[123I]I-Ioflupane. The literature has described several reactions associated with the administration of this medicinal product. The most common effect is rash, pain at the injection site, pruritus, and erythema6. In a safety analysis, Grosset et al.18 noted that 643 ARs were reported out of 1,180 safety evaluable patients. The number of patients with at least 1 ADR was 261 (22%). The number of patients with at least 1 ARR leading to discontinuation from the study was 14 (1%), leading to death was 5 (< 1%), and considered a serious ADR was 44 (4%). The following ARRs were considered to be causally related to the radiopharmaceutical: headache (1%), nausea (< 1%), vertigo, dry mouth, hunger, injection site hematoma, dizziness, paraesthesia, balance disorder, and dysgeusia. [123I]I-oflupane is a well-tolerated radiopharmaceutical that has no causal relationship with serious ARs6,18.

These compounds are grouped under the name “diphosphonates” due to their basic chemical structure, all of which are labelled with technetium6. These compounds include [99mTc]Tc-oxidronate ([99mTc]Tc-HDP), [99mTc] Tc-medronate ([99mTc]Tc-MDP), and [99mTc]Tc-DPD (diisopropyl diphosphonate) and are characterised by their involvement in more ARs than other radiopharmaceuticals15. One reason for this may be because they have been the most widely used radiopharmaceuticals in nuclear medicine for many years. The most frequent ARs associated with this group are erythematous maculopapular rashes, dermographism, vertigo, nausea, pruritus, hypotension, fever, and nasal congestion6,15,19,20.

The most commonly reported ARs of [99mTc]Tc-HDP are rash, oedema, and pruritus. There are also reports of respiratory arrest, loss of consciousness after injection, angioedema and anaphylactic shock6, allergic dermatitis, acute generalised pustulosis, and gastrointestinal disorders19.

Pérez Iruela et al.21 reported an ARR after re-exposure with [99mTc]Tc-HDP in a 43-year-old female patient who had attended a NMS for a bone scan, where she was administered a dose of 740 MBq of [99mTc]-HDP. The patient had no previous history of drug or food allergy. Seven months later, she underwent a new gammagraphic study to follow up her disease. She was administered a new dose of 740 MBq of [99mTc]-HDP, which triggered the ARR in the form of a neck rash accompanied by pruritus, headache, and a tingling sensation on the scalp, nose, and upper lip. She promptly reported these symptoms to the medical staff of the department.

Santos-Oliveira et al.9 reported an ARR that occurred when a patient underwent a bone scan with [99mTc]Tc-MDP. Within 48 hours of administration, she developed a scratchy sore throat, intense pruritus, and an erythematous rash which persisted for 3 to 4 days. After 10 months, she underwent another bone scan with the same radiopharmaceutical, and after 48 hours she developed a sore throat and a macular-papulo rash with pruritus and erythema. Over the passage of a few hours, other symptoms appeared, such as conjunctivitis and hyperemic ulcerated pharynx. Finally, she was given a diagnosis of erythema multiforme due to exposure to the radiopharmaceutical.

The development of a skin rash with [99mTc]MDP is the most common allergic reaction reported for this radiopharmaceutical6,9. It is also the most widely used diphosphonate in nuclear medicine and accounts for the majority of ARRs6,7,9,19,22. The most common symptoms following an AR to [99mTc] MDP are dermographism, nausea, malaise, vertigo, and pruritus.

[99mTc]Tc-Pentetate (diethylenetriaminepentaacetic acid, [99mTc]Tc-DTPA). Cases of paralysis after intrathecal injection have been described. Thus, the Radiopharmacy Committee of the European Association of Nuclear Medicine issued a notice to manufacturers requesting them to specify the prohibition of intrathecal use in the SPC16. In fact, in Europe, this type of severe reaction has been associated with the administration of [99mTc]Tc-DTPA due to the erroneous formulation of the drug. Almost all of its formulations used for renal studies contain a mixture of the calcium and sodium salt of DTPA and must be administered intravenously. However, a manufacturing laboratory used a trisodium salt, which caused severe paraesthesia and double incontinence in 2 patients when this radiopharmaceutical was administered intrathecally16. Animal studies23 have shown that trisodium salt is able to chelate calcium and magnesium from the cerebrospinal fluid when administered intrathecally, thus depleting ions from the cerebrospinal fluid, which was the cause of paralysis in these 2 patients15,16. This radiopharmaceutical is only authorized for intravenous, oral, and inhalation administration24 and not for intrathecal administration. Thus, the 2 patients experienced a medication error that led to a severe ARR.

[99mTc]Tc-albumin nanocolloid. This compound is used in lymphoscintigraphy for sentinel lymph node detection in pre-surgery scans for specific tumours25. Hives has been described as the most common AR to albumin colloids6,16,20,24.

Cotrina-Monroy et al.25 performed the intradermal administration of 74 MBq of [99mTc]-albumin nanocolloid in the periareolar region in a patient undergoing surgical excision of a sentinel lymph node. After 10 minutes, the patient developed an allergic reaction with macular lesions and intense itching on the palms of the hands, forearms, arms, and anterior chest region, which subsided spontaneously within a few minutes. The patient had no previous history of sensitivity to human albumin. The macular lesions and intense pruritus subsided spontaneously without the administration of steroids or antihistamines.

This radiopharmaceutical is also used for scintigraphic studies of the liver, spleen, and bone marrow16. ARRs associated with these scans include pallor, flushing, hypotension, bronchospasm, and dyspnoea16.

[99mTc]Tc-MAA (macroaggregated albumin). The most frequently described ARs to this compund6,16,20 are hypersensitivity, dyspnoea, dizziness, rash, and vomiting. Other ARs include angioedema, cardiac arrest, bradycardia, and respiratory arrest. Three deaths have also been reported6. Of these, two patients had a history of pulmonary hypertension and one had a history of advanced pulmonary vascular disease. The ARs were probably caused by the number and size of the particles6.

In patients with normal pulmonary vascular beds, the administered dose of [99mTc]Tc-MAA would be 0.1 mg to 4 mg with a particle size of 10 m to 50 m, which would produce an occlusion of 0.1% of the cross-sectional area of the pulmonary vascular bed26. When a patient has a disease involving a reduced number of pulmonary capillaries, blocking part of the remaining capillaries can lead to respiratory stress. Because of size differences between particles, larger particles will occlude larger vessels, which involves extra care in patients with pulmonary hypertension or other diffuse pulmonary pathologies. In these cases, the dose to be administered should be appropriately calculated according to the number of particles and slowly administered intravenously7.

[18F]Fluorodeoxyglucose ([18F]FDG). Recently, [18F]-FDG Positron Emission Tomography (PET) scans have begun to play an important role in the assessment of chemotherapy response and in the detection of primary tumours and metastatic lesions in many tumours9. The most commonly described ARs are rash, pruritus, and erythema6, anaphylactic reaction, angioedema, exfoliative dermatitis, seizures, sweating, nausea, vomiting, and diarrhoea27, and two cases of cardiac arrest resulting in death6.

The first reported AR to this compound was provided by Silberstein28. This author described the symptomatology as flushing of the face and trunk that appeared minutes after administration and lasted less than 2 hours.

In addition to the cutaneous ARR mentioned above, other authors19 have described angioedema, exfoliative dermatitis, hyperhidrosis, local reactions, dysgeusia, and convulsions. Two deaths associated with its use have also been reported19. Rocha et al.22 described an ARR to [18F]FDG in a patient undergoing PET scanning that showed tracer accumulation in the tumour and a mediastinal nodule. Biopsy of the nodule showed a sarcoid reaction and no pathological tumour cells were found. The altered biodistribution of the radiopharmaceutical was reported as an ARR.

[131I]Norcholesterol. This radiopharmaceutical has been on the market for more than 30 years29 and its management is well known. It is a norepine-phrine analogue used for adrenal scintigraphic imaging studies in primary aldosteronism and pheochromocytoma. Published ARs suggest the involvement of the adrenergic nervous system, given that some of the ARs resemble pheochromocytoma symptoms30 (increased blood pressure, tachycardia, dyspnoea, sweating, etc.). It often produces mild ARs, the most common being nausea, back pain, and flushing6. Other reports include cases of anaphylactic shock 15 minutes after injection, ventricular tachycardia, and one case of an atypical anaphylactic reaction6,20.

Kazerooni et al.31 described an ARR that required treatment in a 21-year-old patient with a history of ARs to multiple procedures. The patient developed nausea and dizziness at the end of a slow injection of 74 MBq [131I] Norcholesterol. This was accompanied by flushing, headache, shortness of breath, chest and back pain, loss of consciousness for 10 to 20 seconds, tachycardia, and hypertension. After receiving oral diphenhydramine, her symptoms disappeared within 1 hour and her vital signs stabilised. According to the authors31, other patients received injections of the same batch number without experiencing ARs.

Spyridonidis et al.29 assessed the efficacy of [131I]Norcholesterol in a study that reported two cases of AR. In the first case, a 73-year-old woman underwent a [131I]Norcholesterol scan to diagnose an inci-dentaloma. The patient had received premedication for the scan with oral potassium iodate 24 hours before tracer injection, as indicated in the Summary of Product Characteristics (SPC)32. As soon as the tracer infusion started, she developed flushing, chest tightness, increased blood pressure (160/90 mmHg) —although the patient had no history of hypertension— and severe lower back pain at the level of the kidneys. The radiopharmaceutical infusion was discontinued, and hydrocortisone and antihistamine were administered. The patient was transferred to the Emergency Department, but clinical examination showed no significant findings. After a few hours of observation, she was discharged in good clinical condition.

The second case29 occurred in a 57-year-old woman with an incidentaloma. She had also received premedication with oral potassium iodate. Within 3 to 5 minutes after the end of the slow tracer infusion, she developed chest discomfort and lower back pain. The symptoms were not as intense as in the previous case. The lower back pain lasted for about 20 minutes. She did not require any rescue medication. The patient was discharged from the Emergency Department half an hour later. The authors commented that it did not appear to be a pure anaphylactic reaction29. They also noted that in the first case there was an increase in blood pressure, which is not very common in anaphylaxis and unexplained back pain, whereas in the second case the characteristic feature was chest tightness (not associated with bronchospasm). The reported chest tightness, lower back pain, and flushing are described in the SPC of the drug32. These specific symptoms have been attributed to [131I]Norcholesterol as well as others, such as nausea, vomiting, erythema, respiratory reaction, dyspnoea, tachycardia, dizziness, headache, diaphoresis, facial swelling, abdominal pain, metallic taste, and tongue insensitivity32.

According to some authors29, there is a significantly higher incidence of ARRs to [131I]Norcholesterol than to other radiopharmaceuticals more commonly used in nuclear medicine.

Radiosynovectomy in arthritis and synovitis using [90Y]Yttrium citrate and [186Re]Rhenium sulphide is associated with very moderate ARs, which are limited to transient aggravation of pain in a few patients and, very rarely, radionecrosis33. Hung et al.30 published a case of severe skin ulceration due to [90Y]Yttrium chloride therapy which, after 1 hour of administration, was accidentally deposited in the perivascular tissue of the forearm, which necessitated a 2-centimetre surgical excision of the ulcerated area.

[131I]Iobenguane (MIBG; metaiodobenzylguanidine). At low doses this compound is used for diagnosis, whereas at high doses it is administered for therapy. Several cases of ARs have been published6,20,34. A Japanese survey of reported ARRs was conducted between 2000 and 200134. A notable case occurred in a 35-year-old man who presented at a routine medical check-up with hypertension and increased adrenaline secretion. He had no history of allergic reactions. A diagnostic dose of 20 MBq [131I]-MIBG was administered to detect the presence of a possible pheochromocytoma. Within 18 hours of administration, the patient developed a symmetrical erythematous maculopapular rash on both sides of the chest walls, elbows, neck, and face, suggestive of erythema multiforme due to an ARR. Intravenous injection and oral administration of hydrocortisone and olopatadine drastically reduced the rash within 1 day, and oral administration of loratadine completely resolved it 13 days after symptom onset. Based on the sequence of events and the symptomatology, diagnosis was an allergic reaction to [131I]-MIBG.

Intravenous injectables of [131I]-MIBG contain excipients such as acetic acid, sodium acetate, and sodium chloride. There have been reports of hypersensitivity to the ethanol metabolite, acetic acid, sodium acetate and sodium chloride, although this response is extremely rare. If a patient has a history of this type of reaction to these substances further allergic reactions may be expected34.

[131I]INa. This radiopharmaceutical does not usually cause ARs in itself because it is an iodised salt. However, its formulation as a hard gelatin capsule may contain some excipients (sodium thiosulphate pentahydrate, disodium phosphate dihydrate, sodium hydroxide) that can cause reactions35. Most of the ARs to this radiopharmaceutical are caused by the beta radiation of the isotope at high doses36. Jané-Soler et al.36 reported an AR to this radiopharmaceutical after ablative treatment with a therapeutic dose of 5550 MBq [131I]INa in a woman who had undergone surgery for papillary thyroid carcinoma following the administration of recombinant TSH. Six days after administration, the patient began to experience difficulty swallowing and oropharyngeal and oesophageal pain accompanied by erythema and ulcerative lesions at these levels, suggestive of oropharyngeal and oesophageal mucositis. She was treated with corticosteroids and antifungals and the symptoms resolved 3 months after their onset. The authors suggested that the symptoms indicated a mucosal response to the high level of radiation received, given that [131I]INa has a tendency to accumulate in the salivary glands and subsequently can be secreted into the oral cavity and pharynx, thus reaching the oesophagus by swallowing.

Table 1 summarises other ARRs published in the scientific literature.