- ERBITUX® (cetuximab), in combination with radiation therapy, 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 with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
- 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
ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use:
- In combination with FOLFIRI (irinotecan, 5-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
Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.
- ERBITUX® (cetuximab), in combination with radiation therapy, is approved for the initial treatment of a certain type of locally or regionally advanced head and neck cancer
- ERBITUX, in combination with platinum-based chemotherapy with 5-fluorouracil, is approved 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
- ERBITUX is also approved 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
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. FDA-approved tests are used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:
- In combination with FOLFIRI (irinotecan, 5-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 FOR ERBITUX® (cetuximab)
What is the most important information I should know about ERBITUX?
- Severe allergic reactions due to ERBITUX® (cetuximab) therapy have occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies, resulting in death in less than 1 in 1000 patients
- 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, chills, or breathing problems to your doctor or nurse
- Approximately 90% of the severe allergic reactions occurred with the first dose of ERBITUX, although some patients experienced their first severe allergic reaction during a subsequent dose of ERBITUX
- Your doctor or nurse should watch you closely for these symptoms during treatment and may need to stop therapy in the event of an allergic reaction
- Severe allergic reactions require that treatment with ERBITUX be stopped immediately and not started again
- Heart attack and/or sudden death occurred in 4 of 208 patients (2%) with head and neck cancer treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone
- Heart problems resulting in death and/or sudden death occurred in 7 of 219 patients (3%) with head and neck cancer treated with platinum-based chemotherapy with 5-fluorouracil and cetuximab compared to 4 of 215 patients (2%) treated with chemotherapy alone, based on a study conducted in Europe using European cetuximab
- Notify your doctor if you have a history of any heart disease
- Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD
- In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy
- Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients. Acneiform rash usually developed within the first 2 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
- Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis)
- Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae
- Sun exposure may exacerbate these effects
- 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 3-4 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 20 patients (4.4%) in the ERBITUX combination arm and 14 patients (3.0%) in the control arm
- Nine patients in the ERBITUX arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm
- The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint)
- Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2, the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3-4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3-4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy
- Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy
- Replete electrolytes as necessary
- ERBITUX is not indicated for the treatment of patients with colorectal cancer 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 KRAS or NRAS
- Based on retrospective subset analyses of RAS-mutant and wild-type populations across several randomized clinical trials of anti-EGFR-directed monoclonal antibodies, including Study 4, use of cetuximab in patients with RAS mutations resulted in no clinical benefit with treatment related toxicity
- The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membranes (48% vs 39%), esophagus (44% vs 35%), and skin (42% vs 33%) in the ERBITUX and radiation versus radiation-alone arms, respectively
- The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
- In women of childbearing potential and men, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. 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 only be used during pregnancy if the potential benefit justifies the potential risk to the fetus
- It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. 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 ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
- The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus
- The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection
- The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87% vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs 72%), and asthenia (56% vs 49%). The most common grade 3/4 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 most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, 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 frequent adverse reactions seen in patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are 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
- The most frequent adverse reactions seen in patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (incidence ≥50%) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), dry skin (57% vs 15%), pain-other (59% vs 37%), and constipation (53% vs 38%). The most common grade 3/4 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 frequent adverse reactions seen in patients with EGFR-expressing metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse reactions (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)
Please see full Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.
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- Lung disease, which resulted in one death, occurred in 4 of 1570 patients (<0.5%) receiving ERBITUX in several clinical trials in colorectal cancer and head and neck cancer
- Notify your doctor if you develop shortness of breath while receiving ERBITUX
- ERBITUX treatment should be stopped if symptoms worsen or lung disease is confirmed
- In several clinical trials in colorectal cancer and head and neck cancer with ERBITUX, skin problems including an acne-like rash, skin drying and cracking, infections (including infections of the blood, skin, eyes, and lips), and abnormal hair growth were seen
- Sun exposure may worsen these effects
- Patients taking ERBITUX should wear sunscreen and hats to limit sun exposure while receiving and for 2 months following 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
- A related nail disorder that causes painful swelling of the skin around the nails—most often of the large toes and thumbs—also was reported
- Notify your doctor if you develop any of these symptoms while receiving ERBITUX
- In a controlled study, 940 patients with head and neck cancer received either ERBITUX with radiation therapy and cisplatin (a cancer drug) or radiation therapy and cisplatin alone. 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 20 patients (4.4%) in the ERBITUX treatment arm, and 14 patients (3.0%) in the radiation therapy and cisplatin alone treatment arm
- Nine patients in the ERBITUX treatment arm (2.0%) experienced decreased blood flow to the heart compared to 4 patients (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
- Low levels of magnesium and accompanying low calcium and potassium levels have been reported with ERBITUX when given by itself and in combination with other cancer drugs
- Your doctor or nurse should periodically monitor your blood electrolyte levels and administer intravenous replacement as needed
- You should not be treated with ERBITUX if you have colorectal cancer that has mutations in the RAS genes because you will not benefit from ERBITUX treatment and will experience side effects
- The percentage of late radiation side effects was higher in patients given ERBITUX with radiation therapy compared with patients given radiation therapy alone
- The following sites were affected: organs that produce saliva (65% versus 56%), voice box (52% versus 36%), tissue below the skin (49% versus 45%), lining of the mouth and some organs (48% versus 39%), food pipe (44% versus 35%), and skin (42% versus 33%) in the patients given ERBITUX and radiation versus patients given radiation alone, respectively
- The percentage of severe late radiation side effects was similar among patients given radiation therapy alone and patients given ERBITUX plus radiation therapy
- Notify your doctor if you are pregnant or if you become pregnant while receiving ERBITUX. Contraception must be used, in both males and females, during ERBITUX therapy and for 6 months following the last dose of ERBITUX. ERBITUX may be passed from the mother to the developing fetus, and may cause harm to the fetus. ERBITUX should only be used during pregnancy if the potential benefit is greater than the potential risk to the fetus
- ERBITUX may be passed through human breast milk. Because of the potential for serious side effects in nursing infants from ERBITUX, nursing is not recommended during ERBITUX therapy and for 2 months following the last dose of ERBITUX
- The most serious side effects associated with ERBITUX are: allergic reactions, heart attack, skin problems, skin irritation in the radiation area, infection, kidney failure, lung disease, and blood clots in the lung
- The most frequent side effects associated with ERBITUX (reported in at least 25% of patients) are skin problems (including rash, itching, and nail changes), headache, diarrhea, and infection
- The most frequent side effects were: acne-like rash (87% versus 10%), skin irritation in the radiation area (86% versus 90%), weight loss (84% versus 72%), and feeling weak (56% versus 49%)
- Serious side effects reported by at least 10% of patients that received ERBITUX in combination with radiation therapy versus radiation therapy alone included: skin irritation in the radiation area (23% versus 18%), acne-like rash (17% versus 1%), and weight loss (11% versus 7%)
- The most frequent side effects were: acne-like rash (70% versus 2%), nausea (54% versus 47%), and infection (44% versus 27%)
- Serious side effects reported by at least 10% of patients in either arm were: infection (11% versus 8%)
- ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. 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 frequent side effects were: acne-like rash (86% versus 13%) and diarrhea (66% versus 60%)
- Serious side effects reported by at least 10% of patients in either arm were: abnormal decrease in white blood cell count (31% versus 24%), acne-like rash (18% versus <1%), and diarrhea (16% versus 10%)
- ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. In this study, the side effects and severity of adverse reactions seen with European cetuximab were consistent with other studies of U.S. patients receiving ERBITUX for metastatic colorectal cancer
- The most frequent side effects reported were: rash or shedding of the outer layer of the skin (95% versus 21%), feeling tired (91% versus 79%), nausea (64% versus 50%), dry skin (57% versus 15%), other pain (59% versus 37%), and constipation (53% versus 38%)
- Serious side effects reported by at least 10% of patients included: fatigue (31% versus 29%), other pain (18% versus 10%), rash or shedding of the outer layer of the skin (16% versus 1%), shortness of breath (16% versus 13%), other intestinal problems (12% versus 5%) and infection without abnormal decrease in white blood cell count (11% versus 5%)
- The most frequent side effects reported were: acne-like rash (88%), feeling weakness or discomfort (73%), diarrhea (72%), and nausea (55%)
- Serious side effects reported by at least 10% of patients included: diarrhea (22%), decrease in white blood cell count (17%), feeling weakness or discomfort (16%), and acne-like rash (14%)
You are encouraged to report negative side effects of Prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1-800-FDA-1088.
Please see full Prescribing Information for ERBITUX, including Boxed Warnings for allergic reactions and heart attack.
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