0 0.0
(blood)
[99mTc]Tc-succimer 150 1 0 0 0 0 0 0.0
[111In]In-pentetreotide 200 1 0 0 0 0 0 0.0
[123I]iobenguane 300 1 0 0 0 0 0 0.0
Subtotal 993 171 39 121 31 28 2.8
Therapeutic [223Ra]Ra-dichloride 5.0 (4.4–5.8) 7 1 0 2 7 3 42.9
[131I]sodium iodine 924 (800–1048) 2 5 0 0 2 1 50.0
(capsule)
Total 1002 177 39 123 40

ADR adverse drug reaction

*Adverse drug reactions excluding those mentioned in the Summary of Product Characteristics of adenosine [28]

1 week after leaving the nuclear medicine department. We therapeutic radiopharmaceuticals ­( [ 223Ra]Ra-dichloride
found that 58.9% of the patient-reported adverse events and ­[131I]sodium iodine) and 152 adverse drug reactions
were related to two system organ classes (Fig. 2): ‘general in 92 patients were related to diagnostic radiopharma-
disorders and administration site conditions’ (42.0%) and ceuticals (Table 3). Of patients injected with ­[99mTc]Tc-
‘nervous system disorders’ (16.9%). The five most frequently tetrofosmin, 119 adverse drug reactions in 71 patients
reported adverse events were a hot feeling (n = 47), a sense were attributed to adenosine, which is used as a stressing
of oppressed breathing (n = 26), chest discomfort (n = 24), agent with myocardial perfusion imaging [28]. Of these
headache (n = 20) and fatigue (n = 18). 71 patients, seven patients reported both adverse drug
Of the patient-reported adverse events, 163 (43.0%) reactions mentioned in the SmPC of adenosine and those
in 96 patients were determined to be possibly (n = 123; not mentioned in the SmPC of adenosine. After excluding
32.5%) or probably (n = 40; 10.6%) causally related and patients with adverse drug reactions that were related to
further determined as adverse drug reactions. Another adenosine, the frequency of patients with adverse drug
216 (57.0%) patient-reported adverse events in 91 patients reactions related to diagnostic radiopharmaceuticals
were determined to be unrelated (n = 177; 46.7%) or became 2.8% (28/993; Table 3).
unlikely to be related (n = 39; 10.3%; Table 3). Of the The diagnostic radiopharmaceuticals that were most fre-
163 patient-reported adverse drug reactions, 11 adverse quently associated with patient-reported adverse drug reac-
drug reactions in four patients were related to two tions were ­[99mTc]Tc-tetrofosmin and ­[99mTc]Tc-oxidronic
Patient-Reported Adverse Events of Radiopharmaceuticals 217

­ edDRA® system organ class after administration of the

Fig. 2  The proportion of adverse events (AEs) of radiopharmaceuticals categorised per M
radiopharmaceutical and within 1 week after leaving the nuclear medicine department

acid (Table 3). A detailed overview of adverse drug reac- 3.3 Onset, Outcome and Follow‑Up of Adverse
tions in which standardised terminology according to Events From the Patient’s Perspective
­MedDRA® is used for all radiopharmaceuticals can be found
in Table 4. Two reactions in two patients were considered Among the patients who reported an adverse event that
to be important medical events. These two events were res- occurred after the administration of the radiopharmaceuti-
piratory distress with myocardial perfusion imaging using cals, 143 patients reported that the onset of the adverse event
­[99mTc]Tc-tetrofosmin and adenosine, and were considered was shortly after administration with a median time of 1 min
to be related to the use of adenosine. Both of these patients after administration (interquartile range [IQR]: 0.1–5 min).
reported this to the hospital staff. One of the patients was Of the group of patients who reported an adverse event that
reassured by the hospital staff and was given instructions occurred after the administration of the radiopharmaceuti-
for relaxation. He recovered within 2 min. The other patient cals, 138 (90.2%) made a full recovery and the median time
indicated that she was not treated by the hospital staff and to recover was 15 min (IQR: 2–120 min). Twelve patients
recovered within 10 min. When excluding these two patients (7.8%) indicated that they partly recovered and three patients
with an important medical event related to adenosine, no (2.0%) had not yet recovered at the time of the last notifica-
important medical events were related to the administration tion of their status. The adverse events of the patients who
of diagnostic radiopharmaceuticals (0.0%; 0/993). reported not to have recovered were found to be unrelated
or unlikely to be related to the radiopharmaceutical. The
patients reported the adverse events to the hospital staff in
77.1% of cases and indicated that in 8.5% of the cases, they
received treatment (Table 5).

218 N. Schreuder et al.

Table 4  Overview of adverse drug reactions coded according to ­MedDRA® per radiopharmaceutical

Radiopharmaceutical Total Adverse drug reactions (n when > 1) Total no.
no. of of ADRs
patients

[18F]fludeoxyglucose 4 After administration of the radiopharmaceutical: Discomfort, Dysgeusia 2

Within 1 week after leaving the nuclear medicine department: Fatigue, Headache 2
[123I]sodium iodine (capsule) 2 After administration of the radiopharmaceutical: Thyroid pain 1
Within 1 week after leaving the nuclear medicine department: Feeling cold, Malaise, 3
Nausea
[124I]sodium iodine 1 After administration of the radiopharmaceutical: Salivary gland pain 1
Within 1 week after leaving the nuclear medicine department: Vomiting 1
[131I]sodium iodine (capsule) 1 After administration of the radiopharmaceutical: NA 0
Within 1 week after leaving the nuclear medicine department: Dysgeusia, Scar pain 2
[99mTc]Tc-oxidronic acid 12 After administration of the radiopharmaceutical: Headache (2), Arthralgia, Chest dis- 11
comfort, Dysgeusia, Dyspnoea, Feeling cold, Limb discomfort, Nausea, Presyncope,
Sense of oppression
Within 1 week after leaving the nuclear medicine department: Headache, Nasal pruritus, 3
Pruritus generalised
[223Ra]Ra-dichloride 3 After administration of the radiopharmaceutical: Arthralgia, Musculoskeletal chest pain, 3
Musculoskeletal pain
Within 1 week after leaving the nuclear medicine department: Fatigue (2), Diarrhoea, 6
Headache, Listless, Musculoskeletal chest pain
[99mTc]Tc-sestamibi 1 After administration of the radiopharmaceutical: Rash macular 1
Within 1 week after leaving the nuclear medicine department: NA 0
[99mTc]Tc-tetrofosmin (not 8* After administration of the radiopharmaceutical: Abdominal pain (2), Abdominal pain 7
mentioned in SmPC of upper, Hypoesthesia, Lip swelling, Pallor, Throat irritation
adenosine) Within 1 week after leaving the nuclear medicine department: Pruritus 1
[99mTc]Tc-tetrofosmin 71* After administration of the radiopharmaceutical: Feeling hot (29), Chest discomfort 110
(mentioned in SmPC of (16), Sense of oppression (11), Dyspnea (8), Headache (8), Chest pain (6), Dizziness
adenosine [28]) (3), Limb discomfort (3), Nausea (3), Flushing (2), Pain (2), Respiratory d­ istress† (2),
Tachycardia (2), Vision blurred (2), Anxiety, Asthenia, Cardiac disorder, Dizziness
postural, Dysgeusia, Hot flush, Feeling abnormal, Head discomfort, Hypertension,
Musculoskeletal discomfort, Palpitations, Stress, Vomiting
Within 1 week after leaving the nuclear medicine department: Headache (2), Chest dis- 9
comfort, Chest pain, Dizziness, Nausea, Palpitations, Sense of oppression, Urticaria
Total 96 163

ADR adverse drug reaction, NA not available, SmPC Summary of Product Characteristics
*Seven patients reported both ADRs mentioned in the SmPC of adenosine and ADRs not mentioned in the SmPC of adenosine. The total num-
ber of patients who reported an ADR with [­ 99mTc]Tc-tetrofosmin was 72
†Important medical event [24]

Of the patients who reported an adverse event that radiopharmaceutical. One patient indicated at the time of
occurred within 1 week after leaving the nuclear medicine the last notification that he still experienced diarrhoea and
department, 48 reported an onset of adverse events at a fatigue after the administration of ­[223Ra]Ra-dichloride.
median time of 22 h (IQR: 4–39) after administration. Of One patient still suffered from musculoskeletal chest pain,
the group of patients who reported an adverse event that listlessness, fatigue, and headache after the administration
occurred within 1 week after leaving the nuclear medicine of ­[223Ra]Ra-dichloride. One patient still had urticaria and
department, 60.8% made a full recovery and the median pruritus after the administration of ­[99mTc]Tc-tetrofosmin.
time to recover was 2 days (IQR: 1–3 days). Twelve patients Finally, one patient still suffered from malaise, nausea, and
(23.5%) indicated that they had partly recovered and eight a cold feeling after the administration of [­ 123I]sodium iodine.
patients (15.7%) indicated that they had not yet recovered Other adverse events in patients who reported to have not
at the time of the last notification of their status. In four recovered were found to be unlikely to be related or unre-
of the eight patients who had not recovered, the adverse lated to the radiopharmaceutical. A majority of 72.5% of the
events were found to be possibly or probably related to the patients did not contact a healthcare professional about the
Patient-Reported Adverse Events of Radiopharmaceuticals 219

Table 5  Outcome and follow-up of adverse events of radiopharmaceuticals from the perspective of the patient
Time of occurrence Aspect Number
of patients
(%)

After administration of the radiopharmaceutical Time of onset, median (25th–75th percentile) 1 min (0.1*–5) 143
Unknown 10
Patient status Fully recovered 138 (90.2)
Partly recovered 12 (7.8)
Not yet recovered 3 (2.0)
Time to recover, median (25th–75th percentile) 15 min (2–120) 136
Unknown 2
Healthcare professional contacted Hospital staff 118 (77.1)
None 35 (22.9)
Was AE treated? Yes 13 (8.5)
No 140 (91.5)
Within 1 week after leaving the nuclear medi- Time of onset, median (25th–75th percentile) 22 h (4–39) 48
cine department Unknown 3
Status patient Fully recovered 31 (60.8)
Partly recovered 12 (23.5)
Not yet recovered 8 (15.7)
Time to recover, median (25th–75th percentile) 2 days (1–3) 31
Unknown 0
Healthcare professional ­contacted† No healthcare professional 37 (72.5)
General practitioner 8 (15.7)
Referring physician hospital 6 (11.8)
Nurse 4 (7.8)
Pharmacist 3 (5.9)
Nuclear medicine department 1 (2.0)
Unknown 1 (2.0)
Was AE treated? Yes 5 (9.8)
No 46 (90.2)

AE adverse event
*Some patients indicated that the adverse event occurred directly or seconds after the injection
†Some patients contacted more than one healthcare professional

adverse event, and those who did mostly contacted the refer- patient-reported adverse drug reactions to diagnostic radiop-
ring physician of the hospital or their general practitioner. Of harmaceuticals of 2.8%. No important medical events related
all patients reporting an adverse event that occurred within to the administration of diagnostic radiopharmaceuticals
1  week after leaving the nuclear medicine department, were reported, although two important medical events were
five patients (9.8%) indicated that they had been treated attributed to the use of adenosine in myocardial perfusion
(Table 5). imaging. Most adverse events (80.0%) of radiopharmaceuti-
cals occurred shortly after the administration of the radiop-
harmaceutical, and most of these patients recovered (90.2%)
4 Discussion quickly with a median time of 15 min (interquartile range
[IQR]: 2–120 min).
In this study, we found that most patient-reported adverse We found the frequency of patient-reported adverse drug
events of radiopharmaceuticals belonged to the ‘general dis- reactions to diagnostic radiopharmaceuticals to be much
order and administration site conditions’ and ‘nervous sys- higher than the median frequency of 0.0016% that we iden-
tem disorders’ system organ classes. Of the patient-reported tified in our literature review [4], but it seems to correspond
adverse events, 43.0% were possibly or probably causally with one small study that assessed patient-reported adverse
related to the radiopharmaceuticals. We found a frequency of events in 55 patients who received the radiopharmaceutical

220 N. Schreuder et al.

­[99mTc]Tc-medronic acid, in which a frequency of 1.8% able to discriminate effectivity between symptoms attrib-
was reported [16]. Our findings suggest underreporting of uted to the radiopharmaceutical, the disease, or the nuclear
adverse events of radiopharmaceuticals in the literature. medicine examination. Nevertheless, the results of our study
Such underreporting of adverse events is well known for are of value to healthcare professionals, as they illustrate the
other drugs, where a median underreporting rate as high as way that patients experience radiopharmaceuticals. Other
94% has been identified [7]. Further research could deter- studies have shown that patients are interested in their own
mine the reasons for the underreporting of adverse events illnesses and treatment and that both they and healthcare
of radiopharmaceuticals and may identify possible areas for professionals report adverse events. Importantly, patient
improvement in reporting. reporting of adverse events does not replace the informa-
The proportion of serious adverse drug reactions that we tion obtained from the healthcare professional but is a use-
found in this study was lower than in our previously pub- ful complement [30–32]. Indeed, the results of our study
lished systematic review of the literature [4]. Furthermore, demonstrate that patients report different adverse events and
there was a difference in the type of adverse events reported. provide more detail on their experiences with these events
Most of the reported adverse events in our study were ‘gen- in comparison with healthcare professionals.
eral disorders and administration site conditions’ (e.g., a hot A general limitation of studies using a questionnaire is
feeling, a sense of oppressed breathing, chest discomfort, the representativeness of the responders. Even though 1002
and fatigue), and ‘nervous system disorders’ (e.g., head- patients participated in this study, this was 18.2% of the
ache), while in our previously published systematic review 5497 patients approached. A potential for selection bias
of the literature, we found that most reported adverse events may exist and limits the applicability to a larger population.
were ‘skin and subcutaneous tissue disorders’ (e.g., rash and However, the age, gender ratio, and distribution of different
pruritus), and ‘general disorders and administration site con- types of nuclear medicine procedures of our population cor-
ditions’ (e.g., fever; [4]). From these results, it seems that responds with the Dutch population undergoing a nuclear
patients tend to report different adverse events to healthcare medicine examination as presented in two older studies [33,
professionals, which is in line with studies of other drugs 34]. Furthermore, sending the questionnaire 7 days after the
[29]. nuclear medicine examination may have led to underreport-
This study focused on adverse events from the perspec- ing or overreporting of adverse events or have affected the
tive of the patient. We are not aware of other large studies accuracy of reporting due to possible recall bias. Another
with this focus. Regarding the follow-up of adverse events, limitation of this study is that we could not validate the exact
patients who experienced an adverse event of a radiophar- times of the onset and recovery of the patients. The values
maceutical shortly after administration reported this event presented in Table 5 are times according to the perception
to the hospital staff in most cases (77.1%). This result is of the patients and might not correspond with actual times.
as expected, as patients are under close surveillance by However, these times were adequate to perform the causal-
the hospital staff at the nuclear medicine department, such ity assessment. Another study might include a quantitative
as nuclear medicine technologists. As the hospital staff approach to measure actual times. In addition, although we
are likely the first to register an adverse event, they must calculated a frequency, we did not control for confounding.
be aware of this and be prepared to manage such events. Creating a control group could have been an option but this
Patients who experience an adverse event of a radiophar- would have involved difficult practical and ethical aspects.
maceutical after leaving the nuclear medicine department Using Silberstein’s algorithm together with the data that
do not usually contact the nuclear medicine staff but may we obtained with the questionnaire, we were able to suc-
report to their family physician or other. cessfully conduct the causality assessment and establish that
We believe that our study contributes to the area of drug 43% of the patient-reported adverse events were possibly
safety of radiopharmaceuticals, in which little research has or probably related to radiopharmaceuticals. However, the
been conducted. The strengths of our study are that we assessment with Silberstein’s algorithm has two potential
used a validated and tested questionnaire, as well as a large limitations that must be considered. One limitation is that
group of patients. Besides the frequency and type of patient- only adverse events with a known response pattern are clas-
reported adverse events of radiopharmaceuticals, we studied sified as possibly or probably related, leading to an exclusion
the outcome and follow-up of these adverse events from the of new adverse events. A sub-analysis of our data revealed
perspective of the patient, which, according to our knowl- that the classification would change from unlikely related
edge, has not been studied before. to possibly or probably related for only five adverse events
A point of attention is that in this study, we focused (paraesthesia with [­ 18F]fludeoxyglucose; chromaturia, thirst,
specifically on adverse events from the perspective of the and feeling cold with [­ 99mTc]Tc-oxidronic acid; ageusia with
patient. Although we used a validated and tested question- ­[123I]sodium iodine), which we considered to be accepta-
naire, one can argue that patients may not be regarded as ble. Another limitation is the inability of the algorithm to
Patient-Reported Adverse Events of Radiopharmaceuticals 221

distinguish between adverse events due to the radiopharma- to thank the EuroQol group for permitting them to use the EQ-5D
ceutical or interventional drugs, such as adenosine, in our instrument. Acknowledgement statement: The M ­ edDRA® trademark is
owned by the International Federation of Pharmaceutical Manufactur-
study. Although we overcame this limitation in our study by ers and Associations on behalf of ICH.
excluding the adverse drug reactions attributed to adenosine,
it may be necessary to update Silberstein’s algorithm when Declarations 
using it in future research. In general, one should note that
establishing a causal relationship between a suspected drug Funding  No financial support was received for the conduct of this
and an adverse event is difficult and that although algorithms study or preparation of this manuscript.
are often used in pharmacovigilance, these cannot replace a
thorough medical examination of an individual case. Conflict of interest  Nanno Schreuder is employed by GE Healthcare,
The findings of this study have several practical implica- however this work was part of his PhD trajectory at the University of
Groningen. Niels A. Jacobs, Pieter L. Jager, Jos G.W. Kosterink, and
tions. Our results imply that adverse events of radiophar- Eugène P. van Puijenbroek have no conflicts of interest that are directly
maceuticals as experienced by patients are more common relevant to the content of this article.
than previously assumed and that nuclear medicine staff are
likely to be the first to be informed about a potential adverse Ethics approval  Ethical exemption in writing was obtained from the
Medical Ethics Committee of the Isala Hospital in Zwolle in the Neth-
event. It is, therefore, important that the nuclear medicine erlands (Reference number 16.08138), as this study did not require
staff are aware of potential adverse events and are prepared formal approval according to Dutch law.
to counsel, respond, and manage these events. Furthermore,
we suggest that nuclear medicine staff consistently inform Consent to participate  All patients gave their approval for the use of
their data, in agreement with Dutch privacy laws.
patients about the adverse events of radiopharmaceuticals.
It has been supposed that well informed patients may han- Consent for publication  Not applicable.
dle side effects better or may be less concerned about them
than uninformed patients [35]. Patients may be instructed Availability of data and material  The data that support the findings of
this study are available from the corresponding author upon reason-
what to do when they experience an adverse event after able request.
leaving the nuclear medicine department. One final practi-
cal implication is that other healthcare professionals, such as Code availability  Not applicable.
the referring physician of the hospital or a patient’s general
Authors’ contributions  All authors contributed to the study concep-
practitioner, should be aware that symptoms reported by a tion and design. Data collection and analysis was performed by Nanno
patient might be caused by a nuclear medicine examination, Schreuder and Niels A. Jacobs. The first draft of the manuscript was
as they may be contacted by patients who are experiencing written by Nanno Schreuder and Niels A. Jacobs and all authors com-
adverse events. mented on previous versions of the manuscript. All authors read and
approved the final manuscript.

5 Conclusion Open Access  This article is licensed under a Creative Commons Attri-
bution-NonCommercial 4.0 International License, which permits any
non-commercial use, sharing, adaptation, distribution and reproduction
We studied the patient-reported adverse events of radiop- in any medium or format, as long as you give appropriate credit to the
harmaceuticals and found that most were ‘general disorders original author(s) and the source, provide a link to the Creative Com-
and administration site conditions’ and ‘nervous system dis- mons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative
orders’. The reported frequency of patient-reported adverse Commons licence, unless indicated otherwise in a credit line to the
drug reactions to diagnostic radiopharmaceuticals was 2.8%, material. If material is not included in the article’s Creative Commons
which is considerably higher than previously suggested. licence and your intended use is not permitted by statutory regula-
None of the adverse drug reactions related to the admin- tion or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
istration of a diagnostic radiopharmaceutical were consid- http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/.
ered to be an important medical event. Most events occurred
shortly after the administration of the radiopharmaceutical
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