Erbitux Drug Information
Generic name: CETUXIMAB
Epidermal Growth Factor Receptor Antagonist [EPC]
Uses of Erbitux
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 (SCCHN). in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN. as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.
K-Ras Wild-type, EGFR-expressing Colorectal Cancer (CRC) ERBITUX is indicated for the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test: 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.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.
Dosage & Administration of Erbitux
Patient Selection
Select patients with metastatic colorectal cancer (CRC) for treatment with Erbitux based on the presence of: Ras wild-type, EGFR-expressing CRC, or BRAF V600E mutation-positive metastatic CRC Information on FDA-approved tests for the detection of K-Ras or BRAF V600E mutations in CRC in patients with metastatic CRC is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN) In combination with radiation therapy Initial dose: 400 mg/m 2 administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy. Subsequent doses: 250 mg/m 2 administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks). Complete Erbitux administration 1 hour prior to radiation therapy.
As a single-agent or in combination with platinum-based therapy and fluorouracil Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule. Continue treatment until disease progression or unacceptable toxicity.
Recommended Dosage for Colorectal Cancer (CRC) As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule. The recommended subsequent dosage is 250 mg/m 2 weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosage information.
Premedication Premedicate with a histamine-1 (H 1 ) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary.
Dosage Modifications for Adverse Reactions
Reduce, delay, or discontinue Erbitux to manage adverse reactions as described in Table 1. Table 1: Recommended Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease)
Preparation for Administration
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. Visually inspect for foreign particulate matter and discoloration prior to administration, whenever solution and container permit.
Do not use if solution is discolored, cloudy, or contains foreign particulate matter. 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.
| Adverse Reaction | Severity a | Dosage Modification |
|---|---|---|
| a National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0. | ||
| Infusion reactions [see Warnings and Precautions ( 5.1 )] | Grade 1 or 2 | Reduce the infusion rate by 50%. |
| Grade 3 or 4 | Immediately and permanently, discontinue Erbitux. | |
| Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) [see Warnings and Precautions ( 5.4 )] | 1 st occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 250 mg/m 2. If no improvement, discontinue Erbitux. |
| 2 nd occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 200 mg/m 2. If no improvement, discontinue Erbitux. | |
| 3 rd occurrence; Grade 3 or 4 | Delay infusion 1 to 2 weeks; if condition improves, continue at 150 mg/m 2. If no improvement, discontinue Erbitux. | |
| 4 th occurrence; Grade 3 or 4 | Discontinue Erbitux. | |
| Pulmonary toxicity [see Warnings and Precautions ( 5.3 )] | Acute onset or worsening pulmonary symptoms | Delay infusion 1 to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence. If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue Erbitux. |
Side Effects of Erbitux
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 described in Warnings and Precautions reflect exposure to ERBITUX in 1373 patients with SCCHN or CRC enrolled in clinical trials and treated at the recommended dosage for a median of 7 to 14 weeks. The most common adverse reactions in clinical trials with ERBITUX as a single-agent or in combination with radiotherapy or chemotherapy (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.
Squamous Cell Carcinoma of the Head and Neck (SCCHN) In Combination with Radiation Therapy The safety of ERBITUX in combination with radiation therapy compared to radiation therapy alone was evaluated in BONNER. The data described below reflect exposure to ERBITUX in 420 patients with locally or regionally advanced SCCHN. Patients received a median of 8 infusions (range 1 to 11).
Table 2 provides the frequency and severity of adverse reactions in BONNER. Table 2: Selected Adverse Reactions in ≥10% of Patients with Locoregionally Advanced SCCHN (BONNER) a 0 4 0 The overall incidence of late radiation toxicities (any grade) was higher for patients receiving ERBITUX in combination with radiation therapy compared with radiation therapy alone. The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX with radiation treatment groups.
In Combination with Platinum-based Therapy and Fluorouracil The safety of a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone was evaluated in EXTREME. The data described below reflect exposure to a cetuximab product in 434 patients with recurrent locoregional disease or metastatic SCCHN. Because ERBITUX provides approximately 22% higher exposure relative to the cetuximab product, 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.
Patients received a median of 17 infusions (range 1 to 89). Table 3 provides the frequency and severity of adverse reactions in EXTREME. The majority of these events occurred in patients who received cisplatin and fluorouracil with or without cetuximab.
Cardiac disorders were observed in 11% and 12% of patients who received cisplatin and fluorouracil with or without cetuximab, respectively, and 6% and 4% in patients who received carboplatin and fluorouracil with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin and fluorouracil containing subgroup. Death attributed to cardiovascular events or sudden death was reported in 3% of the patients in the cetuximab with platinum-based therapy and fluorouracil arm and in 2% of the patients in the platinum-based therapy and fluorouracil alone arm.
K-Ras Wild-type, EGFR-expressing, Metastatic Colorectal Cancer (mCRC) In Combination with FOLFIRI The safety of a cetuximab product in combination with FOLFIRI or FOLFIRI alone was evaluated in CRYSTAL. The data described below reflect exposure to a cetuximab product in 667 patients with K-Ras wild-type, EGFR-expressing, mCRC. ERBITUX provides approximately 22% higher exposure compared to this product; however, the safety data from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication.
Patients received a median of 24 infusions (range 1 to 224). Serious adverse reactions included pulmonary embolism, which was reported in 4.4% of patients treated with cetuximab with FOLFIRI as compared to 3.4% of patients treated with FOLFIRI alone. Table 4 provides the frequency and severity of adverse reactions in CRYSTAL.
The data described below reflect exposure to ERBITUX in 242 patients with K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC). Table 5 provides the frequency and severity of adverse reactions in Study CA225-025. Table 5: Selected Adverse Reactions in ≥10% of Patients with K-Ras Wild-type, EGFR-expressing, Metastatic Colorectal Cancer Treated with Single-Agent ERBITUX Study CA 0 5 0 In Combination with Irinotecan ERBITUX at the recommended dosage was administered in combination with irinotecan in 354 patients with EGFR-expressing recurrent mCRC in Study CP02-9923 and BOND.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with Encorafenib The safety of ERBITUX (400 mg/m 2 initial dose, followed by 250 mg/m 2 weekly) in combination with encorafenib (300 mg once daily) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with ERBITUX in combination with encorafenib and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with ERBITUX.
The most common (≥ 25%) adverse reactions in patients receiving ERBITUX in combination with encorafenib were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash. Table 6 and Table 7 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC. Table 6: Adverse Reactions Occurring in ≥10% of Patients Receiving ERBITUX in Combination with Encorafenib in BEACON CRC a clinically important adverse reactions occurring in <10% of patients who received ERBITUX in combination with encorafenib were: Gastrointestinal disorders: Pancreatitis Table 7: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving ERBITUX in Combination with Encorafenib in BEACON CRC a 2
Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection 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 cetuximab in the studies below with the incidence of antibodies to cetuximab in other studies or to other products may be misleading. An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. The incidence of anti-cetuximab binding antibodies in 105 patients (from studies I4E-MC-JXBA, I4E-MC-JXBB, and I4E-MC-JXBD) with at least one post-baseline blood sample (≥4 weeks post first ERBITUX administration) was <5%.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of ERBITUX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neurologic: Aseptic meningitis Gastrointestinal: Mucosal inflammation Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis, life-threatening and fatal bullous mucocutaneous disease
| Adverse Reaction | ERBITUX with Radiation (n=208) | Radiation Therapy Alone (n=212) | ||
|---|---|---|---|---|
| Grades 1–4 b | Grades 3 and 4 | Grades 1–4 | Grades 3 and 4 | |
| a Adverse reactions occurring in ≥10% of patients in the ERBITUX combination arm and at a higher incidence (≥5%) compared to the radiation alone arm. | ||||
| b Adverse reactions were graded using the NCI CTC, version 2.0. | ||||
| c Includes cases also reported as infusion reaction. | ||||
| d Infusion reaction 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”. | ||||
| e Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for ERBITUX with Radiation arm; 209–210 for Radiation alone. | ||||
| f Acneiform rash defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. | ||||
| General | ||||
| Asthenia | 56 | 4 | 49 | 5 |
| Fever c | 29 | 1 | 13 | 1 |
| Headache | 19 | <1 | 8 | <1 |
| Chills c | 16 | 0 | 5 | 0 |
| Infusion Reaction d | 15 | 3 | 2 | 0 |
| Infection | 13 | 1 | 9 | 1 |
| Gastrointestinal | ||||
| Nausea | 49 | 2 | 37 | 2 |
| Emesis | 29 | 2 | 23 | 4 |
| Diarrhea | 19 | 2 | 13 | 1 |
| Dyspepsia | 14 | 0 | 9 | 1 |
| Metabolism and Nutrition | ||||
| Weight Loss | 84 | 11 | 72 | 7 |
| Dehydration | 25 | 6 | 19 | 8 |
| Increased Alanine Transaminase e | 43 | 2 | 21 | 1 |
| Increased Aspartate Transaminase e | 38 | 1 | 24 | 1 |
| Increased Alkaline Phosphatase e | 33 | <1 | 24 | 0 |
| Respiratory | ||||
| Pharyngitis | 26 | 3 | 19 | 4 |
| Dermatologic | ||||
| Acneiform Rash f | 87 | 17 | 10 | 1 |
| Radiation Dermatitis | 86 | 23 | 90 | 18 |
| Application Site Reaction | 18 | 0 | 12 | 1 |
| Pruritus | 16 | 0 | 4 | 0 |
| Adverse Reaction | Cetuximab with Platinum-based Therapy and fluorouracil (n=219) | Platinum-based Therapy and fluorouracil Alone (n=215) | ||
|---|---|---|---|---|
| Grades 1–4 b | Grades 3 and 4 | Grades 1–4 | Grades 3 and 4 | |
| a Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the platinum-based therapy and fluorouracil alone arm. | ||||
| b Adverse reactions were graded using the NCI CTC, version 2.0. | ||||
| c Infusion reaction defined as “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. | ||||
| d Infection excludes sepsis-related events which are presented separately. | ||||
| e Acneiform rash defined as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. | ||||
| Chemotherapy = cisplatin and fluorouracil or carboplatin and fluorouracil | ||||
| Eye | ||||
| Conjunctivitis | 10 | 0 | 0 | 0 |
| Gastrointestinal | ||||
| Nausea | 54 | 4 | 47 | 4 |
| Diarrhea | 26 | 5 | 16 | 1 |
| General and Administration Site | ||||
| Pyrexia | 22 | 0 | 13 | 1 |
| Infusion Reaction c | 10 | 2 | <1 | 0 |
| Infections | ||||
| Infection d | 44 | 11 | 27 | 8 |
| Metabolism and Nutrition | ||||
| Anorexia | 25 | 5 | 14 | 1 |
| Hypocalcemia | 12 | 4 | 5 | 1 |
| Hypokalemia | 12 | 7 | 7 | 5 |
| Hypomagnesemia | 11 | 5 | 5 | 1 |
| Dermatologic | ||||
| Acneiform Rash e | 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 |
| Adverse Reaction | Cetuximab with FOLFIRI (n=317) | FOLFIRI Alone (n=350) | ||
|---|---|---|---|---|
| Grades 1–4 b | Grades 3 and 4 | Grades 1–4 | Grades 3 and 4 | |
| a Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the FOLFIRI alone arm. | ||||
| b Adverse reactions were graded using the NCI CTC, version 2.0. | ||||
| c Infusion reaction 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: “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 ischemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. | ||||
| d Acne-like rash defined by the following events: “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”. | ||||
| Hematologic | ||||
| Neutropenia | 49 | 31 | 42 | 24 |
| Eye | ||||
| Conjunctivitis | 18 | <1 | 3 | 0 |
| Gastrointestinal | ||||
| Diarrhea | 66 | 16 | 60 | 10 |
| Stomatitis | 31 | 3 | 19 | 1 |
| Dyspepsia | 16 | 0 | 9 | 0 |
| General and Administration Site | ||||
| Pyrexia | 26 | 1 | 14 | 1 |
| Weight Decreased | 15 | 1 | 9 | 1 |
| Infusion Reaction c | 14 | 2 | <1 | 0 |
| Infections | ||||
| Paronychia | 20 | 4 | <1 | 0 |
| Metabolism and Nutrition | ||||
| Anorexia | 30 | 3 | 23 | 2 |
| Dermatologic | ||||
| Acne-like Rash d | 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 |
| Adverse Reaction | ERBITUX with BSC (n=118) | BSC alone (n=124) | ||
|---|---|---|---|---|
| Grades 1–4 b | Grades 3 and 4 | Grades 1–4 | Grades 3 and 4 | |
| a Adverse reactions occurring in ≥10% of patients in the ERBITUX with BSC arm and at a higher incidence (≥5%) compared to the BSC alone arm. | ||||
| b Adverse reactions were graded using the NCI CTC, version 2.0. | ||||
| c Infusion reaction 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. | ||||
| Dermatologic | ||||
| 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 |
| General | ||||
| Fatigue | 91 | 31 | 79 | 29 |
| Fever | 25 | 3 | 16 | 0 |
| Infusion Reactions c | 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 | 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 |
| Neurological | ||||
| 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 |
| Adverse Reaction | ERBITUX with encorafenib N=216 | ERBITUX with irinotecan or ERBITUX with FOLFIRI N=193 | ||
|---|---|---|---|---|
| All Grades (%) | ≥ Grade 3 b (%) | All Grades (%) | ≥ Grade 3 (%) | |
| a Grades per National Cancer Institute CTCAE v4.03. | ||||
| b Grade 4-5 adverse reactions in the ERBITUX with encorafenib arm were limited to Grade 5 hemorrhage (n=1). | ||||
| c Represents a composite of multiple, related preferred terms. | ||||
| General Disorders and Administration Site Conditions | ||||
| Fatigue c | 51 | 7 | 50 | 8 |
| Pyrexia c | 17 | 1 | 15 | 1 |
| Gastrointestinal Disorders | ||||
| Nausea | 34 | 1 | 41 | 1 |
| Diarrhea c | 33 | 2 | 48 | 10 |
| Abdominal pain c | 30 | 4 | 32 | 5 |
| Vomiting | 21 | 1 | 29 | 3 |
| Constipation | 15 | 0 | 18 | 1 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 27 | 2 | 27 | 3 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgia c | 27 | 4 | 3 | 0 |
| Myopathy c | 15 | 1 | 4 | 0 |
| Pain in extremity | 10 | 0 | 1 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Dermatitis acneiform c | 32 | 1 | 43 | 3 |
| Rash c | 26 | 0 | 26 | 2 |
| Pruritus c | 14 | 0 | 6 | 0 |
| Melanocytic nevus | 14 | 0 | 0 | 0 |
| Dry skin c | 13 | 0 | 12 | 1 |
| Nervous System Disorders | ||||
| Headache c | 20 | 0 | 3 | 0 |
| Peripheral neuropathy c | 12 | 1 | 6 | 0 |
| Vascular Disorders | ||||
| Hemorrhage c | 19 | 2 | 9 | 0 |
| Psychiatric Disorders | ||||
| Insomnia c | 13 | 0 | 6 | 0 |
| Laboratory Abnormality b | ERBITUX with encorafenib | ERBITUX with irinotecan or ERBITUX with FOLFIRI | ||
|---|---|---|---|---|
| All Grades (%) b b | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| a Grades per National Cancer Institute CTCAE v4.03. | ||||
| b Based on the number of patients with available baseline and at least one on-treatment laboratory test. | ||||
| Hematology | ||||
| Anemia | 34 | 4 | 48 | 5 |
| Lymphopenia | 24 | 7 | 35 | 5 |
| Increased Activated Partial Thromboplastin Time | 13 | 1 | 7 | 1 |
| Chemistry | ||||
| Hypomagnesemia | 19 | 0 | 22 | 1 |
| Increased Alkaline Phosphatase | 18 | 4 | 30 | 7 |
| Increased ALT | 17 | 0 | 29 | 3 |
| Increased AST | 15 | 1 | 22 | 2 |
| Hypokalemia | 12 | 3 | 32 | 5 |
| Hyponatremia | 11 | 2 | 13 | 2 |
Warnings & Cautions for Erbitux
Infusion Reactions ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients.
Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. 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). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX.
Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion.
Premedicate with a histamine-1(H 1 ) receptor antagonist as recommended. Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction.
Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity.
Cardiopulmonary Arrest ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients treated with radiation therapy and ERBITUX in BONNER. 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.
In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of 219 patients treated with a cetuximab product in combination with platinum-based therapy and fluorouracil. Carefully consider use of ERBITUX with radiation therapy or platinum-based therapy with fluorouracil in patients with SCCHN with a history of coronary artery disease, congestive heart failure, or arrhythmias. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX.
Pulmonary Toxicity ERBITUX can cause interstitial lung disease (ILD). ILD, including 1 fatality, 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 Toxicity ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, 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 10% of patients.
Acneiform rash usually developed within the first two 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. 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 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 main efficacy outcome of the study was progression-free survival (PFS). The addition of ERBITUX to radiation and cisplatin did not improve PFS.
ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.
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 In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition of 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. 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.
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.
Pregnancy Safety for Erbitux
Pregnancy Risk Summary Based on findings from animal studies 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 ( see Data ). Human IgG is known to cross the placental barrier; therefore, cetuximab may be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams on GD 49.
While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development), and can cause developmental anomalies and early death in surviving fetuses.
Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling.
Pediatric Use of Erbitux
Pediatric Use The safety and effectiveness of ERBITUX in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. No new safety signals were identified in pediatric patients.
The pharmacokinetics of cetuximab between the two age groups were similar following a single dose of. The volume of the distribution appears to be independent of dose and approximates the vascular space of.
Clinical Studies of Erbitux
Squamous Cell Carcinoma of the Head and Neck (SCCHN) In Combination with Radiation Therapy BONNER (NCT00004227) was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either ERBITUX in combination with radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily).
Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. The main efficacy outcome measure was duration of locoregional control. Another outcome measure was overall survival (OS).
There were 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen.
Efficacy results are presented in Table 8. Table 8: Efficacy Results in Locoregionally Advanced SCCHN in BONNER In Combination with Platinum-based Therapy with Fluorouracil EXTREME (NCT00122460) was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone.
Choice of cisplatin or carboplatin was at the discretion of the investigator. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. In the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity.
If chemotherapy was delayed because of adverse reactions, weekly cetuximab was continued. If chemotherapy was discontinued for adverse reactions, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. The main efficacy outcome measure was OS.
Other outcome measures were PFS and objective response rate (ORR). Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease.
Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period.
Efficacy results are presented in Table 9 and Figure 1. Table 9: Efficacy Results in Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME in Patients with Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME CT = Platinum-based therapy with fluorouracil CET = another cetuximab product In exploratory subgroup analyses by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab in combination with cisplatin and fluorouracil compared to cisplatin and fluorouracil alone, the difference in median OS was 3.3 months 10.6 versus 7.3 months; HR The difference in median PFS was 2.1 months 5.6 versus 3.5 months; HR The ORR was 39% and 23%, respectively OR For patients (N=149) receiving cetuximab in combination with carboplatin and fluorouracil compared to carboplatin and fluorouracil alone, the difference in median OS was 1.4 months 9.7 versus 8.3 months; HR The difference in median PFS was 1.7 months 4.8 versus 3.1 months, respectively; HR The ORR was 30% and 15%, respectively OR Figure 1 As Single-Agent EMR 62202-016 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen.
The ORR was Patients were randomized (1:1) to receive either a cetuximab product in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (Western Europe versus Eastern Europe versus other). Study treatment continued until disease progression or unacceptable toxicity.
The main efficacy outcome measure was PFS assessed by an independent review committee (IRC). Other outcome measures were OS and ORR. Demographics and baseline characteristics were similar between study arms.
Baseline characteristics and demographics in the K-Ras wild-type subset were similar to that seen in the overall population. A statistically significant improvement in PFS was observed for the cetuximab with FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85, p-value=0.036). OS was not significantly different at the planned, final analysis based on 838 events (HR=0.93, 95% CI, p-value 0.327).
Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 10 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras wild-type tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutant tumors.
Table 10: Efficacy Results in First-line EGFR-expressing, Metastatic Colorectal Cancer in YSTAL Figure 2 As Single-Agent Study CA225-025 (NCT00079066) was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either ERBITUX with best supportive care (BSC) or BSC alone. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.
Efficacy results are presented in Table 11 and Figure 3. Table 11: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer in Study CA225-025 Metastatic Colorectal Cancer in Study CA225-025 Figure 3 In Combination with Irinotecan BOND was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status.
Patients were randomized (2:1) to receive either ERBITUX in combination with irinotecan (218 patients) or ERBITUX single-agent (111 patients). In the ERBITUX with irinotecan arm, irinotecan was added to ERBITUX using the same dosage for irinotecan as the patient had previously failed. The efficacy of ERBITUX with irinotecan or ERBITUX single-agent, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory and irinotecan and oxaliplatin failures.
Approximately two-thirds had previously failed oxaliplatin treatment. In patients receiving ERBITUX with irinotecan, the ORR was median DoR was 5.7 months, and median time to progression was 4.1 months. In patients receiving ERBITUX as a single-agent, the ORR was median DoR was 4.2 months, and median time to progression was 1.5 months.
Similar response rates were observed in the pre-defined subsets in both the combination arm and single-agent arm.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) ERBITUX in combination with encorafenib was evaluated in a randomized, active-controlled, open label, multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E mutation-positive metastatic CRC, as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit, with disease progression after 1 or 2 prior regimens. Other key eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0–1.
Randomization was stratified by ECOG performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-approved). Patients were randomized 1:1:1 to one of the following treatment arms: ERBITUX in combination with encorafenib 300 mg orally once daily (ERBITUX/encorafenib arm) ERBITUX in combination with binimetinib and encorafenib 300 mg orally once daily ERBITUX with irinotecan or ERBITUX with FOLFIRI (control arm) The dosage of cetuximab in all patients was 400 mg/m 2 intravenously for the first dose followed by 250 mg/m 2 weekly. Only the results of the approved regimen (ERBITUX in combination with encorafenib) are described below.
The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and DoR as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomized patients.
ORR and DoR were assessed in the subset of the first 220 patients included in the randomized portion of the ERBITUX/encorafenib and control arm of the study. A total of 220 patients were randomized to the ERBITUX/encorafenib arm and 221 to the control arm. ERBITUX in combination with encorafenib demonstrated a statistically significant improvement in OS, ORR, and PFS compared to the active comparator.
Efficacy results are summarized in Table 12 and Figure 4. Table 12: Efficacy Results in BRAF V600E Mutation-Positive Metastatic Colorectal Cancer in BEACON in Patients with BRAF V600E Mutation-Positive Metastatic Colorectal Cancer in BEACON Figure 4
| ERBITUX plus Radiation (n=211) | Radiation Alone (n=213) | Hazard Ratio (95% CI a ) | Stratified Log-rank p-value | |
|---|---|---|---|---|
| a CI = confidence interval. | ||||
| Locoregional Control | ||||
| Median duration (months) | 24.4 | 14.9 | 0.68 (0.52–0.89) | 0.005 |
| Overall Survival | ||||
| Median duration (months) | 49.0 | 29.3 | 0.74 (0.57–0.97) | 0.03 |
| Cetuximab with Platinum-based Therapy and Fluorouracil (n=222) | Platinum-based Therapy and Fluorouracil (n=220) | |
|---|---|---|
| a CI = confidence interval. | ||
| b CMH = Cochran-Mantel-Haenszel. | ||
| Overall Survival | ||
| Median Duration (months) | 10.1 | 7.4 |
| Hazard Ratio (95% CI a ) | 0.80 (0.64, 0.98) | |
| Stratified Log-rank p-value | 0.034 | |
| Progression-free Survival | ||
| Median Duration (months) | 5.5 | 3.3 |
| Hazard Ratio (95% CI a ) | 0.57 (0.46, 0.72) | |
| Stratified Log-rank p-value | <0.0001 | |
| Objective Response Rate | 35.6% | 19.5% |
| Odds Ratio (95% CI a ) | 2.33 (1.50, 3.60) | |
| CMH b Test p-value | 0.0001 | |
| All Randomized | K-Ras Wild-type | K-Ras Mutant | ||||
|---|---|---|---|---|---|---|
| Cetuximab with FOLFIRI (n=608) | FOLFIRI (n=609) | Cetuximab with FOLFIRI (n=320) | FOLFIRI (n=356) | Cetuximab with FOLFIRI (n=216) | FOLFIRI (n=187) | |
| a Based on the Stratified Log-rank test. | ||||||
| b Post-hoc updated OS analysis, results based on an additional 162 events. | ||||||
| Progression-Free Survival | ||||||
| Number of Events (%) | 343 (56) | 371 (61) | 165 (52) | 214 (60) | 138 (64) | 112 (60) |
| Median (months) (95% CI) | 8.9 (8.0, 9.4) | 8.1 (7.6, 8.8) | 9.5 (8.9, 11.1) | 8.1 (7.4, 9.2) | 7.5 (6.7, 8.7) | 8.2 (7.4, 9.2) |
| HR (95% CI) | 0.85 (0.74, 0.99) | 0.70 (0.57, 0.86) | 1.13 (0.88, 1.46) | |||
| p-value a | 0.0358 | |||||
| Overall Survival b | ||||||
| Number of Events (%) | 491 (81) | 509 (84) | 244 (76) | 292 (82) | 189 (88) | 159 (85) |
| Median (months) (95% CI) | 19.6 (18, 21) | 18.5 (17, 20) | 23.5 (21, 26) | 19.5 (17, 21) | 16.0 (15, 18) | 16.7 (15, 19) |
| HR (95% CI) | 0.88 (0.78, 1.0) | 0.80 (0.67, 0.94) | 1.04 (0.84, 1.29) | |||
| Objective Response Rate | ||||||
| ORR (95% CI) | 46% (42, 50) | 38% (34, 42) | 57% (51, 62) | 39% (34, 44) | 31% (25, 38) | 35% (28, 43) |
| a Based on the Stratified Log-rank test. | ||||||
| All Randomized | K-Ras Wild-type | K-Ras Mutant | ||||
| ERBITUX with BSC (N=287) | BSC (N=285) | ERBITUX with BSC (N=117) | BSC (N=128) | ERBITUX with BSC (N=108) | BSC (N=100) | |
| Median (months) (95% CI) | 6.1 (5.4, 6.7) | 4.6 (4.2, 4.9) | 8.6 (7.0, 10.3) | 5.0 (4.3, 5.7) | 4.8 (3.9, 5.6) | 4.6 (3.6, 4.9) |
| HR (95% CI) | 0.77 (0.64, 0.92) | 0.63 (0.47, 0.84) | 0.91 (0.67, 1.24) | |||
| p-value a | 0.0046 | |||||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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