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INDICATIONS

Head and Neck Cancer

  • ERBITUX® (cetuximab), in combination with radiation therapy (RT), is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)
  • ERBITUX is indicated in combination with platinum-based therapy and fluorouracil (CT) for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN
  • ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

  • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

INDICATIONS

Head and Neck Cancer

ERBITUX® (cetuximab) is approved:
  • In combination with radiation therapy for the initial treatment of a certain type of locally or regionally advanced head and neck cancer
  • In combination with platinum-based chemotherapy and fluorouracil for the initial treatment of patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body
  • For use alone to treat patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body and whose disease has progressed following platinum-based chemotherapy

Metastatic Colorectal Cancer

ERBITUX is approved for the treatment of certain patients who have colorectal cancer that has spread to other parts of the body. Only patients whose tumors are KRAS wild-type (which means they have a KRAS mutation-negative gene), and whose tumors have a protein called epidermal growth factor receptor (EGFR), should receive ERBITUX. An FDA-approved test is used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:

  • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for patients who are being treated for this type of cancer for the first time
  • In combination with another chemotherapy drug, irinotecan, for patients whose disease has progressed after receiving chemotherapy with irinotecan
  • As a single agent:
    • For patients whose disease has progressed after receiving both irinotecan and oxaliplatin
    • For patients who are unable to tolerate chemotherapy with irinotecan

ERBITUX is not approved to treat colorectal cancer in patients whose tumors have mutations in genes called RAS (often called "RAS mutant"), or in patients for whom the mutational status of the genes is not known.

ERBITUX is available by prescription only.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS

IMPORTANT SAFETY INFORMATION FOR ERBITUX® (cetuximab)

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions:

ERBITUX can cause serious and fatal infusion reactions. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients receiving ERBITUX in clinical trials. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.

Cardiopulmonary Arrest:

ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck receiving radiation therapy and ERBITUX in BONNER. In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of the 219 patients with squamous cell carcinoma of the head and neck treated with a cetuximab product in combination with platinum-based therapy and fluorouracil. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration.

WARNING: ALLERGIC REACTIONS AND HEART ATTACK

ERBITUX can cause serious and sometimes fatal allergic reactions. Serious allergic reactions due to ERBITUX therapy occurred in 2.2% of patients receiving ERBITUX during clinical studies; 1 patient died. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of certain antibodies which can react to ERBITUX.

  • Symptoms can include trouble with breathing (including tightening of the airways, wheezing, or hoarseness), low blood pressure, shock, loss of consciousness, and/or heart attack. Report these signs and symptoms of infusion reactions, as well as fever, and/or chills to your doctor or nurse.
  • Approximately 90% of the severe allergic reactions occurred with the first treatment with ERBITUX (even if the patient had been premedicated with antihistamines), although some patients experienced their first severe allergic reaction during a later treatment.
  • Your doctor or nurse should watch you closely for these symptoms during treatment and for at least 1 hour following treatment and may need to stop therapy in the event of an allergic reaction. After the allergic reaction resolves, your doctor may be able to restart therapy.
  • If you have a severe allergic reaction, treatment with ERBITUX must be stopped immediately and not started again.

ERBITUX can cause heart attack or sudden death.

  • Heart attack or sudden death occurred in 2% of 208 patients with head and neck cancer treated with radiation therapy and ERBITUX in a clinical study. Three patients with a prior history of coronary artery disease died within six weeks after receiving the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX.
  • Heart problems resulting in death or sudden death occurred in 3% of 219 patients with head and neck cancer treated with ERBITUX and platinum-based chemotherapy with fluorouracil in a clinical study.
  • Notify your doctor if you have a history of any heart disease.

Pulmonary Toxicity

  • ERBITUX can cause interstitial lung disease (ILD). ILD, which was fatal in one case, occurred in <0.5% of 1570 patients receiving ERBITUX in clinical trials. Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD.

Dermatologic Toxicities

  • ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (e.g., S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis
    • Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed within the first 2 weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.
    • Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has been observed in patients who received ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis).
    • Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae.
    • Sun exposure may exacerbate these effects. Instruct patients to limit sun exposure during ERBITUX therapy.
    • Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease.

Risks Associated with Use in Combination with Radiation and Cisplatin

  • ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.
  • In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either ERBITUX in combination with radiation therapy and cisplatin, or radiation therapy and cisplatin alone. The addition of ERBITUX resulted in an increase in the incidence of Grade 3 and 4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone.
  • Adverse reactions with fatal outcome were reported in 4% of patients in the ERBITUX combination arm and 3% in the control arm.
  • In the ERBITUX arm, 2% experienced myocardial ischemia compared to 0.9% in the control arm.
  • The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint).

Hypomagnesemia and Accompanying Electrolyte Abnormalities

  • ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%. In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced grade 3 or 4 hypomagnesemia. The onset of hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX.
    • Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX.
    • Replete electrolytes as necessary.

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras--Mutant mCRC

  • ERBITUX is not indicated for the treatment of patients with CRC that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-Ras or N-Ras and hereafter referred to as “Ras” or when the Ras status is unknown.
  • Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX.

Embryo-Fetal Toxicity

  • Based on animal data and its mechanism of action, ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX. Verify pregnancy status in females of reproductive potential prior to initiating ERBITUX.

Adverse Reactions

  • 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 common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (BONNER) were acneiform rash (87% vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs 72%), asthenia (56% vs 49%), nausea (49% vs 37%), increased alanine transaminase (43% vs 21%), increased aspartate transaminase (38% vs 24%), increased alkaline phosphatase (33% vs 24%), fever (29% vs 13%), emesis (29% vs 23%), pharyngitis (26% vs 19%) and dehydration (25% vs 19%). The most common grade 3 and 4 adverse reactions for ERBITUX in combination with radiation therapy (≥10%) versus radiation alone included: radiation dermatitis (23% vs 18%), acneiform rash (17% vs 1%), and weight loss (11% vs 7%). The overall incidence of late radiation toxicities (any grade) was higher for patients receiving ERBITUX in combination with radiation therapy, versus radiation therapy alone. The following sites were affected: salivary glands (65% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membrane (48% vs 39%), esophagus (44% vs 35%), skin (42% vs 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between radiation therapy alone and the ERBITUX with radiation treatment groups.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving a cetuximab product in combination with platinum-based therapy and fluorouracil (CT) (n=219) versus CT alone (n=215) (EXTREME) were acneiform rash (70% vs 2%), nausea (54% vs 47%), infection (44% vs 27%), rash (28% vs 2%), diarrhea (26% vs 16%) and anorexia (25% vs 14%). The most common grade 3 and 4 adverse reactions for a cetuximab product in combination with CT (≥10%) versus CT alone was infection (11% vs 8%). Because ERBITUX provides approximately 22% higher exposure relative to the cetuximab product used in EXTREME, the data provided above 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.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with a cetuximab product in combination with FOLFIRI (n=317) versus FOLFIRI alone (n=350) (CRYSTAL) were acne-like rash (86% vs 13%), diarrhea (66% vs 60%), neutropenia (49% vs 42%), rash (44% vs 4%), stomatitis (31% vs 19%), anorexia (30% vs 23%), dermatitis acneiform (26% vs <1%) and pyrexia (26% vs 14%). The most common grade 3 and 4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). ERBITUX provides approximately 22% higher exposure compared to the cetuximab product used in CRYSTAL; however, the safety data from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (CA225-025) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), pain-other (59% vs 37%), dry skin (57% vs 15%), constipation (53% vs 38%), dyspnea (49% vs 44%), pruritis (47% vs 11%), neuropathy-sensory (45% vs 38%), diarrhea (42% vs 23%), vomiting (40% vs 26%), headache (38% vs 11%), infection without neutropenia (38% vs 19%), other-dermatology (35% vs 7%), stomatitis (32% vs 10%), nail changes (31% vs 4%), cough (30% vs 19%), insomnia (27% vs 13%) and fever (25% vs 16%). The most common grade 3 and 4 adverse reactions (≥10%) included: fatigue (31% vs 29%), pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea (16% vs 13%), other-gastrointestinal (12% vs 5%), and infection without neutropenia (11% vs 5%).
  • The most common adverse reactions (all grades) seen in patients with EGFR-expressing recurrent mCRC (n=354) treated with ERBITUX plus irinotecan in clinical trials (CP02-9923 and BOND) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3-4 adverse reactions included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

Use in Specific Populations

  • Lactation: There is no information regarding the presence of ERBITUX in human milk, the effects of the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, advise women not to breastfeed during treatment with ERBITUX and for at least 2 months after the last dose of ERBITUX.
  • Pediatric Use: The safety and effectiveness of ERBITUX in pediatric patients have not been established. No new safety signals were identified in pediatric patients when ERBITUX in combination with irinotecan was administered in an open-label, single-arm dose-finding study in 27 patients with refractory solid tumors aged 1 to 12 years old and in 19 patients aged 13 to 18 years old.
  • Geriatric Use: In mCRC clinical studies, no overall differences in safety or efficacy of ERBITUX were observed between patients >65 years of age and younger patients. In SCCHN clinical studies of ERBITUX there were insufficient number of patients >65 years of age to determine whether they respond differently from younger patients.

Please see full Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.

CE HCP ISI_ALL 03JUL2018

  • ERBITUX can cause lung disease. Lung disease occurred in less than 0.5% of 1570 patients receiving ERBITUX in clinical trials for colorectal cancer and head and neck cancer; 1 patient died.
    • Notify your doctor if you develop shortness of breath, a new or worsening cough and/or chest pain while receiving ERBITUX
    • ERBITUX treatment should be stopped if breathing symptoms worsen, and should not be restarted if lung disease is diagnosed
  • ERBITUX can cause skin problems including an acne-like rash, skin drying and cracking, infections (including infections of the blood, skin, eyes, and lips), swelling of the base of the nails or loss of the nails, inflammation of the eye or eyelid, decreased vision and abnormal hair growth. These symptoms were seen in several clinical trials for colorectal cancer and head and neck cancer with ERBITUX.
    • Sun exposure may worsen these effects. Patients taking ERBITUX should wear sunscreen and hats to limit sun exposure during treatment and for 2 months after the last dose of ERBITUX.
    • Severe reactions with symptoms of rash; blistering of the skin, mouth, eyes, and genitals; and shedding of the skin have been seen in patients treated with ERBITUX. These reactions may be life-threatening and possibly lead to death. It is not clear if these reactions are related to the way ERBITUX works or to an immune response, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Your doctor may withhold, reduce dose or discontinue ERBITUX based on the severity of these symptoms.
    • Notify your doctor if you develop any of these symptoms while receiving ERBITUX.
  • Risks when using ERBITUX with radiation and cisplatin. In a study of 940 patients with head and neck cancer, patients received either a combination of radiation and cisplatin (a cancer drug), or ERBITUX in combination with radiation and cisplatin. Adding ERBITUX resulted in an increase in occurrence of severe or life-threatening redness and sores of the lining of the mouth, lips or throat and other digestive organs; skin reactions caused by certain cancer drugs given after radiation; acne-like rash; heart problems; and blood electrolyte disturbances (compared to radiation and cisplatin alone)
    • Side effects resulting in death occurred in 4% of patients in the ERBITUX plus radiation and cisplatin treatment arm, and 3% in the radiation therapy and cisplatin alone treatment arm
    • 2% of patients in the ERBITUX plus radiation and cisplatin treatment arm experienced decreased blood flow to the heart, compared to 0.9% in the radiation therapy and cisplatin alone treatment arm
    • The main point of the study was to measure how long patients survived before their cancer got worse. Adding ERBITUX to radiation and cisplatin did not improve this measure
  • ERBITUX when given by itself and in combination with other cancer drugs can cause low levels of magnesium, calcium and potassium.
    • Your doctor or nurse should periodically monitor your blood electrolyte levels during and for at least 8 weeks after treatment with ERBITUX, and administer intravenous replacement as needed
  • If you have colorectal cancer with mutations in the Ras genes, you should not be treated with ERBITUX because you will not benefit from ERBITUX treatment and will experience side effects.
  • ERBITUX can harm your unborn baby. If you are able to become pregnant, you should use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX.

What are the most common side effects of ERBITUX?

  • The most common side effects (all grades of severity) reported in patients with head and neck cancer treated with ERBITUX in combination with radiation therapy versus radiation therapy alone (incidence ≥25%) were: feeling weak, fever, nausea, vomiting, weight loss, dehydration, elevated liver enzymes in blood tests, sore throat, acne-like rash, and skin irritation in the radiation area. In areas treated with radiation therapy, the addition of ERBITUX to the radiation therapy increases the risk of damage to surrounding healthly tissues in the area treated with radiation. The most common serious side effects (incidence ≥10%) reported by patients included skin irritation in the radiation area, acne-like rash, and weight loss.
  • The most common side effects (all grades of severity) in patients with head and neck cancer treated with the European version of ERBITUX in combination with platinum-based chemotherapy with fluorouracil versus chemotherapy alone (incidence ≥25%) were: acne-like rash, nausea, infection, rash, diarrhea and anorexia, a psychological disorder characterized by a loss of appetite. Most common serious side effects (incidence ≥10%) reported by patients in either arm was: infection. ERBITUX results in approximately 22% higher blood levels of cetuximab as compared to the European version of ERBITUX. It is possible that U.S. patients receiving ERBITUX may experience more frequent or severe side effects than patients in the study conducted in Europe.
  • The most common side effects (all grades of severity) in patients with Epidermal Growth Factor Receptor (EGFR) positive, KRAS wild-type colorectal cancer that has spread to other parts of the body who were treated with the European version of ERBITUX in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) versus FOLFIRI alone (incidence ≥25%) were: abnormal decrease in certain white blood cell counts, diarrhea, sore mouth, fever, anorexia, a psychological disorder characterized by a loss of appetite and rash which includes a rash including acne-like rash. Most common serious side effects (incidence ≥10%) reported by patients in either arm were: abnormal decrease in certain white blood cell counts, acne-like rash, and diarrhea. In this study, the type and severity of side effects seen with European cetuximab were similar to other studies of U.S. patients receiving ERBITUX for metastatic colorectal cancer.
  • The most common side effects (all grades of severity) in patients with Epidermal Growth Factor Receptor (EGFR) positive, KRAS wild-type colorectal cancer that has spread to other parts of the body who were treated with ERBITUX and supportive care versus supportive care alone (incidence ≥25%) were: rash including shedding of the outer layer of the skin, dry skin, itchy skin, other skin problems, nail changes, feeling tired, fever, other pain, headache, shortness of breath, cough, nausea, constipation, diarrhea, vomiting, sore mouth, infection without decrease in certain white blood cell counts, sensory neuropathy (weakness, numbness and pain from nerve damage usually in the hands and feet) and problems sleeping. Most common serious side effects (incidence ≥10%) reported by patients included: feeling tired, other pain, rash including shedding of the outer layer of the skin, shortness of breath, other intestinal problems and infection without abnormal decrease in certain white blood cell counts.
  • The most common side effects (all grades of severity) in patients with colorectal cancer that has spread to other parts of the body whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR) treated with ERBITUX and irinotecan were: acne-like rash, feeling weakness or discomfort, diarrhea, and nausea. The most common serious side effects reported included: diarrhea, decrease in white blood cell count, feeling weakness or discomfort, and acne-like rash.

You are encouraged to report negative side effects of Prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

What should I tell my doctor before starting treatment with ERBITUX?

Before you start treatment with ERBITUX, tell your doctor:
  • If you have any history of heart disease or a heart condition.
  • If you have a history of breathing problems or other lung problems.
  • If you are pregnant or if you plan on becoming pregnant. Because ERBITUX can harm an unborn baby, you should use contraception and not become pregnant during treatment with ERBITUX and for at least 2 months after your last dose of ERBITUX. If you become pregnant during your treatment or within 2 months after your last dose, discuss this with your doctor.
  • If you are breastfeeding or plan to breastfeed. ERBITUX may be passed through human breast milk. Because of the potential for serious side effects in nursing infants from ERBITUX, you should not breastfeed during ERBITUX therapy and for 2 months after the last dose of ERBITUX.
  • Tell your doctor about all the medications you are taking, including prescription and over-the-counter medications.

ERBITUX is available by prescription only.

Please see full Prescribing Information for ERBITUX, including Boxed Warnings for allergic reactions and heart attack.

CE CON ISI_ALL 16AUG2018