SPECIAL CONTRIBUTION

Prevalence of Adverse Reactions in Nuclear MedicineEdward B. Silberstein, Janet Ryan and the Pharmacopeia Committee of the Society of Nuclear MedicineThe Eugene L. Saenger Radioisotope Laboratory, Division of Nuclear Medicine, Department of Radiology, University ofCincinnati Hospital, Cincinnati, Ohio

This investigation sought to determine the prevalence of adversereactions to radiopharmaceuticals and to nonradioactive drugs usedin interventional nuclear medicine. We also tabulated all adversereactions reported to manufacturers of radiopharmaceuticals commercially available in the United States. Methods: A prospective5-yr study was performed of 18 collaborating institutions using a

questionnaire which enumerated monthly the number of proceduresused and adverse reactions noted. An algorithm to determine thelevel of etiologic probability of an adverse reaction from an administered radiopharmaceutical was developed. We reviewed all available literature on adverse reactions in nuclear medicine. Results:During this period, 783,525 radiopharmaceutical and 67,835 nonradioactive drug administrations were analyzed. Ten of the 18 adversereactions to radiopharmaceuticals were rashes. No patient experiencing an adverse reaction to a radiopharmaceutical required hos-pitalization or had significant sequelae. Reproducibility of the adverse reactions algorithm was validated by independent evaluationof 30 adverse reaction reports from the U.S. Pharmacopeia-Societyof Nuclear Medicine adverse reaction reporting system. All adversereactions to 49 commercially available radiopharmaceuticals weretabulated and referenced. Conclusion: Radiopharmaceuticals havean excellent safety record. An algorithm to evaluate putative radio-pharmaceutical reactions is highly reproducible.

Key Words: adverse reactions;radiopharmaceuticalsJ NucíMed 1996; 37:185-192

U nlike drugs given for therapeutic purposes, radiopharmaceuticals rarely cause adverse reactions. The explanation for thesafety of radiopharmaceuticals lies not only in the very smallmass of drug injected or ingested, usually in the microgramrange, but also because radiopharmaceuticals are typicallyadministered only once or a very limited number of times to anygiven patient. The use of a radiopharmaceutical is not basedupon its ability to produce a pharmacological effect, but ratheron differences in the distribution and pharmacokinetics of theagent between normal and abnormal physiological processes. Infact, the production of pharmacological or physiological effectsby a radiopharmaceutical is undesirable since the agent shouldnot modify the parameter it is attempting to measure. Unusual("idiosyncratic") sensitivity to a pharmacologie effect is vir

tually never seen.Estimates of adverse reaction prevalence are difficult to

assess, partly because of physician ignorance of availablereporting schemes. In a recent study of 3000 randomly selectedphysicians, only 57% were aware of any adverse reactionreporting system. Whereas 14% of the total had observed anadverse drug reaction in the prior year, only 21, or 0.7% of thetotal, had reported the occurrence. There are many reasons fornot filling out adverse reaction reporting forms. Physicians maybe too busy, be concerned about the time required, not have theform readily available, be anxious about potential liability or

Received Aug. 30, 1995; revision accepted Oct. 11, 1995.For correspondence or reprint contact: E.B. Silberstein, MD, Division of Nuclear

Medicine, University of Cincinnati Hospital, 234 Goodman Street, P.O. Box 670577,Cincinnati, OH 45267-0577.

believe that the reaction is common knowledge (7 ). A reactionmay also be missed if the patient leaves the nuclear medicineservice before its occurrence (2 ). Confusion may also exist overthe basic definition of adverse reaction. For example, thedefinition used by the Food and Drug Administration (FDA) foradverse drug experiences precludes any consideration of causality and includes types of adverse reactions not relevant toradiopharmaceuticals.

The current reporting system for adverse reactions in nuclearmedicine has evolved over two decades in collaboration withthe United States Pharmacopeia (USP) and FDA (3-5). Since1986, the U.S.P. Drug Product Problem Reporting Program hasprovided, in cooperation with the Society of Nuclear Medicine(SNM), a form to be used for reporting both adverse reactionsand altered radiopharmaceutical biodistribution. A copy of eachcompleted report is sent to the FDA.

The prevalence of adverse reactions for radiopharmaceuticals, based on a variety of reporting systems and assumptions,has been estimated to range between 0.3 and 33/105 administrations (3,4,6-9). For comparison, the reaction frequency toradiographie contrast media ranges between 3.8%-12.7% (3.8-12.7/102) for ionic contrast and 0.6%-3.1% (0.6-3.1/102) for

nonionic contrast (10-13). Adverse drug reactions for all

administered drugs in the hospital setting have been measuredat 0.7%-1.5% or higher (14,15).

Estimation of the true frequency of adverse reactions isdifficult not only because of reporting problems but alsobecause the exact total number of doses administered is unknown. To obtain a more realistic estimate of the frequency ofadverse reactions to radiopharmaceuticals, the SNM's Pharma

copeia Committee undertook a 5-yr prospective study of theprevalence of adverse reactions to radiopharmaceuticals andinterventional drugs used in nuclear medicine beginning inSeptember 1989.

MATERIALS AND METHODSBy consensus, the Pharmacopeia Committee established the

following operational definition for an adverse reaction:

1. The reaction is a noxious and unintended clinical manifestation (symptoms, signs, laboratory data abnormalities) following the administration of a radiopharmaceutical or nonradioactive adjunct pharmaceutical.

2. The reaction is unanticipated from the known pharmacologieaction of the nonradioactive pharmaceutical.

3. The reaction is not the result of an overdose (which is amisadministration).

4. The reaction is not the result of injury caused by poorinjection technique.

5. The reaction is not caused by a vasovagal response (slowpulse and low blood pressure).

6. The reaction is not caused by deterministic effects of radiopharmaceuticals intended for therapeutic uses.

7. The definition excludes altered biodistribution which causesno symptoms, signs or laboratory abnormalities.

ADVERSEREACTIONSFROMRADIOPHARMACEUTICALS•Silberstein and Ryan 185

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Significant adverse reactions to be reported included:

1. Untoward effects whether previously reported frequently orrarely.

2. Untoward effects never before seen or reported followingadministration of the radiopharmaceutical.

3. Only life-threatening (i.e., requiring hospitalization) or fatalreactions from nonradioactive drugs (i.e., drugs used forpharmacologie intervention).

4. Reactions unanticipated from the known pharmacologie action of a nonradioactive interventional drug.

5. Anaphylactoid or allergic reactions.

Reactions not to be reported included:

1. Overdosages (misadministration).2. Vasovagal responses (reported in European registries).3. Injury from poor injection technique.4. Deterministic effects from therapy with unsealed sources

(e.g., myelosuppression from a therapeutic agent).

The Pharmacopeia Committee also addressed the problem ofcausality, the likelihood that an administered radiopharmaceuticalcauses an observed subsequent adverse reaction, by devising analgorithm which attempted to define the likelihood of an administered radiopharmaceutical leading to an observed adverse effect.Previous efforts devised for this purpose have been fraught withmultiple problems:

1. It is difficult to be absolutely and unequivocally certain thatan adverse reaction is or is not related to an injectedradiopharmaceutical because there is always an underlyingdisease for which the test has been ordered.

2. The reaction rate is extremely low, so there is no vastexperience with specific adverse reactions to radiopharma-ceuticals being reported.

3. Literature references to radiopharmaceuticals are commonlybased on case reports with no proof of causality.

4. The clinical and laboratory features of most reactions toradiopharmaceuticals are not unique.

5. Every radiopharmaceutical experience involves dechallengeor discontinuation of the drug following a single dose.

6. Rechallenge may not reproduce the adverse event, is notalways feasible and, under some circumstances, could beunethical.

AlgorithmThe following algorithm is suggested to categorize probabilities

of causation.Not Related. This category is applicable to those adverse

experiences which, after careful medical consideration, are judgedto be not related to the test material. Neither painful local sensationfrom drug infiltration nor hematoma at the injection site is anadverse reaction. An adverse experience may be considered causally not related if or when:

1. Only a vasovagal response to a radiopharmaceutical isdocumented (hypotension and slow pulse).

or, any three of the following are found:

2. It does not follow a reasonable time sequence from administration of the test material.

3. It could readily have been produced by the patient's clinical

state, environmental effects or toxic factors of other materialsadministered to the patient.

4. It does not follow a known response pattern to the suspectedtest material.

5. It does not reappear or worsen if the test material isreadministered.

Conditional, Unlikely or Remote. This category applies to thoseadverse experiences which, after careful medical consideration,cannot be placed in either "possibly related" or "not related"

categories. This definition is to be used when exclusion of drugcausality of a clinical event seems plausible but the precise criteriain the "not related" category cannot be met. It can represent the

first reported true side effect of a radiopharmaceutical, but since ithas never been reported before it would be registered in this categoryand would be moved to the "probable" list at a later time if more

reports of the same reaction occurred. An adverse experience may beconsidered causally conditional, remote or unlikely if or when:

1. It follows a reasonable time sequence but does not follow aknown response pattern to the test material administered.

2. It does not follow a reasonable time sequence from administration of the test material but does follow a knownresponse pattern to the suspected test material.

Possible (Must Have All Three of the Following Criteria). Thiscategory applies to those adverse experiences for which, aftercareful medical consideration, the causality of the adverse reactionby the radiopharmaceutical appears possible if or when:

1. It follows a reasonable time sequence from administration ofthe test material.

2. It follows a known response pattern to the suspected testmaterial.

3. It could also have been produced by the patient's clinical

state, environmental or toxic factors, other diagnostic ortherapeutic interventions, including other medications, contrast media, etc. administered to the patient.

Probable (Must Have First Two Plus Numbers 3 or 4). Thiscategory applies to these adverse experiences which, after carefulmedical consideration, are thought, with a high degree of certainty,to be related to the test material. Causality of an adverse experiencemay be considered probable if or when:

1. It follows a reasonable time sequence from administration ofthe test material.

2. It follows a known pattern of response to the suspected testmaterial.

3. It could not be reasonably explained solely by the knowncharacteristics of the patient's clinical state, environmental or

toxic factors or other medications, contrast media, etc.administered to the patient.

4. If rechallenge is medically necessary, the reaction recurs.

We independently rated 30 case reports from the SNM ReportingProgram for the level of causality to test the reproducibility of thisalgorithm.

Participating InstitutionsOn a prospective basis, a total of 18 institutions (Appendix A)

that perform a high volume of nuclear medicine procedurescompleted and returned a form (Appendix B) indicating thenumber of radiopharmaceuticals and interventional pharmacologieadministrations each month. Reported adverse reactions to specificradiopharmaceuticals by these institutions were investigated using thecategories for causation described above. All reactions we have listedfulfilled the criteria for "possible" or "probable" adverse reactions.

In addition, we tabulated all adverse reactions reported for eachradiotracer commercially available in the United States in 1995 ina matrix format which references all reported reactions. We wereunable to classify the degree of association of these tabulatedreported reactions with the allegedly causative radiotracer becausethere was not always enough clinical information.

186 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 1 •January 1996

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TABLE 1Adverse Reactions to 783,525 Radiopharmaceutical Dosages in

the Study Population 1989-1994

TABLE 3Prevalence of Adverse Reactions in Nuclear Medicine

Radiopharmaceutical Adverse reactionNumberof cases

^Gajgallium citrate[131l]iobenguane(MIBG)

"Tc-macroaggregated

albumin (MAA)""Tc-medronate (MDP)

"Tc-oxidronate (HDP)

"Tc-pentetate (DTPA)"Tc-sestamibi

Stannous pyrophosphate(nonradioactive)*

""Tc-sulfur colloid

Total

RashChest discomfort,light headednessRash

RashNauseaMild anaphylaxisRashDiaphoresisRashRashMild anaphylaxis

Light headednessNausea, vomiting,rash, headache

21141112

11

18

'Administered intravenously to permit in vivo radiolabeling of erythrocytes

and considered part of the final radiophanmaceutical.

RESULTSWe found 100% agreement on the classifications of the 30

cases analyzed from the SNM-U.S.P. Drug Problem ReportingProgram using the described algorithm. Table 1 summarized 18adverse reactions to radiopharmaceuticals in the "possible" or"probable" categories based on 783,525 injections. None of

these was severe enough to cause hospitalization. The 95%confidence limits for the prevalence of such reactions is 1.2-3.4per 100,000 injections. For interventional drugs, we recordedonly adverse reactions leading to hospitalization (Table 2).There were no deaths. The 95% confidence limits for thesereactions are 0.1-11.7 per 100,000 injections. Table 3 lists theprevalence of adverse reactions to both radiopharmaceuticalsand nonradioactive Pharmaceuticals appear. None of these wassevere. In no case was hospitalization required and there wereno sequelae.

Table 4 lists all referenced adverse reactions to commerciallyavailable radiopharmaceuticals.

DISCUSSIONThe FDA uses the term adverse drug experience rather than

adverse reaction and defines this as "any adverse event asso

ciated with the use of a drug in humans, whether or notconsidered drug related, including the following: an adverseevent occurring in the course of the use of a drug product in

TABLE 2Severe Adverse Reactions to 67,835 Doses of Nonradioactive

Pharmaceuticals Used in Nuclear Medicine

DrugDipyridamoleGlucagon

TotalReactionProlonged

chest painSyncopeModerate anaphylaxisNumber

ofcases2

11

4

Total 95%adverse Total confidencereactions dosages Prevalence limits

RadiopharmaceuticalsNonradioactive drugs18 4773,52567,8352.3/1055.9/1 0s1.

2-3.4/1 050.1-11.7/1 0s

professional practice; an adverse event occurring from drugoverdose, whether accidental or intentional; an adverse eventoccurring from drug withdrawal; and any significant failure ofexpected pharmacologie action" (16). Radiopharmaceutical

manufacturers are bound by this definition. It precludes, however, any consideration of causality and includes types ofreactions not relevant to nuclear medicine. It was for thesereasons that we developed a definition for adverse reactions thatpermits one to obtain a true estimate of the frequency of patientadverse reactions to radiopharmaceuticals.

Use of the prospective study approach with the 18 collaborating institutions guaranteed a reliable numerator and denominator for the frequency of adverse reactions. Our results (Table3) are in the lower range of previous reported estimates. Noneof the observed reactions to radiopharmaceuticals were severe,requiring or prolonging hospitalization. There were no sequelaeof any adverse reactions. Adverse reactions to radiopharmaceuticals are quite uncommon, occurring with a prevalence of2.3/105 in our study (0.0023%). Interventional pharmaceuticals

(not tracers) used in nuclear medicine were also quite safe, withthe risk of hospitalization following administration to be only of5.9/105. No lethal reactions occurred.

Moreover, we agreed on the classification of all 30 adversereaction reports from the Society of Nuclear Medicine-U.S.P.Drug Problem Reporting Program, which further validates ouralgorithm.

The radiopharmaceuticals most commonly linked to adverse reactions over the past decade include 99mTc-sulfurcolloid, 99mTc-methylene and hydroxymethylene diphospho-

nates (bisphosphonates) and Tc-human albumin micro-spheres, which is no longer produced. Any adverse event notpreviously described must be registered if there is even aremote chance of a causal relationship. The probability ofcausation between radiopharmaceuticals and effect will increase as more examples of the reaction are reported.

CONCLUSIONA prospective 5-yr study of the incidence of adverse reactions

to radiopharmaceuticals and nonradioactive drugs used asadjuncts in nuclear medicine procedures was conducted by theSNM Pharmacopeia Committee. The total number of radiophar-maceutical and adjunct nonradioactive drug injections duringthis time period were 783,525 and 67,835, respectively. Thetotal number of adverse reactions for radiopharmaceuticals andadjunct nonradioactive drugs were 18 and 4, respectively. Theincidence rate for adverse reactions for radiopharmaceuticalsand adjunct nonradioactive drug injections were 0.0023% and0.0059%, respectively. These incident rates are 1000 timeslower than that reported for x-ray contrast media and for drugsadministered in a hospital setting.

Ten of the 18 adverse reactions reported in this study wererashes. None of the patients exhibiting an adverse reaction to aradiopharmaceutical required hospitalization; nor did any patient exhibit any lasting symptoms or sequelae. Interventional

ADVERSEREACTIONSFROMRADIOPHARMACEUTICALS•Silberstein and Ryan 187

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ADVERSEREACTIONSFROMRADIOPHARMACEUTICALS•Silberstein and Ryan 191

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Pharmaceuticals used as an adjunct to the nuclear medicineprocedure can rarely lead to temporary hospitalization but at aprevalence of about 6 per 100,000 injections. None of thesepatients exhibited any sequelae.

APPENDIX A

Collaborating InstitutionsUniversity of Alabama, Birmingham, AL; M.D. Anderson

Cancer Center, Houston, TX; University Hospitals of Cleveland, Cleveland, OH; Cornell Medical Center, New York, NY;Dana Farber Cancer Center, Boston, MA; Duke UniversityMedical Center, Durham, NC; Cross Cancer Center, Edmonton,Alberta; Indiana University, Indianapolis, IN; University ofIowa, Iowa City, IA; University of Kentucky, Lexington, KY;Mallinckrodt Institute of Radiology, St. Louis, MO; MarshfieldClinic, Marshfield, WI; Massachusetts General Hospital, Boston, MA; Mayo Clinic, Rochester, MN; State University of NewYork, Syracuse, NY; Temple University Hospital, Philadelphia,PA; Univerity of Utah, Salt Lake City, UT; and Department ofVeterans Affairs Hospital, Bay Pines, FL.

APPENDIX B

Monthly Radiopharmaceutical and Adverse ReactionReporting Form

Society of Nuclear MedicinePharmacopeia Committee

Institution Month Year1.

2. Total radiopharmaceutical doses for month (include IND,NDA and all other radioactive drugs and biologies fordiagnosis and therapy)

3. Adverse reactions to radiopharmaceuticals:Yes No Date(If yes, describe with attached copy of U.S.P. DrugProduct Problem Reporting Program form, which detailsthe radiopharmaceutical, dose, route, reaction, etc.).

4. Total nonradioactive pharmaceutical doses for monthused for procedures (include dipyridamole, adenosine,etc.)

5. Total nonradioactive pharmaceutical reactions causinghospitalization or death

6. Person completing form

Please Print Phone Date

Definition of Adverse ReactionPatient adverse drug reaction is any response to a drug which isnoxious and unintended, occurring at doses used in man forprophylaxis, diagnosis, therapy of disease, or for modification ofphysiological function.

Significant adverse drug reactions which should be reportedinclude:

1. Untoward effects whether observed frequently or rarely.2. Untoward effects never before seen following administration

of the radiopharmaceutical.3. Only life-threatening (requiring hospitalization) or fatal reac

tions from nonradiopharmaceuticals (i.e., interventional drugs).4. Reactions unanticipated from the known pharmacologie ac

tion of a nonradioactive pharmaceutical.5. Anaphylactoid or allergic reactions.

Do not report reactions from:

1. Overdose (this is a misadministration).2. Vasovagal response.3. Injury from poor injection technique.4. Deterministic effects from therapy with unsealed sources

(e.g., myelosuppression from a therapeutic agent).

ACKNOWLEDGMENTSWe thank the many members of the Pharmacopeia Committee,

SNM for their assistance from 1989 to 1995, especially Henry H.Kramer, PhD, Dennis Swanson, DPh and Gopal Subramanian,PhD.

REFERENCES! Rogers AS. Israel E, Smith CR, et al. Physician knowledge, attitudes and behavior

related to reporting adverse drug events. Arch intern Med 1988;I48:1596-1600.

2. Sampson CB, Hesslewood SR. Adverse reactions to and drug incompatibilities withradiopharmaceuticals In: Theobold AE, ed. Radiopharmaceuticals: using radioactivecompounds in pharmaceutics and medicine. Chichester, U.K.: Ellis Horwood Co.;1989;132-151.

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192 THE JOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 1 •January 1996

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1996;37:185-192.J Nucl Med.   Edward B. Silberstein, Janet Ryan and Pharmacopeia Committee of the Society of Nuclear Medicine  Prevalence of Adverse Reactions in Nuclear Medicine

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