Indian Journal of Nuclear Medicine
Home | About IJNM | Search | Current Issue | Past Issues | Instructions | Ahead of Print | Online submissionLogin 
Indian Journal of Nuclear Medicine
  Editorial Board | Subscribe | Advertise | Contact
Users Online: 148 Print this page  Email this page Small font size Default font size Increase font size


 
 Table of Contents     
REVIEW ARTICLE
Year : 2021  |  Volume : 36  |  Issue : 2  |  Page : 163-167  

Review of adverse reactions associated with the use of common diagnostic radiopharmaceuticals


1 Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
2 Department of Nuclear Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
3 Department of Nuclear Medicine, Royal Free London NHS Foundation Trust, London, England

Date of Submission28-Oct-2020
Date of Decision01-Dec-2020
Date of Acceptance02-Dec-2020
Date of Web Publication21-Jun-2021

Correspondence Address:
Dr. Kanhaiyalal Agrawal
All India Institute of Medical Sciences, Bhubaneswar, Odisha
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnm.ijnm_219_20

Rights and Permissions
   Abstract 


Radiopharmaceuticals are used in the diagnosis and management of various diseases. There are several reports of adverse reactions related to the use of radiopharmaceuticals, though it is not as common as conventional drugs. Adverse reactions related to radiopharmaceuticals have been not widely reported and documented. In this review, we have tried to summarize the adverse reactions associated with some of the commonly used radiopharmaceuticals.

Keywords: Adverse drug reaction, adverse events, radionuclides, radiotracers, side effects


How to cite this article:
Meher BR, Agrawal K, Gnanasegaran G. Review of adverse reactions associated with the use of common diagnostic radiopharmaceuticals. Indian J Nucl Med 2021;36:163-7

How to cite this URL:
Meher BR, Agrawal K, Gnanasegaran G. Review of adverse reactions associated with the use of common diagnostic radiopharmaceuticals. Indian J Nucl Med [serial online] 2021 [cited 2021 Jul 27];36:163-7. Available from: https://www.ijnm.in/text.asp?2021/36/2/163/318884




   Introduction Top


Adverse drug reaction (ADR) is a common occurrence in clinical practice. It is responsible for significant morbidity, mortality, and the overall increase in patients' health-care expenditure.[1],[2] ADR and the side effect are not the same. ADR is defined as “a response to a drug that is noxious and unintended, and which occurs at doses normally used in human beings for prophylaxis, diagnosis or therapy of disease or the modification of physiological function.[3]” Side effect of a drug is “any unintended effects occurring at the normal dose and related to that particular drug's pharmacological properties.[3]

Radiopharmaceuticals (medicinal radio compounds) are medicinal formulations containing both radioactive component and the drug component.[4] They have become indispensable to the health-care system because of their broader application in diagnosis and therapy of various benign and malignant diseases.[5],[6]

Unlike traditional drugs, adverse reactions with radiopharmaceuticals are relatively uncommon. A possible explanation could be that radiopharmaceuticals are distinct from conventional pharmaceutical agents. Usually, they do not exhibit pharmacological effects, dose–response relationships, and are administered in minute quantity for a limited number of times to patients.[7] The British Nuclear Medicine Society (BNMS) maintains an online database of adverse reactions to radiopharmaceuticals (ARRPs). The prevalence of ARRPs reported in the BNMS database was very less, only 3.1 and 2.5 in 2013 and 2015, respectively, per 100,000 administrations of radiopharmaceuticals. Most of those reported reactions were trivial reactions such as skin rash, pruritus, and vomiting.[8] However, national pharmacovigilance database of France revealed 304 reports of ARRPs between the years 1989 and 2013. Of those, 131 (43%) were classified as serious adverse events, which led to 12 deaths, 15 life-threatening complications, 89 patients required hospitalization, and 15 other serious conditions.[9] Similarly, there are instances when radiopharmaceutical agents such as Technetium-99m (99mTc) Fanolesomab had to be withdrawn from use due to severe adverse reactions leading to life-threatening events and death.[10] Therefore, though the chance of an adverse reaction following the radiopharmaceutical agent's administration is less in comparison to conventional pharmaceutical agents, the possibility still exists. Hence, it is crucial to record any untoward occurrences associated with their use.

Our review article's content is based on a narrative literature review undertaken with the use of various scientific and pharmacovigilance databases. Our literature review focused mainly on the adverse reactions observed with some of the commonly used diagnostic radiopharmaceuticals [Table 1].
Table 1: Summary of adverse reactions and associated radiopharmaceuticals

Click here to view



   Adverse Reactions to Single-Photon-Emission Computed Tomography Radiopharmaceuticals Top


Technetium-99m methyl diphosphonate

99mTc methyl diphosphonate (99mTc-MDP) is a commonly used radiopharmaceutical for the bone scintigraphy. It is one of the common examples of radiopharmaceuticals that cause adverse effects. Erythema, nausea, vomiting, and malaise are typical adverse reactions associated with 99mTc-MDP.[11],[12],[13]

There are also reports of other types of reactions associated with 99mTc MDP. Garcia-Souto et al. had reported a skin reaction following the administration of 99mTc diphosphonate. In a patient referred for a bone scan, hyperpigmented linear lesions appeared at the injection site in the forearm after the bone scan. The patient did not have any history of trauma. The patient also did not have any pain or itching. The patient informed that lesions had resolved spontaneously, leaving slight residual hyperpigmentation at medical consultation.[14]

Similarly, Balan et al. had reported an incidence of severe systemic reaction in a 42-year-old female suffering from breast carcinoma following the administration of 99mTc MDP. After 24 h of 99mTc MDP injection, the patient sensed uneasiness. Subsequently, an erythematous rash was developed on the trunk and around the eyes accompanied by puffiness. She also developed oliguria and jaundice. His postscan biochemical test was compared with that of pre-scan, and the findings were suggestive of abnormal liver and kidney function. The patient was managed with a regime of intravenous fluids and corticosteroids, and her renal and live function became normal 15 and 21 days after the bone scan, respectively. Her skin manifestations resolved within 1 week.[15]

Technetium-99m SestaMIBI

99mTc SestaMIBI is commonly used for parathyroid scintigraphy and myocardial perfusion imaging. Many patients had developed adverse reactions following the administration of 99mTc-SestaMIBI. The reported adverse reactions include vomiting, malaise, and some severe reactions such as generalized exfoliative dermatitis, angioedema, and erythema multiforme.[16],[17] A case report by Thompson et al. describes an adverse reaction to 99mTc-SestaMIBI 48 h after administration. The patient developed an erythematous papulovesicular rash on the trunk, arms, and scalp with target lesions suggestive of erythema multiforme. The patient had no history of drug allergy or any dermatological disorders.[18] There are reports of patients developing angioedema and anaphylaxis following injection of 99mTc-SestaMIBI during nuclear stress testing for suspected coronary artery disease.[19],[20]

Technetium-99m sulfur colloid

99mTc-sulfur colloid is a commonly used radiopharmaceutical for liver/spleen scintigraphy, lymphoscintigraphy, and gastric emptying scintigraphy. Some of the common adverse events reported with the use of 99mTc-sulfur colloid were injection-site pain, fever, and mild hypersensitivity reaction. Rare serious adverse events were also reported with the administration of 99mTc-sulfur colloid. One patient developed an anaphylactic reaction followed by renal failure and another patient experienced a loss of consciousness.[16],[21]

Technetium-99m nanocolloid

99mTc-nanocolloid is used for sentinel node detection and bone marrow scintigraphy. It is used for bone marrow scintigraphy and lymphoscintigraphy. Adverse reaction to this radiopharmaceutical is uncommon. However, there are few reports of Type-1 hypersensitivity reaction manifested as urticaria, generalized, erythema, and angioedema following administration of 99mTc-nanocolloid.[22]

Technetium-99m technegas

99mTc-technegas is used for lung perfusion imaging. The adverse event associated with use of 99mTc-technegas was low oxygen saturation. A study done in series of patients undergoing ventilation scintigraphy transient decrease in oxygen saturation was observed in 87% of patients. In preoxygenated patients, fall in oxygen saturation was less than those who were not preoxygenated.[23]

Technetium-99m pertechnetate

99mTc-pertechnetate is used as a radiopharmaceutical for various indications such as thyroid scintigraphy, testicular scintigraphy, and Meckel diverticulum scan. There are many reports of adverse events following the administration of pertechnetate. The most common were hypersensitivity, rash, and nausea.[16] Two serious adverse events were also recorded in which two patients lost consciousness following the injection of 99mTc pertechnetate.[16]

Diagnostic 123I and 131I labeled tracers

Radioactive iodine is used in nuclear medicine practice to evaluate thyroid disorder such as hyperthyroidism, hypothyroidism, thyroiditis, goiter, and thyroid cancer. The most common adverse events reported with radioactive iodine use were nausea, vomiting, and back pain. The use of sodium iodide 131I also sometimes causes hypersensitivity reactions.[24]

A few patients developed anaphylactic shocks and ventricular tachycardia following the administration of 131I nor-cholesterol.[25] Similarly, few cases of were also reported along with the use of other 131I preparations such as 131I iodohippurate.[16]

Gallium-67 citrate

The use of gallium-67 (67Ga) citrate is not much after the widespread use of fluorodeoxyglucose (FDG) positron-emission tomography–computed tomography (PET-CT). 67Ga-citrate is used in the infection imaging, sarcoidosis diagnosis, and diagnosis of various malignancies such as Hodgkin's disease and lung cancer. Severe itching, erythema, and rash were observed in some patients following the administration of 67Ga. The rare occurrence of severe anaphylaxis reactions also has been reported in association with 67Ga use.

Schreuder et al. mentioned about 92 adverse events reported with 67Ga. Most of those were trivial events such as rash, pruritus, or fever. Only two patients had serious events: one developed bradycardia and another lost consciousness.[16],[26],[27]


   Adverse Events Associated with Positron-Emitting Tracers Top


18F-fluorodeoxyglucose

18F FDG PET-CT plays a vital role in detecting diagnosis, staging, restaging, and treatment response evaluation in various malignancies. It is also useful in infectious condition, cause of fever of unknown origin, and in cardiology and neurology. The common adverse events reported were minor nonserious reactions such as rash, pruritus, and erythema.[28],[29] However, Lee et al. had reported a case of anaphylactic reaction following the administration of FDG.[30] Silberstein had reported a case of adverse reaction where flushing of the face and trunk occurred a few minutes after the injection of FDG and resolved within 2 h of administration.[31]

18F-fluciclovine

US-FDA has approved 18F-fluciclovine in 2016 to image patients with suspected prostate cancer recurrence following treatment. Adverse reactions with 18F-fluciclovine is uncommon and observed in less than 1% of participants during clinical trials of 18F-fluciclovine.[32] The most common adverse reactions reported were dysgeusia and pain and erythema at the injection site.[33]

68Ga-DOTATATE

Gallium-68 (68Ga) DOTATATE is a somatostatin receptor analog and a PET diagnostic agent for diagnosis, staging, and response to treatment evaluation of somatostatin receptor-expressing tumors. Adverse events have been reported in patients using this agent. Deppen et al. have recorded three events: tachycardia, increase in serum transaminase enzyme, and increase in blood glucose level in four patients after injection of 68Ga-DOTATATE in 78 patients. These events were observed only for a short period.[34]

68Ga-DOTATOC

Four adverse events were reported in a study done to assess the safety and tolerability of 68Ga-DOTATOC in 20 patients with biopsy-proven Grade 1–2 gastroenteropancreatic neuroendocrine tumors and most of them were minor reactions such as rash and pruritus.[35],[36]


   Conclusion Top


The prevalence of ARRPs is relatively less frequent in comparison to conventional pharmaceutical agents. Most of the ARRPs found in the public domain were cases reported long ago. There are very few cases reported in recent times which suggest that the frequency of reaction ARRPs appears to be decreasing. The possible explanation could be due to improved quality control of radiopharmaceuticals in recent times. Another possible reason for the low frequency of adverse events in the public domain could be due to the under-reporting of associated adverse events. In general, under-reporting adverse events is a significant issue, whether with conventional pharmaceutical or radiopharmaceutical agents or medical devices.[3],[37] Medical professionals have cited multiple reasons for this under-reporting of adverse events associated with drugs or devices. One of the common reasons is the lack of awareness about the importance of adverse reaction reporting and the existing pharmacovigilance program.

As most of the diagnostic radiopharmaceutical agents are administered only once, rechallenge and test is mostly not feasible. Hence, it is difficult to establish the cause–effect relationship of an adverse event associated with radiopharmaceuticals. This review found that majority of the adverse reaction reported with diagnostic radiopharmaceuticals agents are minor reactions and resolved without any major complications. We have also observed that the incidences of reported adverse reactions are very few in comparison to the dose administered in a total number of patients. Many of the reported events were published in the literature many years back when quality control of radiopharmaceutical preparation was a big issue. Since then, it has improved considerably.

Although adverse reactions following the administration of radiopharmaceuticals to patients are rare, most of the time, they are nonfatal. However, it is still important to regularly record and report any suspected adverse events associated with their use as it will help detect unknown adverse events and create a database for future reference. Further, this will enhance nuclear medicine physician's knowledge of these ARRPs leading to better patient care.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200-5.  Back to cited text no. 1
    
2.
Rodríguez-Monguió R, Otero MJ, Rovira J. Assessing the economic impact of adverse drug effects. Pharmacoeconomics 2003;21:623-50.  Back to cited text no. 2
    
3.
Meher BR, Joshua N, Asha B, Mukherji D. A questionnaire based study to assess knowledge, attitude and practice of pharmacovigilance among undergraduate medical students in a Tertiary Care Teaching Hospital of South India. Perspect Clin Res 2015;6:217-21.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Radiopharmaceuticals. Available from: https://www.who.int/medicines/publications/pharmacopoeia/Radgenmono.pdf. [Last accessed on 2020 Apr 26].  Back to cited text no. 4
    
5.
Meher BR, Agrawal K, Padhy BM. The global perspective of pharmacovigilance in nuclear medicine practice. Indian J Nucl Med 2018;33:269-72.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
The Radiopharmacy. Available from: https://www.eanm.org/content-eanm/uploads/2016/11/tech_radiopharmacy.pdf. [Last accessed on 2020 Mar 15].  Back to cited text no. 6
    
7.
Santos-Oliveira R. Undesirable events with radiopharmaceuticals. Tohoku J Exp Med 2009;217:251-7.  Back to cited text no. 7
    
8.
Kennedy-Dixon TG, Gossell-Williams M, Cooper M, Trabelsi M, Vinjamuri S. Evaluation of radiopharmaceutical adverse reaction reports to the British Nuclear Medicine Society from 2007 to 2016. J Nucl Med 2017;58:2010-2.  Back to cited text no. 8
    
9.
Laroche ML, Quelven I, Mazère J, Merle L. Adverse reactions to radiopharmaceuticals in France: Analysis of the national pharmacovigilance database. Ann Pharmacother 2015;49:39-47.  Back to cited text no. 9
    
10.
Information for Healthcare Professionals-Technetium (99m Tc) Fanolesomab Marketed as NeutroSpec (12/2005). Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-healthcare-professionals-technetium-99m-tc-fanolesomab-marketed-neutrospec-122005. [Last accessed on 2020 May 12].  Back to cited text no. 10
    
11.
Hesslewood SR, Keeling DH. Frequency of adverse reactions to radiopharmaceuticals in Europe. Eur J Nucl Med 1997;24:1179-82.  Back to cited text no. 11
    
12.
Spicer JA, Preston DF, Stephens RL. Adverse allergic reaction to technetium-99m methylene diphosphonate. J Nucl Med 1985;26:373-4.  Back to cited text no. 12
    
13.
Mooser G, Gall H, Peter RU. Delayed-type allergy to technetium Tc 99m. Contact Dermatitis 1998;39:269-70.  Back to cited text no. 13
    
14.
Garcia-Souto F, Coronel-Perez IM, Crespo-Cruz A, Escudero-Ordoñez J. Cutaneous reaction following technetium-99 m diphosphonate administration: An exceptional case. J Eur Acad Dermatol Venereol 2020;34:e135-6.  Back to cited text no. 14
    
15.
Balan KK, Choudhary AK, Balan A, Wishart G. Severe systemic reaction to (99m) Tc-methylene diphosphonate: A case report. J Nucl Med Technol 2003;31:76-8.  Back to cited text no. 15
    
16.
Schreuder N, Koopman D, Jager PL, Kosterink JG, van Puijenbroek E. Adverse events of diagnostic radiopharmaceuticals: A systematic review. Semin Nucl Med 2019;49:382-410.  Back to cited text no. 16
    
17.
Doukaki S, Aricò M, Bongiorno MR. Erythroderma related to the administration of 99mTc-sestamibi: The first report. J Nucl Cardiol 2010;17:520-2.  Back to cited text no. 17
    
18.
Thomson LE, Allman KC. Erythema multiforme reaction to sestamibi. J Nucl Med 2001;42:534.  Back to cited text no. 18
    
19.
Makaryus JN, Makaryus AN, Azer V, Diamond JA. Angioedema after injection of Tc-99m sestamibi tracer during adenosine nuclear stress testing. J Nucl Cardiol 2008;15:e26-7.  Back to cited text no. 19
    
20.
Mujtaba B, Adenaike M, Yaganti V, Mujtaba N, Jain D. Anaphylactic reaction to Tc-99m sestamibi (Cardiolite) during pharmacologic myocardial perfusion imaging. J Nucl Cardiol 2007;14:256-8.  Back to cited text no. 20
    
21.
Block MB, Thompson JS, Polcyn RE: Anaphylactoid reaction to technetium-99m sulfur colloid stabilized with gelatin: Report of a case. Am J Dig Dis 1970;15:569-71.  Back to cited text no. 21
    
22.
Chicken DW, Mansouri R, Ell PJ, Keshtgar MR. Allergy to technetium-labelled nanocolloidal albumin for sentinel node identification. Ann R Coll Surg Engl 2007;89:W12-3.  Back to cited text no. 22
    
23.
James JM, Lloyd JJ, Leahy BC, Shields RA, Prescott MC, Testa HJ. The incidence and severity of hypoxia associated with 99Tcm Technegas ventilation scintigraphy and 99mTc MAA perfusion scintigraphy. Br J Radiol 1992;65:403-8.  Back to cited text no. 23
    
24.
Intravenous Radiocontrast Media: A Review of Allergic Reactions. Available from: https://www.uspharmacist.com/article/intravenous-radiocontrast-media-a-review-of-allergic-reactions. [Last accessed on 2020 May 04].  Back to cited text no. 24
    
25.
Maltby PJ, Smith ML. An adverse reaction to [6-131I] iodomethylnorcholestrol. Nucl Med Commun 2002;23:505-6.  Back to cited text no. 25
    
26.
Gallium Citrate Ga 67 Injection. For Diagnostic Use. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017478s016lbl.pdf. [Last accessed on 2020 May 02].  Back to cited text no. 26
    
27.
Commandeur C, Richard M, Renzi PM. Severe hypersensitivity reaction to injectable Gallium 67 in a worker exposed to silica. Allergy 1992;47:337-9.  Back to cited text no. 27
    
28.
Santos-Oliveira R, Fleming B. Are radiopharmaceuticals safe? The case of FDG-18. Adv Pharmacoepidem Drug Saf 2012;1:102.  Back to cited text no. 28
    
29.
Pinto SR, Santos LFC, Dos Reis SR, Bastos MK, Gomes VD, Vieira TO, et al. Adverse reactions to radiopharmaceuticals: A survey based on clinical cases using criteria of systematic review. Ther Innov Regul Sci 2018;52:109-13.  Back to cited text no. 29
    
30.
Lee DY, Lee JJ, Kwon HS, Moon WY, Jin SY, Lee SJ, et al. An unusual case of anaphylaxis after fluorine-18-labeled fluorodeoxyglucose injection. Nucl Med Mol Imaging 2013;47:201-4.  Back to cited text no. 30
    
31.
Silberstein EB. Prevalence of adverse events to radiopharmaceuticals from 2007 to 2011. J Nucl Med 2014;55:1308-10.  Back to cited text no. 31
    
32.
FDA Approves AXUMIN™ (fluciclovine F 18) Injection for Positron Emission Tomography (PET) Imaging in Men with Suspected Prostate Cancer Recurrence. Available from: https://www.accp1.org/ACCP1/5Publications_and_News/FDA_Approves_AXUMINTM_.aspx. [Last accessed on 2020 May 02].  Back to cited text no. 32
    
33.
Bach-Gansmo T, Nanni C, Nieh P, Zanoni L, Bogsrud T, Sletten H, et al. Staging of biochemically relapsing prostate cancer using the positron emission tomography tracer fluciclovine F18. Int J Radiat Oncol Biol Phys 2016;96:S112.  Back to cited text no. 33
    
34.
Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, et al. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med 2016;57:708-14.  Back to cited text no. 34
    
35.
Nam J. FDA Approves Lutetium Lu 177 Dotatate for Gastroenteropancreatic Neuroendocrine Tumors. Available from: https://www.cancertherapyadvisor.com/home/cancer-topics/gastrointestinal-cancers/fda-approves-lutetium-lu-177-dotatate-for-gastroenteropancreatic-neuroendocrine-tumors/. [Last accessed on 2020 May 06].  Back to cited text no. 35
    
36.
de Lima BM, de Carvalho JR, Gaspar PR, Pujatti PB, Gonçalves R. Liver Steatosis Secondary to PRRT with 177Lu-DOTATATE: An Unknown Adverse Effect. Clin Nucl Med 2020;45:374-6.  Back to cited text no. 36
    
37.
Meher BR. Materiovigilance: An Indian perspective. Perspect Clin Res 2018;9:175-8.  Back to cited text no. 37
[PUBMED]  [Full text]  



 
 
    Tables

  [Table 1]



 

Top
  
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Adverse Reaction...
    Adverse Events A...
   Conclusion
    References
    Article Tables

 Article Access Statistics
    Viewed342    
    Printed0    
    Emailed0    
    PDF Downloaded41    
    Comments [Add]    

Recommend this journal