The importance of early identification of infusion-related reactions to monoclonal antibodies

Figures & data

Table 1 IRRs reported in the technical files of all mAb drugs

L. ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS L01. ANTINEOPLASTIC AGENTS
ATC code	Drug (brand name)	IRRs	Frequency	Prevention/treatment
L01X. OTHER ANTINEOPLASTIC AGENTS L01XC. Monoclonal Antibodies
02	Rituximab (MabThera^®)	Headache, itching, sore throat, Redness, rashes, urticaria, hypertension and fever.* Generalized edema, bronchospasm, wheezing, laryngeal edema, angioneurotic edema, generalized pruritus, anaphylaxis, anaphylactoid reaction.**	*Very common **Uncommon	Pre-medication is advised with analgesic/antipyretic and antihistamine drug. Methylprednisolone i.v. may also be useful before the infusion to lower incidence rate and severity of IRRs. Mild or moderate IRRs are solved by reducing infusion speed.
03	Trastuzumab (Herceptin^®)	Chills, fever, dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation, respiratory distress, rash, nausea, vomiting and headache.	Very common	In case of IRR stop or slowdown infusion and monitor the patient until the resolution of all observed symptoms. Symptoms can be treated with analgesic/antipyretic as meperidine or paracetamol, as well as an antihistaminic agent (diphenhydramine) Severe IRRs were satisfactory treated with support measures such as oxygen, beta-agonists and corticoids.
05	Gemtuzumab (Mylotarg^®)	Fever, chills, hypotension, tachycardia and respiratory symptoms.	Common	Perform perfusion under close clinical supervision, including control of pulse, blood pressure and temperature. Pre-medication with a corticosteroid, antihistamine and paracetamol is recommended 1 hr before administration.
06	Cetuximab (Erbitux^®)	Bronchospasm, urticaria, increased or decreased blood pressure, loss of consciousness or shock.	Very common (mild and moderate) Common (severe)	In case of severe IRRs, it is mandatory to stop infusion and possibly withdraw permanently. Emergency treatment or measures may be needed. The first dose must be slowly infused and speed must not be >5 mg/min while vital signs are monitored for at least 2 hrs. If any reaction related with the infusion is observed during the first 15 mins of the first administration, the infusion must be stopped.
07	Bevacizumab (Avastin^®)	Dyspnea/shortness of breath, flushing/redness/rash, hypotension o hypertension, oxygen desaturation, chest pain, shivering and nausea/vomiting.	Common	If any reaction related with the infusion is observed, the infusion must be stopped and suitable medical treatment and support immediately administered. Pre-medication is not systematically considered as necessary.
08	Panitumumab (Vectibix^®)	Shivering, fever or dyspnea.	Uncommon	In case of severe IRRs, or a life-threatening reaction, it is mandatory to stop infusion and possibly withdraw permanently. In mild or moderate IRRs it is advisable to slowdown infusion.
11	Ipilimumab (Yervoy^®)	Is not specified.	Common	In case of mild or moderate IRRs patients can receive ipilimumab in combination with nivolumab with close monitoring and pre-medication according to local prophylactic treatment guidelines. In case of severe IRR the infusion of ipilimumab or ipilimumab in combination with nivolumab should be discontinued and appropriate medical treatment should be administered.
12	Brentuximab vedotin (Adcetris^®)	Rash, shortness of breath, breathless sensation, chest tightness, fever and back pain.	Very common	If an IRR occurs, the infusion should be discontinued and appropriate medical treatment instituted. The infusion can be restarted at a slower rate after resolution of symptoms. Patients who have undergone a previous IRR should be pre-medicated before the following infusions (paracetamol, antihistamine and corticosteroid).
13	Pertuzumab (Perjeta^®)	Fever, shivering, tiredness, headache, asthenia, hypersensibility and vomiting.	Very common	If an IRR occurs, the infusion should be discontinued and appropriate medical treatment instituted. Treatment with oxygen, beta-agonists, antihistamines, iv. fluids and antipyretics can help to relieve symptoms.
14	Trastuzumab emtansine (Kadcyla^®)	Flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm and tachycardia.	Common	If an IRR occurs, the infusion should be discontinued and appropriate medical treatment instituted. The treatment must be stopped and withdrawn in case of severe IRRs.
15	Obinutuzumab (Gazyvaro^®)	Nausea, shivering, hypotension, pyrexia, vomiting, dyspnea, redness, hypertension, headache, tachycardia and diarrhea, bronchospasm, laryngeal irritation, wheezing, laryngeal edema and auricular fibrillation.	Very common	Stop antihypertensive treatment 12 hrs before each infusion. In the case of Grade 4 IRRs, the infusion should be stopped and treatment discontinued permanently. In the case of Grade 3 IRRs, the infusion should be temporarily discontinued and appropriate medication given to treat the symptoms. In the case of Grades 1 and 2 IRR, the infusion rate should be reduced and the symptoms treated appropriately.
16	Dinutuximab (Qarziba^®)	Fever, hypotension, urticaria, bronchospasm.	Very common (hypersensitivity and CRS) Common (anaphylaxis)	Pre-medication with antihistaminic iv should be administered (eg diphenhydramine) approximately 20 mins before the start of each infusion. It is recommended to repeat the administration of antihistamine medication every 4–6 hrs as needed during perfusion.
17	Nivolumab (Opdivo^®)	Is not specified.	Common	In case of mild or moderate IRRs can receive nivolumab or nivolumab in combination with ipilimumab with close monitoring and pre-medication according to local prophylactic treatment guidelines. In case of severe IRRs, nivolumab or nivolumab in combination with ipilimumab should be discontinued and appropriate medical treatment should be administered.
18	Pembrolizumab (Keytruda^®)	Hypersensitivity, anaphylactic shock, and CRS.	Common	In case of mild or moderate IRR, patients can continue to receive pembrolizumab with close monitoring; you can assess the previous medication with antipyretics and antihistamines. In severe infusion reactions, the infusion should be stopped and pembrolizumab should be permanently discontinued.
19	Blinatumomab (Blincyto^®)	Pyrexia, CRS, hypotension, myalgia, acute kidney injury, hypertension, and erythematous rash. Infusion reactions may be clinically indistinguishable from the manifestations of CRS.	Very common	The use of antipyretics (eg, paracetamol) is recommended to help in reducing pyrexia during the first 48 hrs of each cycle.
21	Ramucirumab (Cyramza^®)	Tremors, spasms/back pain, pain and/or chest tightness, chills, flushing, dyspnea, wheezing, hypoxia and paresthesias, bronchospasm, supraventricular tachycardia and hypotension.	Is not specified	The administration of a histamine H1 antagonist (eg diphenhydramine) is recommended as a pre-infusion medication. If a patient presents IRRs of Grade 1 or 2, he/she must receive previous histamine/antipyretic medication in all subsequent infusions. Dexamethasone (or equivalent) should be administered if a patient has a second IRR of Grade 1 or 2. For the following infusions, previously administer a histamine H1 antagonist iv (diphenhydramine), paracetamol and dexamethasone.
22	Necitumumab (Portrazza^®)	Chills, fever or dyspnea.	Common	In case of previous hypersensitivity or IRR of Grade 1 or 2, pre-medication with a corticosteroid and an antipyretic is recommended in addition to an antihistamine.
23	Elotuzumab (Empliciti^®)	Fever, chills and hypertension.	Common	Pre-medication should be administered 45–90 mins before perfusion: Dexamethasone 8 mg iv, diphenhydramine (25–50 mg vo or iv) or equivalent, ranitidine (50 mg iv or 150 mg vo) or equivalent, paracetamol (650–1000 mg vo).
24	Daratumumab (Darzalex^®)	Nasal congestion, cough, chills, throat irritation, vomiting, nausea, bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension.	Very common	Pre-medication with antihistamine, antipyretics and corticosteroids should be administered to reduce the risk of IRR before treatment. The perfusion should be discontinued at any IRR of any intensity and medical/supportive treatment should be instituted as appropriate. In patients with IRR of Grade 1, 2 or 3, when the perfusion is resumed, the perfusion rate should be reduced.
26	Inotuzumab ozogamicin (Besponsa^®)	Hypotension, hot flashes or respiratory problems.	Very common	Depending on the severity of the IRR, consider the interruption of the perfusion or the administration of steroids and antihistamines. In case of serious or life-threatening reactions due to perfusion, stop treatment permanently.
27	Olaratumab (Lartruvo^®)	Chills, fever or dyspnea.	Very common	Pre-medication with antihistamine (eg diphenhydramine) and dexamethasone iv should be administered 30–60 mins before perfusion.
L04. IMMUNOSUPPRESSANTS L04A. IMMUNOSUPPRESSANTS L04AA. Selective immunosuppressants
23	Natalizumab (Tysabri^®)	Dizziness, nausea, urticaria and tremors.	Very common (urticaria) Uncommon (hypersensitivity)	No measures are specified.
25	Eculizumab (Soliris^®)	Is not specified.	Uncommon	In all cases of patients with severe IRR, the administration of eculizumab should be stopped, and appropriate medical treatment should be instituted.
26	Belimumab (Benlysta^®)	Bradycardia, myalgia, headache, rash, urticaria, pyrexia, hypotension, hypertension, dizziness, and arthralgia.	Common	If an IRR occurs, the infusion should be discontinued and appropriate medical treatment instituted. Pre-medication can be administered (antihistamine with or without an antipyretic). Sufficient data is not available at the moment to establish whether pre-medication can reduce frequency or minimize the severity of IRRs.
33	Vedolizumab (Entyvio^®)	Dyspnea, bronchospasm, urticaria, redness, rash, hypertension and tachycardia.	Uncommon	In the event of severe IRR or anaphylactic reaction discontinue administration immediately and initiate appropriate treatment (epinephrine and antihistamines). In case of mild to moderate IRR, the infusion may be interrupted or slowed down, and appropriate treatment initiated. Consider pretreatment (antihistamines, hydrocortisone and/or paracetamol) before the next infusion in the case of patients with a history of mild to moderate IRR.
34	Alemtuzumb (Lemtrada^®)	Headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, shivering, redness, tiredness, dyspnea, dysgeusia, chest discomfort, hives, tachycardia, dyspepsia, dizziness and pain.	Common	Patients should be pre treated with corticosteroids immediately prior to administration. In addition, pre treatment with antihistamines and/or antipyretics may be considered. If an IRR occurs, provide symptomatic treatment. In case of severe infusion reactions, immediate discontinuation of infusion should be considered.
36	Ocrelizumab (Ocrevus^®)	Itching, rash, urticaria, erythema, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, redness, hypotension, pyrexia, fatigue, headache, dizziness, nausea and tachycardia.	Very common	Pre-medication with 100 mg of methylprednisolone iv (or equivalent) approximately 30 mins before each perfusion and antihistamine approximately 30–60 mins before each infusion. The administration of an antipyretic (eg, paracetamol) may be considered approximately 30–60 mins before each infusion. If during the infusion there are signs of a potentially fatal or incapacitating IRR, the infusion should be discontinued immediately and definitively and the patient given the appropriate treatment. In mild or moderate IRR reduce the rate of infusion.
L04AB Inhibitors of tumor necrosis factor alpha (anti-TNF-α)
02	Infliximab (Inflectra^®)	Anaphylactic shock and hypersensibility delayed reactions. Evanescent macular rash that disappears within minutes or hours, chest tightness, dizziness or shortness of breath, headache, hypotension, hypertension, nausea, sweating, and hyperthermia.	Very common	If acute reactions occur, the infusion should be stopped immediately. Patients can be previously treated with, for example, an antihistamine, hydrocortisone and/or acetaminophen to prevent mild and temporary effects.
L04AC Inhibitors of the interleukins
05	Ustekinumab (Stelara^®)	Exanthemas, urticaria.	Uncommon (urticaria) Rare (anaphylaxis, angioedema)	Is not specified
07	Tocilizumab (RoActemra^®)	Hypertension, headache, nausea and hypotension.	Common	If an anaphylactic reaction or another severe hypersensitivity/severe reaction related to the perfusion occurs, treatment should be stopped immediately and definitively discontinued.
11	Siltuximab (Sylvant^®)	Symptoms of IRRs are not specified in the technical file.	Common (anaphylaxis)	Mild to moderate infusion reactions may improve if the infusion rate is reduced or the infusion is discontinued. Once the reaction has subsided, the resumption of perfusion at a lower rate and the therapeutic administration of antihistamines, acetaminophen and corticosteroids may be considered. It should be discontinued in patients with severe infusion-related hypersensitivity reactions (eg, anaphylaxis)

Notes: Classification of the frequency of the adverse reactions as per the Guidelines for preparing core clinical-safety information on drugs second edition – report of CIOMS working groups III and V.³⁸ Very common ≥1/10 (≥10%), common (frequent) ≥1/100 and <1/10 (≥1% and <10%), uncommon (infrequent) 1/1000 and ≤1/100 (≥0.1% and <1%), rare ≥1/10,000 and <1/1000 (≥0.01% and <0.1%), and very rare ≤1/10,000 (<0.01%). This table has been made according to the technical specifications of the Spanish Agency of Medicines and Health Products, as per Cima (aemps).¹²

Abbreviations: mAbs, Monoclonal Antibodies; ATC, Anatomic-Therapeutic-Chemical Classification; IRR, Infusion-related reaction; CRS, Cytokine-release syndrome.

Table 2 Extracts from the Common Terminology Criteria for Adverse Events v5.0 (CTCAE)

Adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Infusion-related reaction A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.	Mild transient reaction; infusion interruption not indicated; intervention not indicated	Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (for example, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤24 hrs	Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae	Life-threatening consequences; urgent intervention indicated	Death
Anaphylaxis A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.	–	–	Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy related edema/angio-edema; hypotension	Life-threatening consequences; urgent intervention indicated	Death
Allergic reaction A disorder characterized by an adverse local or general response from exposure to an allergen. If related to infusion, use Injury, poisoning and procedural complications: Infusion-related reaction. Do not report both.	Systemic intervention not indicated	Oral intervention indicated	Bronchospasm; hospitalization indicated for clinical sequelae; intravenous intervention indicated	Life-threatening consequences; urgent intervention indicated	Death
Cytokine-release syndrome A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. Also consider reporting other organ dysfunctions including neurological toxicities such as: Psychiatric disorders: Hallucinations or Confusion; Nervous system disorders: Seizure, Dysphasia, Tremor, or Headache	Fever with or without constitutional symptoms	Hypotension responding to fluids; hypoxia responding to <40% O2	Hypotension managed with one pressor; hypoxia requiring ≥40% O2	Life-threatening consequences; urgent intervention indicated	Death

Notes: Adapted from: Common Terminology Criteria for Adverse Events (CTCAE) v5.0. US Department of Health and Human Services; National Institutes of Health; National Cancer Institute; 2017. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.²⁹

Abbreviations: ALS, advanced life support; CARPA, complement activation-related; CRS, cytokine-release syndrome; CTCAE, common terminology criteria for adverse events; IRR, infusion-related reaction; mAbs, monoclonal antibodies; ATC, anatomic-therapeutic-chemical classification; NSAIDs, non-steroidal anti-inflammatory drug.

Figure 1 Algorithm proposed as a daily-practice guide to manage the use of mAb.

Abbreviations: IRR, infusion-related reaction; ALS, advanced life support; mAbs, monoclonal antibodies; po, per oral; iv, intravenous; sl, sublingual; sc, subcutaneous.

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