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Erbitux (Cetuximab) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

  • Infusion reactions [See Boxed Warning , Warnings and Precautions .]
  • Cardiopulmonary arrest [See Boxed Warning , Warnings and Precautions .]
  • Pulmonary toxicity [See Warnings and Precautions .]
  • Dermatologic toxicity [See Warnings and Precautions .]
  • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions .]

The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies .]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck

Erbitux in Combination with Radiation Therapy

Table 2 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 2: Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN
Body System
Preferred Term
Erbitux plus Radiation
(n=208)
Radiation Therapy Alone
(n=212)
Grades
1–4
Grades
3 and 4
Grades
1–4
Grades
3 and 4
% of Patients
a Includes cases also reported as infusion reaction.
b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.
c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.
d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
Body as a Whole        
Asthenia 56 4 49 5
Fevera 29 1 13 1
Headache 19 <1 8 <1
Infusion Reactionb 15 3 2 0
Infection 13 1 9 1
Chillsa 16 0 5 0
Digestive        
Nausea 49 2 37 2
Emesis 29 2 23 4
Diarrhea 19 2 13 1
Dyspepsia 14 0 9 1
Metabolic/Nutritional        
Weight Loss 84 11 72 7
Dehydration 25 6 19 8
Alanine Transaminase, highc 43 2 21 1
Aspartate Transaminase, highc 38 1 24 1
Alkaline Phosphatase, highc 33 <1 24 0
Respiratory        
Pharyngitis 26 3 19 4
Skin/Appendages        
Acneiform Rashd 87 17 10 1
Radiation Dermatitis 86 23 90 18
Application Site Reaction 18 0 12 1
Pruritus 16 0 4 0

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity

The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil

Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology ].

Table 3 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

Table 3: Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN
System Organ Class
Preferred Term
EU-Approved Cetuximab
plus Platinum-based Therapy
with 5-FU
(n=219)
Platinum-based Therapy
with 5-FU Alone
(n=215)
Grades
1–4
Grades
3 and 4
Grades
1–4
Grades
3 and 4
% of Patients
a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing.
b Infection – this term excludes sepsis-related events which are presented separately.
c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”.
Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil
Eye Disorders        
Conjunctivitis 10 0 0 0
Gastrointestinal Disorders        
Nausea 54 4 47 4
Diarrhea 26 5 16 1
General Disorders and Administration Site Conditions        
Pyrexia 22 0 13 1
Infusion Reactiona 10 2 <1 0
Infections and Infestations        
Infectionb 44 11 27 8
Metabolism and Nutrition Disorders        
Anorexia 25 5 14 1
Hypocalcemia 12 4 5 1
Hypokalemia 12 7 7 5
Hypomagnesemia 11 5 5 1
Skin and Subcutaneous Tissue Disorders        
Acneiform Rashc 70 9 2 0
Rash 28 5 2 0
Acne 22 2 0 0
Dermatitis Acneiform 15 2 0 0
Dry Skin 14 0 <1 0
Alopecia 12 0 7 0

For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.

Colorectal Cancer

Study 4: EU-Approved Cetuximab in Combination with FOLFIRI

Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology ].

Table 4 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions ]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224).

Table 4: Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera
Body System
Preferred Term
EU-Approved Cetuximab
plus FOLFIRI
(n=317)
FOLFIRI Alone
(n=350)
Grades
1–4b
Grades
3 and 4
Grades
1–4
Grades
3 and 4
% of Patients
a  Adverse reactions occurring in at least 10% of Erbitux combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm.
b  Adverse reactions were graded using the NCI CTC, V 2.0.
c  Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”.
d  Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”.
Blood and Lymphatic System Disorders        
Neutropenia 49 31 42 24
Eye Disorders        
Conjunctivitis 18 <1 3 0
Gastrointestinal Disorders        
Diarrhea 66 16 60 10
Stomatitis 31 3 19 1
Dyspepsia 16 0 9 0
General Disorders and Administration Site Conditions        
Infusion-related Reactionc 14 2 <1 0
Pyrexia 26 1 14 1
Infections and Infestations        
Paronychia 20 4 <1 0
Investigations        
Weight Decreased 15 1 9 1
Metabolism and Nutrition Disorders        
Anorexia 30 3 23 2
Skin and Subcutaneous Tissue Disorders        
Acne-like Rashd 86 18 13 <1
   Rash 44 9 4 0
   Dermatitis Acneiform 26 5 <1 0
   Dry Skin 22 0 4 0
   Acne 14 2 0 0
   Pruritus 14 0 3 0
Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1
Skin Fissures 19 2 1 0

Erbitux Monotherapy

Table 5 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions ]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51).

Table 5: Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya
Body System
Preferred Term
Erbitux plus BSC
(n=118)
BSC alone
(n=124)
Grades
1–4b
Grades
3 and 4
Grades
1–4
Grades
3 and 4
% of Patients
a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm.
b Adverse reactions were graded using the NCI CTC, V 2.0.
c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related.
Dermatology/Skin        
Rash/Desquamation 95 16 21 1
Dry Skin 57 0 15 0
Pruritus 47 2 11 0
Other-Dermatology 35 0 7 2
Nail Changes 31 0 4 0
Constitutional Symptoms        
Fatigue 91 31 79 29
Fever 25 3 16 0
Infusion Reactionsc 18 3 0 0
Rigors, Chills 16 1 3 0
Pain        
Pain-Other 59 18 37 10
Headache 38 2 11 0
Bone Pain 15 4 8 2
Pulmonary        
Dyspnea 49 16 44 13
Cough 30 2 19 2
Gastrointestinal        
Nausea 64 6 50 6
Constipation 53 3 38 3
Diarrhea 42 2 23 2
Vomiting 40 5 26 5
Stomatitis 32 1 10 0
Other-Gastrointestinal 22 12 16 5
Dehydration 13 5 3 0
Mouth Dryness 12 0 6 0
Taste Disturbance 10 0 5 0
Infection        
Infection without neutropenia 38 11 19 5
Musculoskeletal        
Arthralgia 14 3 6 0
Neurology        
Neuropathy-sensory 45 1 38 2
Insomnia 27 0 13 0
Confusion 18 6 10 2
Anxiety 14 1 5 1
Depression 14 0 5 0

Erbitux in Combination with Irinotecan

The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Aseptic meningitis
  • Mucosal inflammation


REPORTS OF SUSPECTED ERBITUX SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Erbitux. The information is not vetted and should not be considered as verified clinical evidence.

Possible Erbitux side effects / adverse reactions in 72 year old male

Reported by a consumer/non-health professional from Germany on 2011-10-02

Patient: 72 year old male

Reactions: Hyperbilirubinaemia, Presyncope, Pyrexia, Neutropenia

Adverse event resulted in: hospitalization

Suspect drug(s):
Erbitux

Other drugs received by patient: Irinotecan HCL; Lederfoline; Lenograstim; Aldactone; Fluorouracil



Possible Erbitux side effects / adverse reactions in 57 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-03

Patient: 57 year old male weighing 81.0 kg (178.2 pounds)

Reactions: Stomatitis, Oral Pain, Dehydration

Adverse event resulted in: hospitalization

Suspect drug(s):
Cisplatin
    Dosage: last dose on 12jun2007 also delayed for 7 days
    Indication: Head and Neck Cancer
    Start date: 2007-06-12

Erbitux
    Dosage: last dose on 26jun2007 1271.5mg
    Indication: Head and Neck Cancer
    Start date: 2007-06-26



Possible Erbitux side effects / adverse reactions in 49 year old female

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-03

Patient: 49 year old female

Reactions: Oesophageal Pain, Vomiting, Dysphonia, Oesophagitis

Adverse event resulted in: hospitalization

Suspect drug(s):
Erbitux
    Indication: non-Small Cell Lung Cancer
    Start date: 2011-07-25
    End date: 2011-08-29

Taxol
    Indication: non-Small Cell Lung Cancer
    Start date: 2011-07-25
    End date: 2011-08-29

Carboplatin
    Indication: non-Small Cell Lung Cancer
    Start date: 2011-07-25
    End date: 2011-08-29

Doxycycline



See index of all Erbitux side effect reports >>

Drug label data at the top of this Page last updated: 2013-08-01

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