HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ERBITUX safely and effectively. See full prescribing information for
`ERBITUX.
`
`ERBITUX® (cetuximab)
`Solution for intravenous infusion
`Initial U.S. Approval: 2004
`
`WARNING: SERIOUS INFUSION REACTIONS and
`CARDIOPULMONARY ARREST
`See full prescribing information for complete boxed warning.
`Serious infusion reactions, some fatal, occurred in approximately
`3% of patients. (5.1)
`Cardiopulmonary arrest and/or sudden death occurred in 2% of
`patients receiving Erbitux
`in combination with radiation
`therapy. (5.2, 5.6)
`
`•
`
`•
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage
` Colorectal Cancer (1.2) 07/2009
`Warnings and Precautions
` Infusion Reactions (5.1)
` Dermatologic Toxicity (5.4)
`
` 09/2008
` 09/2008
`
`•
`
`---------------------------INDICATIONS AND USAGE----------------------------
`Erbitux® is an epidermal growth factor receptor (EGFR) antagonist indicated
`for treatment of:
`Head and Neck Cancer
`Locally or regionally advanced squamous cell carcinoma of the head and
`•
`neck in combination with radiation therapy. (1.1, 14.1)
`Recurrent or metastatic squamous cell carcinoma of the head and neck
`progressing after platinum-based therapy. (1.1, 14.1)
`Colorectal Cancer
`As a single agent, EGFR-expressing metastatic colorectal cancer after
`•
`failure of both irinotecan- and oxaliplatin-based regimens or in patients
`who are intolerant to irinotecan-based regimens. (1.2, 14.2)
`In combination with irinotecan, EGFR-expressing metastatic colorectal
`carcinoma
`in patients who are
`refractory
`to
`irinotecan-based
`chemotherapy. Approval is based on objective response rate; no data are
`available demonstrating an improvement in increased survival. (1.2,
`14.2)
`Retrospective subset analyses of metastatic or advanced colorectal
`cancer trials have not shown a treatment benefit for Erbitux in patients
`whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is
`not recommended for the treatment of colorectal cancer with these
`mutations. (1.2, 12.1, 14.2)
`
`•
`
`•
`
`2
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS INFUSION REACTIONS AND
`CARDIOPULMONARY ARREST
`1
`INDICATIONS AND USAGE
`1.1
`Squamous Cell Carcinoma of the Head and Neck
`(SCCHN)
`1.2
`Colorectal Cancer
`DOSAGE AND ADMINISTRATION
`2.1
`Squamous Cell Carcinoma of the Head and Neck
`2.2
`Colorectal Cancer
`2.3
`Recommended Premedication
`2.4
`Dose Modifications
`2.5
`Preparation for Administration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`A
`WARNINGS AND PREC UTIONS
`Infusion Reactions
`5.1
`Cardiopulmonary Arrest
`5.2
`5.3
`Pulmonary Toxicity
`5.4
`Dermatologic Toxicity
`5.5
`Use of Erbitux in Combination With Radiation and
`Cisplatin
`Hypomagnesemia and Electrolyte Abnormalities
`Epidermal Growth Factor Receptor (EGFR) Expression
`and Response
`ADVERSE REACTIONS
`
`5.6
`5.7
`
`6
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`•
`Premedicate with an H1 antagonist. (2.3)
`Administer 400 mg/m2 initial dose as a 120-minute intravenous infusion
`•
`followed by 250 mg/m2 weekly infused over 60 minutes. (2.1, 2.2)
`Initiate Erbitux one week prior to initiation of radiation therapy. (2.1)
`Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 infusion
`reactions and non-serious NCI CTC Grades 3–4 infusion reactions. (2.4)
`Permanently discontinue for serious infusion reactions. (2.4)
`•
`• Withhold infusion for severe, persistent acneform rash. Reduce dose for
`recurrent, severe rash. (2.4)
`
`•
`•
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`100 mg/50 mL, single-use vial (3)
`•
`200 mg/100 mL, single-use vial (3)
`•
`
`------------------------------CONTRAINDICATIONS-------------------------------
`
`None (4)
`
`•
`
`----------------------WARNINGS AND PRECAUTIONS----------------------
`Infusion Reactions: Immediately stop and permanently discontinue
`•
`Erbitux for serious infusion reactions. Monitor patients following
`infusion. (5.1)
`Cardiopulmonary Arrest: Closely monitor serum electrolytes during
`and after Erbitux. (5.2, 5.6)
`Pulmonary Toxicity: Interrupt therapy for acute onset or worsening of
`pulmonary symptoms. (5.3)
`Dermatologic Toxicity: Limit sun exposure. Monitor for inflammatory
`or infectious sequelae. (2.4, 5.4)
`
`•
`
`•
`
`-------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (incidence ≥25%) are: cutaneous adverse
`reactions (including rash, pruritus, and nail changes), headache, diarrhea, and
`infection. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`Pregnancy: Administer Erbitux to a pregnant woman only if the
`•
`potential benefit justifies the potential risk to the fetus. (8.1)
`Nursing Mothers: Discontinue nursing during and for 60 days
`following treatment with Erbitux. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION
`
`•
`
`Revised: 07/2009
`
`6.1
`Clinical Trials E periencex
`
`
`Immunogenicity
`6.2
`DRUG INTERACTIONS
`USE IN SPECIFI
` POPULATIONS
`C
`8.1
`Pregnancy
`Nursing Mothers
`8.3
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2
`Animal Pharmacology and/or Toxicology
`CLINICAL STUDIES
`14.1
`Squamous Cell Carcinoma of the Head and Neck
`(SCCHN)
`14.2
`Colorectal Cancer
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`7
`8
`
`10
`11
`12
`
`13
`
`14
`
`16
`17
`
`* Sections or subsections omitted from the full prescribing information
`are not listed
`
`1
`
`AVENTIS EXHIBIT 2199
`Mylan v. Aventis IPR2016-00712
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: SERIOUS INFUSION REACTIONS and
`CARDIOPULMONARY ARREST
`
`Infusion Reactions: Serious infusion reactions occurred with the administration of
`Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in
`less than 1 in 1000. [See Warnings and Precautions (5.1) and Adverse Reactions (6).]
`Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion
`reactions. [See Warnings and Precautions (5.1) and Dosage and Administration (2.4).]
`
`Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2%
`of 208 patients with squamous cell carcinoma of the head and neck treated with radiation
`therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium,
`potassium, and calcium, during and after Erbitux. [See Warnings and Precautions (5.2,
`5.6).]
`
`1
`
`1.1
`
`INDICATIONS AND USAGE
`
`Squamous Cell Carcinoma of the Head and Neck
`(SCCHN)
`
`Erbitux® is indicated in combination with radiation therapy for the initial treatment of
`locally or regionally advanced squamous cell carcinoma of the head and neck. [See
`Clinical Studies (14.1).]
`
`Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or
`metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based
`therapy has failed. [See Clinical Studies (14.1).]
`
`1.2
`
`Colorectal Cancer
`
`Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor
`receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan-
`and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the
`treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant
`to irinotecan-based regimens. [See Clinical Studies (14.2) and Warnings and Precautions
`(5.7).]
`
`2
`
`

`
`
`
`treatment of
`the
`for
`indicated
`is
`irinotecan,
`in combination with
`Erbitux,
`EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to
`irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with
`irinotecan is based on objective response rates. Currently, no data are available that
`demonstrate an improvement in disease-related symptoms or increased survival with
`Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic
`colorectal carcinoma. [See Clinical Studies (14.2) and Warnings and Precautions (5.7).]
`
`Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not
`shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in
`codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer
`with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1)].
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`Squamous Cell Carcinoma of the Head and Neck
`
`Erbitux in combination with radiation therapy:
`
`•
`
`•
`
`The recommended initial dose is 400 mg/m2 administered one week prior to
`initiation of a course of radiation therapy as a 120-minute intravenous infusion
`(maximum infusion rate 10 mg/min).
`
`The recommended subsequent weekly dose (all other infusions) is 250 mg/m2
`infused over 60 minutes (maximum infusion rate 10 mg/min) for the duration of
`radiation therapy (6–7 weeks). Complete Erbitux administration 1 hour prior to
`radiation therapy.
`
`Erbitux monotherapy:
`
`•
`
`•
`
`The recommended initial dose is 400 mg/m2 administered as a 120-minute
`intravenous infusion (maximum infusion rate 10 mg/min).
`
`The recommended subsequent weekly dose (all other infusions) is 250 mg/m2
`infused over 60 minutes (maximum infusion rate 10 mg/min) until disease
`progression or unacceptable toxicity.
`
`3
`
`

`
`
`
`2.2
`
`Colorectal Cancer
`
`•
`
`•
`
`The recommended initial dose, either as monotherapy or in combination with
`irinotecan, is 400 mg/m2 administered as a 120-minute intravenous infusion
`(maximum infusion rate 10 mg/min).
`
`The recommended subsequent weekly dose, either as monotherapy or in
`combination with irinotecan, is 250 mg/m2 infused over 60 minutes (maximum
`infusion rate 10 mg/min) until disease progression or unacceptable toxicity.
`
`2.3
`
`Recommended Premedication
`
`Premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously 30–60
`minutes prior to the first dose; premedication should be administered for subsequent
`Erbitux doses based upon clinical judgment and presence/severity of prior infusion
`reactions.
`
`2.4
`
`Dose Modifications
`
`Infusion Reactions
`
`Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC
`Grades 3–4 infusion reactions.
`
`Immediately and permanently discontinue Erbitux for serious infusion reactions,
`requiring medical intervention and/or hospitalization. [See Warnings and Precautions
`(5.1).]
`
`Dermatologic Toxicity
`
`Recommended dose modifications for severe (NCI CTC Grade 3 or 4) acneform rash are
`specified in Table 1. [See Warnings and Precautions (5.4).]
`
`4
`
`

`
`
`
`Table 1:
`
`Erbitux Dose Modification Guidelines for Rash
`
`Severe Acneform
`Rash
`
`Erbitux
`
`1st occurrence
`
`
`2nd occurrence
`
`
`3rd occurrence
`
`4th occurrence
`
`Delay infusion 1 to 2 weeks
`
`
`Delay infusion 1 to 2 weeks
`
`
`Delay infusion 1 to 2 weeks
`
`Discontinue Erbitux
`
`Outcome
`
`Improvement
`No Improvement
`
`Improvement
`No Improvement
`
`Improvement
`No Improvement
`
`
`Erbitux Dose
`Modification
`Continue at 250 mg/m2
`Discontinue Erbitux
`Reduce dose to 200 mg/m2
`Discontinue Erbitux
`Reduce dose to 150 mg/m2
`Discontinue Erbitux
`
`
`2.5
`
`Preparation for Administration
`
`Do not administer Erbitux as an intravenous push or bolus.
`
`Administer via infusion pump or syringe pump. Do not exceed an infusion rate of
`10 mg/min.
`
`Administer through a low protein binding 0.22-micrometer in-line filter.
`
`Parenteral drug products should be inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit.
`
`The solution should be clear and colorless and may contain a small amount of easily
`visible, white, amorphous, cetuximab particulates. Do not shake or dilute.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`100 mg/50 mL, single-use vial
`
`200 mg/100 mL, single-use vial
`
`4
`
`CONTRAINDICATIONS
`
`None.
`
`5
`
`

`
`WARNINGS AND PRECAUTIONS
`
` 5
`
`
`
`5.1
`
`Infusion Reactions
`
`Serious infusion reactions, requiring medical intervention and immediate, permanent
`discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm,
`stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction,
`and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in
`2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.
`
`Approximately 90% of severe infusion reactions occurred with the first infusion despite
`premedication with antihistamines.
`
`Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation
`equipment and other agents necessary
`to
`treat anaphylaxis (eg, epinephrine,
`corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer
`to confirm resolution of the event in patients requiring treatment for infusion reactions.
`
`Immediately and permanently discontinue Erbitux in patients with serious infusion
`reactions. [See Boxed Warning and Dosage and Administration (2.4).]
`
`5.2
`
`Cardiopulmonary Arrest
`
`Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated
`with radiation therapy and Erbitux as compared to none of 212 patients treated with
`radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three
`patients with prior history of coronary artery disease died at home, with myocardial
`infarction as the presumed cause of death. One of these patients had arrhythmia and one
`had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of
`Erbitux. One patient with no prior history of coronary artery disease died one day after
`the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation
`therapy in head and neck cancer patients with a history of coronary artery disease,
`congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum
`electrolytes, including serum magnesium, potassium, and calcium, during and after
`Erbitux. [See Boxed Warning and Warnings and Precautions (5.6).]
`
`6
`
`

`
`
`
`5.3
`
`Pulmonary Toxicity
`
`Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients
`receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of
`pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD.
`
`5.4
`
`Dermatologic Toxicity
`
`Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial
`inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation,
`cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in
`patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients
`receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.
`
`Acneform rash usually developed within the first two weeks of therapy and resolved in a
`majority of the patients after cessation of treatment, although in nearly half, the event
`continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities
`and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy.
`[See Dose Modifications (2.4).]
`
`5.5
`
`Use of Erbitux in Combination With Radiation and
`Cisplatin
`
`The safety of Erbitux in combination with radiation therapy and cisplatin has not been
`established. Death and serious cardiotoxicity were observed in a single-arm trial with
`Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced
`SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown
`cause. Four patients discontinued treatment due to adverse events. Two of these
`discontinuations were due to cardiac events.
`
`5.6
`
`Hypomagnesemia and Electrolyte Abnormalities
`
`In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients
`(199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The
`onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to
`months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia,
`hypocalcemia, and hypokalemia, during and for at least 8 weeks following the
`completion of Erbitux. Replete electrolytes as necessary.
`
`7
`
`

`
`
`
`5.7
`
`Epidermal Growth Factor Receptor (EGFR) Expression
`and Response
`
`Because expression of EGFR has been detected in nearly all SCCHN tumor specimens,
`patients enrolled in the head and neck cancer clinical studies were not required to have
`immunohistochemical evidence of EGFR tumor expression prior to study entry.
`
`Patients enrolled in the colorectal cancer clinical studies were required to have
`immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor
`from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit.
`Specimens were scored based on the percentage of cells expressing EGFR and intensity
`(barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either
`the percentage of positive cells or the intensity of EGFR expression.
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the
`label:
`•
`Infusion reactions [See Boxed Warning and Warnings and Precautions (5.1).]
`• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions (5.2).]
`• Pulmonary toxicity [See Warnings and Precautions (5.3).]
`• Dermatologic toxicity [See Warnings and Precautions (5.4).]
`• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions
`(5.6).]
`
`The most common adverse reactions with Erbitux (incidence ≥25%) are 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 all studies, Erbitux was discontinued in 3–10% of patients because of adverse
`reactions.
`
`8
`
`

`
`
`
`6.1
`
`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 colorectal cancer or
`SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials
`treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See
`Clinical Studies (14).]
`
`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
`
`Table 2 contains selected adverse events 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).
`
`9
`
`

`
`
`
`Table 2:
`
`Body System
`Preferred Term
`
`
`Incidence of Selected Adverse Events (≥10%) in Patients with
`Locoregionally Advanced SCCHN
`Erbitux plus Radiation
`(n=208)
`
`Radiation Therapy Alone
`(n=212)
`
`Grades
`1–4
`
`Grades
`Grades
`1–4
`3 and 4
`% of Patients
`
`Grades
`3 and 4
`
`Body as a Whole
`Asthenia
`Fever1
`Headache
`Infusion Reaction2
`Infection
`Chills1
`Digestive
`Nausea
`Emesis
`Diarrhea
`Dyspepsia
`Metabolic/Nutritional
`Weight Loss
`Dehydration
`Alanine Transaminase, high3
`
`Aspartate Transaminase, high3
`Alkaline Phosphatase, high3
`Respiratory
`Pharyngitis
`Skin/Appendages
`Acneform Rash4
`86
`Radiation Dermatitis
`18
`Application Site Reaction
`16
`Pruritus
`1 Includes cases also reported as infusion reaction.
`2 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”.
`3 Based on laboratory measurements, not on reported adverse events, the number of subjects with tested
`samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.
`
`
`49
`13
`
`8
`2
`
`9
`5
`
`
`37
`23
`13
`9
`
`72
`19
`21
`
`24
`
`24
`
`19
`
`10
`
`90
`12
`4
`
`5
`1
`
`<1
`0
`
`1
`0
`
`2
`4
`1
`1
`
`7
`8
`1
`
`1
`
`0
`
`4
`
`1
`
`18
`1
`0
`
`
`
`
`
`4
`1
`
`<1
`3
`
`1
`0
`
`2
`2
`2
`0
`
`11
`6
`2
`
`1
`
`<1
`
`3
`
`17
`
`23
`0
`0
`
`
`56
`29
`
`19
`15
`
`13
`16
`
`
`49
`29
`19
`14
`
`84
`25
`43
`
`38
`
`33
`
`26
`
`87
`
`10
`
`

`
`
`
`Table 2:
`
`Incidence of Selected Adverse Events (≥10%) in Patients with
`Locoregionally Advanced SCCHN
`Erbitux plus Radiation
`(n=208)
`
`Radiation Therapy Alone
`(n=212)
`
`Body System
`Grades
`Grades
`Preferred Term
`1–4
`3 and 4
`
`% of Patients
`4 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular
`rash”, “dry skin”, or “exfoliative dermatitis”.
`
`Grades
`1–4
`
`Grades
`3 and 4
`
`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.
`
`Colorectal Cancer
`
`Table 3 contains selected adverse events in 562 patients receiving best supportive care
`(BSC) alone or with Erbitux monotherapy for metastatic colorectal cancer in Study 3.
`Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial
`dose, followed by 250 mg/m2 weekly).
`
`11
`
`

`
`
`
`Table 3:
`
`Incidence of Selected Adverse Events Occurring in ≥10% of
`Patients with Advanced Colorectal Carcinoma1 Treated with
`Erbitux Monotherapy
`Erbitux plus BSC
`(n=288)
`
`BSC alone
`(n=274)
`
`Body System
`Preferred Term
`
`Dermatology
`Rash/Desquamation
`Dry Skin
`Pruritus
`Other-Dermatology
`Nail Changes
`Body as a Whole
`Fatigue
`Fever
`Infusion Reactions3
`Rigors, Chills
`Pain
`Abdominal Pain
`Pain-Other
`Headache
`Bone Pain
`Pulmonary
`Dyspnea
`Cough
`Gastrointestinal
`Constipation
`Diarrhea
`Vomiting
`Stomatitis
`Other-Gastrointestinal
`Mouth Dryness
`Infection
`Infection without neutropenia
`Neurology
`Insomnia
`Confusion
`Anxiety
`Depression
`
`Any
`Grades2
`
`Any
`Grades
`Grades
`3 and 4
`% of Patients
`
`Grades
`3 and 4
`
`
`89
`49
`40
`27
`21
`
`89
`30
`
`20
`13
`
`59
`51
`33
`15
`
`48
`29
`
`46
`39
`37
`25
`23
`11
`
`35
`
`30
`15
`14
`13
`
`12
`0
`2
`1
`0
`
`33
`1
`
`5
`<1
`
`14
`16
`4
`3
`
`16
`2
`
`4
`2
`6
`1
`10
`0
`
`13
`
`1
`6
`2
`1
`
`12
`
`16
`11
`8
`6
`4
`
`76
`18
`
`
`4
`
`52
`34
`11
`7
`
`43
`19
`
`38
`20
`29
`10
`18
`4
`
`17
`
`15
`9
`8
`6
`
`
`<1
`0
`0
`1
`0
`
`26
`<1
`
`
`0
`
`16
`7
`0
`2
`
`12
`1
`
`5
`2
`6
`<1
`8
`0
`
`6
`
`1
`2
`1
`<1
`
`

`
`
`
`Table 3:
`
`Incidence of Selected Adverse Events Occurring in ≥10% of
`Patients with Advanced Colorectal Carcinoma1 Treated with
`Erbitux Monotherapy
`Erbitux plus BSC
`(n=288)
`
`BSC alone
`(n=274)
`
`Any
`Grades2
`
`Body System
`Any
`Grades
`Preferred Term
`Grades
`3 and 4
`
`% of Patients
`1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.
`2 Adverse events were graded using the NCI CTC, V 2.0.
`3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest
`tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain,
`pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as
`infusion-related.
`BSC = best supportive care
`
`Grades
`3 and 4
`
`The most frequently reported adverse events in 354 patients treated with Erbitux plus
`irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea
`(72%), and nausea (55%). The most common Grades 3–4 adverse events included
`diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).
`
`6.2
`
`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.
`
`13
`
`

`
`DRUG INTERACTIONS
`
` 7
`
`
`
`A drug interaction study was performed in which Erbitux was administered in
`combination with irinotecan. There was no evidence of any pharmacokinetic interactions
`between Erbitux and irinotecan.
`
`8
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`
`Pregnancy Category C
`
`There are no adequate and well-controlled studies of Erbitux in pregnant women. Based
`on animal models, EGFR has been implicated in the control of prenatal development and
`may be essential for normal organogenesis, proliferation, and differentiation in the
`developing embryo. Human IgG is known to cross the placental barrier; therefore,
`Erbitux may be transmitted from the mother to the developing fetus, and has the potential
`to cause fetal harm when administered to pregnant women. Erbitux should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended
`human dose of cetuximab (based on body surface area) during the period of
`organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid
`and in the serum of embryos from treated dams at GD 49. No fetal malformations or
`other teratogenic effects occurred in offspring. However, significant increases in
`embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the
`recommended human dose of cetuximab (based on total body surface area).
`
`8.3
`
`Nursing Mothers
`
`It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as
`Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk
`and because of the potential for serious adverse reactions in nursing infants from Erbitux,
`a decision should be made whether to discontinue nursing or to discontinue the drug,
`taking into account the importance of the drug to the mother. If nursing is interrupted,
`based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3)], nursing
`should not be resumed earlier than 60 days following the last dose of Erbitux.
`
`14
`
`

`
`
`
`8.4
`
`Pediatric Use
`
`The safety and effectiveness of Erbitux in pediatric patients have not been established.
`The pharmacokinetics of cetuximab have not been studied in pediatric populations.
`
`8.5
`
`Geriatric Use
`
`Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five
`studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No
`overall differences in safety or efficacy were observed between these patients and
`younger patients.
`
`Clinical studies of Erbitux conducted in patients with head and neck cancer did not
`include sufficient number of subjects aged 65 and over to determine whether they
`respond differently from younger subjects. Of the 208 patients with head and neck cancer
`who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.
`
`10
`
`OVERDOSAGE
`
`The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No
`adverse events were reported for this patient.
`
`11
`
`DESCRIPTION
`
`Erbitux (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that
`binds specifically to the extracellular domain of the human epidermal growth factor
`receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR
`antibody with human IgG1 heavy and kappa light chain constant regions and has an
`approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian
`(murine myeloma) cell culture.
`
`Erbitux is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small
`amount of easily visible, white, amorphous cetuximab particulates. Erbitux is supplied at
`a concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use
`vials. Cetuximab is formulated in a preservative-free solution containing 8.48 mg/mL
`sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL
`sodium phosphate monobasic monohydrate, and Water for Injection, USP.
`
`15
`
`

`
`
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane
`glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including
`EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal
`epithelial tissues, including the skin and hair follicle. Expression of EGFR is also
`detected in many human cancers including those of the head and neck, colon, and rectum.
`
`Cetuximab binds specifically to the EGFR on both normal and tumor cells, and
`competitively inhibits the binding of epidermal growth factor (EGF) and other ligands,
`such as transforming growth factor–alpha. In vitro assays and in vivo animal studies have
`shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of
`receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis,
`and decreased matrix metalloproteinase and vascular endothelial growth factor
`production. Signal transduction through the EGFR results in activation of wild-type
`KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant
`KRAS protein is continuously active and appears independent of EGFR regulation.
`
`In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against
`certain human tumor types. In vitro assays and in vivo animal studies have shown that
`cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No
`anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR
`expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor
`xenograft models in mice resulted in an increase in anti-tumor effects compared to
`radiation therapy or chemotherapy alone.
`
`12.3
`
`Pharmacokinetics
`
`Erbitux administered as monotherapy or in combination with concomitant chemotherapy
`or radiation
`therapy exhibits nonlinear pharmacokinetics. The area under
`the
`concentration time curve (AUC) increased in a greater than dose proportional manner
`while clearance of cetuximab decreased from 0