SeroScience Ltd.

SeroScience Ltd. specializes in immune toxicity evaluation of intravenous drugs, biologicals, nanodrugs and contrast media, with special expertise in the prediction of complement-mediated pseudoallergic infusion reactions.

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Recent R&D and clinical experience with novel biopharmaceuticals, controlled-release and targeted drug formulations has brought to light novel adverse effects, including those afflicting the immune system. Acute hypersensitivity, or infusion reactions leading to possibly severe and even fatal anaphylactoid shock represent a newly emerging toxicity of many state-of-art drugs and drug candidates, which contain antibodies and/or particles in the microbial size range.

A common feature of these agents is that they can activate the complement system, the nonspecific, humoral arm of antimicrobial immune defense. Complement activation has been recently proposed as a major underlying or contributing cause of infusion reactions, referred to as complement-activation related pseudoallergy (CARPA).

CARPA: Symptoms, Significance and Examples

The manifestations of CARPA include, among other symptoms, mild-to-severe flushing, skin rash, dyspnea, chest and back pain, hyper- or hypotension, tachycardia, angioedema and anxiety. In rare cases it can lead to anaphylactoid shock with death, mostly in patients with pre-existing cardiac and/or pulmonary condition.

Apart from being potentially fatal, in the majority of cases the clinical relevance of CARPA lies in the subjective and objective inconvenience it causes, the exclusion of patients from a promising treatment or diagnostic procedure and the economic burden to health systems caused by treatment of the reaction and the premedication. Pharmaceutical companies suffer major losses when a promising product fails clinical trials because of infusion reactions, or needs to be withdrawn from the market, such as the case of Neutrospec®.

External link: Contrast medium Neutrospec withdrawn from market.

Evidence accumulated over the past few years suggests that CARPA may be a major underlying cause, or contributing factor to the hypersensitivity reactions (HSRs) caused by many successful drugs, such as Taxol®, Taxotere® and Doxil®. Based on the identity of symptoms and common structural features of reactogenic agents, there is strong reason to suggest that HSRs to radiocontrast media and many other drugs can also be attributed to CARPA, including the liposomal drugs Ambisome® and DaunoXome® and monoclonal antibodies, such as Erbitux® (cetuximab), Rituxan® (rituximab), Herceptin® (trastuzumab) and Remicade® (infliximab).

Marketed Drugs Known to Cause Infusion Reactions

LESS SEVERE / LESS FREQUENT

MORE SEVERE / MORE FREQUENT

Avastin

Avonex

Abbokinase

Actimmune

Aldurazyme

Cancidas

Copaxone

Enbrel

Herceptin

Humira

Neupogen

Neulasta

Magnevist

Raptiva

Synagis

Xolair

Activase

Campath

DaunoXome

Doxil

Erbitux

Fasturtek

Mylotarg

Plenaxis

Remicade

Rituxan

Taxol

Taxotere

Tysabri

Zevalin

Vectibix

The following box warnings found in the prescribing information of the above-mentioned pharmaceuticals, illustrate the clinical relevance and some facts about the phenomenon.

Taxol® (paclitaxel) Injection

WARNING Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite premedication. … Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug. … Hypersensitivity Reactions to Taxol: Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL (eg., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of TAXOL and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL. (Bristol-Myers Squibb, www.taxol.com).

Taxotere®

WARNING: Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Taxotere® must not be given to patients who have a history of severe hypersensitivity reactions to Taxotere® or to other drugs formulated with polysorbate 80. All patients should be premedicated with oral corticosteroids such as dexamethasone (Aventis, www.taxotere.com)

Doxil®

WARNING: Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with Doxil®. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use Doxil® should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions (Alza, Johnson & Johnson, Schering Plough Co., www.doxil.com)

DaunoXome®

A triad of back pain, flushing, and chest tightness has been reported in 13.8% of the patients (16/116) treated with DaunoXome in the randomized clinical trial and in 2.7% of treatment cycles (27/994). This triad generally occurs during the first five minutes of the infusion, subsides with interruption of the infusion, and generally does not recur if the infusion is then resumed at a slower rate. This combination of symptoms appears to be related to the lipid component of DaunoXome, as a similar set of signs and symptoms has been observed with other liposomal products not containing daunorubicin. Other allergic or immune reactions may also be seen, and have been reported to be associated with hypotension. Anaphylactic reactions have been reported in rare cases.

Erbitux®

WARNING: Infusion Reactions: Severe infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were associated with the first infusion of ERBITUX. Severe infusion reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension and/or cardiac arrest. Severe infusion reactions require immediate interruption of the ERBITUX infusion and permanent discontinuation from further treatment. Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% (4/208) of patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX as compared to none of 212 patients treated with radiation therapy alone (Bristol-Myers Squibb, www.erbitux.com).

Rituxan®

WARNING: Fatal Infusion Reactions: Deaths within 24 hours of Rituxan infusion have been reported. These fatal reactions followed an infusion reaction complex, which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Rituxan has caused severe infusion reactions. In some cases, these reactions were fatal. These severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes. Signs and symptoms of severe infusion reactions may include urticaria, hypotension, angioedema, hypoxia, or bronchospasm, and may require interruption of Rituxan administration. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. … Management of severe infusion reactions: The Rituxan infusion should be interrupted for severe reactions. Medications and supportive care measures including, but not limited to, epinephrine, antihistamines, glucocorticoids, intravenous fluids, vasopressors, oxygen, bronchodilators, and acetaminophen, should be available for immediate use and instituted as medically indicated for use in the event of a reaction during administration (Genentech, Inc. and Biogen Idec Inc, www.rituxan.com).

Herceptin®

Serious infusion reactions and lung problems have also been seen; rarely these have been fatal. Treatment may be stopped if you begin to have a severe allergic reaction, swelling, lung problems, inflammation of the lung, or severe shortness of breath. … Infusion Reactions During the first infusion with Herceptin, a symptom complex most commonly consisting of chills and/or fever was observed in approximately 40% of patients in clinical trials. The symptoms were usually mild to moderate in severity and were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively (Genentech Inc., Roche)

Remicade®

Infusion Reactions. Adverse effects during administration of REMICADE have included flu-like symptoms, headache, dyspnea, hypotension, transient fever, chills, gastrointestinal symptoms, and skin rashes. Anaphylaxis might occur at any time during REMICADE infusion. Approximately 20% of REMICADE-treated patients in all clinical trials experienced an infusion reaction compared with 10% of placebo-treated patients….Prior to infusion with REMICADE, premedication may be administered at the physician’s discretion. Premedication could include antihistamines (anti-H1 +/- anti-H2), acetaminophen and/or corticosteroids. During infusion, mild to moderate infusion reactions may improve following slowing or suspension of the infusion, and upon resolution of the reaction, reinitiation at a lower infusion rate and/or therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these interventions, REMICADE should be discontinued. During or following infusion, patients that have severe infusion-related hypersensitivity reactions should be discontinued from further REMICADE treatment. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs… Approximately 3% of patients discontinued REMICADE because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. .. In a study where 37 of 41 patients with Crohn’s disease were retreated with infliximab … infusion-related adverse events associated with their initial infliximab therapy… occurred in 39% (9/23) of patients who had received liquid formulation which is no longer in use and 7% (1/14) of patients who received lyophilized formulation (www.remicade.com).