CYRAMZA

Ramucirumab is a human VEGFR2 antagonist. It is a recombinant human IgG1 monoclonal antibody. Ramucirumab has an approximate molecular weight of 147 kDa. Ramucirumab is produced in genetically engineered mammalian NS0 cells. CYRAMZA (ramucirumab) injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution. CYRAMZA is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-dose vials. CYRAMZA is formulated in glycine (9.98 mg/mL), histidine (0.65 mg/mL), histidine monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 mg/mL), sodium chloride (4.383 mg/mL), and Water for Injection, USP, pH 6.0.

CYRAMZA ® is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist indicated: as a single agent or in combination with paclitaxel, for treatment of adults with advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. ( 1.1 ) in combination with erlotinib, for first-line treatment of adults with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. ( 1.2 ) in combination with docetaxel, for treatment of adults with metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. ( 1.2 ) in combination with FOLFIRI, for the treatment of adults with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. ( 1.3 ) as a single agent, for the treatment of adults with hepatocellular carcinoma in patients who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib. ( 1.4 ) 1.1 Gastric Cancer CYRAMZA ® , as a single agent or in combination with paclitaxel, is indicated for the treatment of adults with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. 1.2 Non-Small Cell Lung Cancer CYRAMZA, in combination with erlotinib, is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. CYRAMZA, in combination with docetaxel, is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. 1.3 Colorectal Cancer CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of adults with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 1.4 Hepatocellular Carcinoma CYRAMZA, as a single agent, is indicated for the treatment of adults with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

For intravenous infusion only. Do not administer as an intravenous push or bolus. ( 2.7 ) Premedicate before each infusion. ( 2.1 ) Gastric Cancer : Administer CYRAMZA 8 mg/kg every 2 weeks as a single agent or in combination with weekly paclitaxel. ( 2.2 ) Non-Small Cell Lung Cancer : Administer CYRAMZA 10 mg/kg every 2 weeks with daily erlotinib. ( 2.3 ) Administer CYRAMZA 10 mg/kg on Day 1 of a 21-day cycle prior to docetaxel. ( 2.3 ) Colorectal Cancer : Administer CYRAMZA 8 mg/kg every 2 weeks prior to FOLFIRI. ( 2.4 ) Hepatocellular Carcinoma : Administer CYRAMZA 8 mg/kg every 2 weeks. ( 2.5 ) 2.1 Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride) [see Warnings and Precautions ( 5.6 )] . For patients who have experienced a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion [see Dosage and Administration ( 2.6 )] . 2.2 Recommended Dosage for Gastric Cancer The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel. Refer to the prescribing information for paclitaxel for dosage information. 2.3 Recommended Dosage for Non-Small Cell Lung Cancer EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Refer to the prescribing information for erlotinib for dosage information. Disease Progression On Or After Platinum-based Chemotherapy – CYRAMZA in Combination with Docetaxel The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Refer to the prescribing information for docetaxel for dosage information. 2.4 Recommended Dosage for Colorectal Cancer The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information. 2.5 Recommended Dosage for Hepatocellular Carcinoma The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. 2.6 Dosage Modifications for Adverse Reactions Reduce dose, withhold dose, or discontinue CYRAMZA to manage adverse reactions as described in Table 1 . Table 1: Dosage Modifications for CYRAMZA Adverse Reaction Severity a Dosage Modification a National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0 used to identify adverse reactions Hemorrhage [see Warnings and Precautions ( 5.1 )] Grade 3 or 4 Permanently discontinue CYRAMZA Gastrointestinal Perforation [see Warnings and Precautions ( 5.2 )] All Grades Permanently discontinue CYRAMZA Wound Healing Complications [see Warnings and Precautions ( 5.3 )] All Grades Withhold CYRAMZA for 28 days prior to elective surgery. Resume CYRAMZA no sooner than 2 weeks after surgery and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established. Arterial Thromboembolic Events [see Warnings and Precautions ( 5.4 )] All Grades Permanently discontinue CYRAMZA Hypertension [see Warnings and Precautions ( 5.5 )] Severe hypertension Withhold CYRAMZA until controlled with medical management Severe hypertension that cannot be controlled with antihypertensive therapy Permanently discontinue CYRAMZA Infusion-Related Reaction (IRR) [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.6 )] Grade 1 or 2 IRR Reduce the infusion rate of CYRAMZA by 50% Grade 3 or 4 IRR Permanently discontinue CYRAMZA Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.8 )] All Grades Permanently discontinue CYRAMZA Proteinuria [see Warnings and Precautions ( 5.9 )] First occurrence of increased urine protein levels greater than or equal to 2 g per 24 hours Withhold CYRAMZA until urine protein level is less than 2 g per 24 hours Resume CYRAMZA at a reduced dose: Reduce 8 mg/kg dose to 6 mg/kg Reduce 10 mg/kg dose to 8 mg/kg Reoccurrence of urine protein level greater than 2 g per 24 hours following initial dose reduction Withhold CYRAMZA until urine protein level is less than 2 g per 24 hours Resume CYRAMZA at a reduced dose: Reduce 6 mg/kg dose to 5 mg/kg Reduce 8 mg/kg dose to 6 mg/kg Urine protein level greater than 3 g per 24 hours or in the setting of nephrotic syndrome Permanently discontinue CYRAMZA 2.7 Preparation and Administration Preparation Visually inspect vials for particulate matter and discoloration. Discard if particulate matter or discolorations are identified. Calculate the dose and the required volume of CYRAMZA needed for the calculated dose. Withdraw the required volume of CYRAMZA and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use dextrose containing solutions . Do not shake. Gently invert the container to ensure adequate mixing. Do not dilute with other solutions or co-infuse with other electrolytes or medications. Do not freeze . Store diluted solution for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C [77°F]). Discard any unused portion of CYRAMZA. Administration Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Discard if particulate matter or discolorations are identified. Do not administer CYRAMZA as an intravenous push or bolus. Administer diluted CYRAMZA solution via infusion pump through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile 0.9% Sodium Chloride Injection at the end of the infusion.

None None ( 4 )

The following serious adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.1 )] . Gastrointestinal Perforations [see Warnings and Precautions ( 5.2 )] . Impaired Wound Healing [see Warnings and Precautions ( 5.3 )] . Arterial Thromboembolic Events [see Warnings and Precautions ( 5.4 )] . Hypertension [see Warnings and Precautions ( 5.5 )] . Infusion-Related Reactions [see Warnings and Precautions ( 5.6 )] . Worsening of Pre-existing Hepatic Impairment [see Warnings and Precautions ( 5.7 )] . Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions ( 5.8 )] . Proteinuria Including Nephrotic Syndrome [see Warnings and Precautions ( 5.9 )] . Thyroid Dysfunction [see Warnings and Precautions ( 5.10 )] . The most common adverse reactions observed in single agent CYRAMZA-treated gastric cancer patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. ( 6.1 ) The most common adverse reactions observed in patients treated with CYRAMZA with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. ( 6.1 ) The most common adverse reactions observed in patients treated with CYRAMZA with erlotinib at a rate of ≥30% and ≥2% higher than placebo with erlotinib were, infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities at a rate of ≥30% and ≥2% higher difference in incidence between arms were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. ( 6.1 ) The most common adverse reactions observed in patients treated with CYRAMZA with docetaxel at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. ( 6.1 ) The most common adverse reactions observed in patients treated with CYRAMZA with FOLFIRI at a rate of ≥30% and ≥2% higher than placebo with FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. ( 6.1 ) The most common adverse reactions observed in single agent CYRAMZA-treated HCC patients at a rate of ≥15% and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities at a rate of ≥30% and a ≥2% higher difference in incidence between arms were thrombocytopenia, hypoalbuminemia, and hyponatremia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section reflect exposure to CYRAMZA in 2137 patients from six studies: REGARD, RAINBOW, RAISE, REVEL, REACH-2, and RELAY. Gastric Cancer The safety of CYRAMZA was evaluated in REGARD and RAINBOW [see Clinical Studies ( 14.1 )] . Patients in both trials had locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) and had previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Both trials excluded patients with uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. REGARD excluded patients with bilirubin ≥1.5 mg/dL and RAINBOW excluded patients with bilirubin >1.5 times the upper limit of normal (ULN). CYRAMZA Administered as a Single Agent (REGARD) Patients received either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients randomized to CYRAMZA received a median of 4 doses; the median duration of exposure was 8 weeks and 32 (14% of 236) patients received CYRAMZA for at least six months. The most common serious adverse reactions with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. The most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. Table 2 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in REGARD. Table 2: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in REGARD a Hypertension is a consolidated term. Adverse Reactions CYRAMZA (N=236) Placebo (N=115) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Vascular Hypertension a 16 8 8 3 Gastrointestinal Diarrhea 14 1 9 2 Nervous System Headache 9 0 3 0 Metabolism and Nutrition Hyponatremia 6 3 2 1 Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in REGARD were: Neutropenia (4.7%) Epistaxis (4.7%) Rash (4.2%) Intestinal obstruction (2.1%) Arterial thromboembolic events (1.7%) Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRR. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRR was 0.4%. CYRAMZA Administered in Combination with Paclitaxel (RAINBOW) Patients received paclitaxel 80 mg/m 2 on Days 1, 8, and 15 of each 28-day cycle with either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients randomized to CYRAMZA received a median of 9 doses; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months. The most common serious adverse reactions in patients who received CYRAMZA with paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in ≥2% of patients in RAINBOW were neutropenia (4%) and thrombocytopenia (3%). The most common adverse reactions (all grades) observed in patients who received CYRAMZA with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. Table 3 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAINBOW. Table 3: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RAINBOW a Neutropenia, gastrointestinal hemorrhage events, hypertension, proteinuria, and hypoalbuminemia are consolidated terms. b Includes 1 fatal event in the CYRAMZA arm. Adverse Reactions CYRAMZA + Paclitaxel (N=327) Placebo + Paclitaxel (N=329) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) General Fatigue/Asthenia 57 12 44 6 Peripheral edema 25 2 14 1 Hematology Neutropenia a 54 41 31 19 Thrombocytopenia 13 2 6 2 Gastrointestinal Diarrhea 32 4 23 2 Stomatitis 20 1 7 1 Gastrointestinal hemorrhage events a,b 10 4 6 2 Respiratory, Thoracic, and Mediastinal Epistaxis 31 0 7 0 Vascular Hypertension a 25 15 6 3 Renal and Urinary Proteinuria a 17 1 6 0 Metabolism and Nutrition Hypoalbuminemia a 11 1 5 1 Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with paclitaxel were: Sepsis (3.1%), including 5 fatal events Gastrointestinal perforations (1.2%), including 1 fatal event Non-Small Cell Lung Cancer CYRAMZA Administered in Combination with Erlotinib (RELAY) The safety of CYRAMZA was evaluated in RELAY [see Clinical Studies ( 14.2 )] . Patients had previously untreated EGFR exon 19 deletion or exon 21 (L858R) substitution mutation-positive metastatic NSCLC. Patients had ECOG PS 0 or 1. RELAY excluded patients with bilirubin greater than the ULN, central nervous system (CNS) metastases, clinically active interstitial lung disease (ILD), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months. The study also excluded patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously every two weeks in combination with erlotinib 150 mg taken orally once daily. Patients randomized to CYRAMZA received a median of 21 doses; the median duration of exposure was 11 months, and 90 (41% of 221) patients received CYRAMZA for at least 12 months. The most common serious adverse reactions in patients who received CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo. Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%). The most common adverse reactions (all grades) observed in CYRAMZA with erlotinib-treated patients at a rate of ≥30% of patients and ≥2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities ≥30% and ≥2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Table 4 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 5 provides the incidence and severity of laboratory abnormalities in RELAY. Table 4: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RELAY Abbreviations: N/A = not applicable. a Includes all preferred terms that are part of the System Organ Class Infections and Infestations. Most common (≥1%) Grade ≥3 infections and frequencies for CYRAMZA with erlotinib compared to placebo with erlotinib, respectively, include pneumonia (3% versus 0%), cellulitis (1% versus 0%), paronychia (4% versus 3%), skin infection (1% versus 0%), and urinary tract infection (1% versus 0%). b Includes 3 fatal events in the CYRAMZA arm. c Gastrointestinal hemorrhage, proteinuria, and pulmonary hemorrhage are consolidated terms. d Grade ≥3 does not exist in CTCAE. e Includes 1 fatal event in the CYRAMZA arm. Adverse Reactions CYRAMZA + Erlotinib (N=221) Placebo + Erlotinib (N=225) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Infections Infections a,b 81 17 76 7 Vascular Hypertension 45 24 12 5 Gastrointestinal Diarrhea 70 7 71 1 Stomatitis 42 2 36 1 Gastrointestinal hemorrhage c 10 1 3 <1 Gingival bleeding 9 0 1 0 Renal and Urinary Proteinuria c 34 3 8 0 Skin and Subcutaneous Tissue Alopecia 34 N/A d 20 N/A d Respiratory, Thoracic, and Mediastinal Epistaxis 34 0 12 0 Pulmonary hemorrhage c,e 7 <1 2 <1 General Peripheral edema 23 <1 4 0 Nervous System Headache 15 <1 7 0 Table 5: Laboratory Abnormalities Worsening from Baseline in ≥20% (All Grades) of Patients Receiving CYRAMZA with Erlotinib with a Difference Between Arms of ≥2% in RELAY a The denominator used to calculate the incidence varied based on the number of patients with a baseline and at least one on-study laboratory measurement: CYRAMZA-treated patients (range 215-218 patients) and placebo-treated patients (range 224-225 patients). Laboratory Abnormality CYRAMZA + Erlotinib a Placebo + Erlotinib a All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Chemistry Alanine aminotransferase increased 74 11 60 13 Aspartate aminotransferase increased 71 6 47 4 Alkaline phosphatase increased 25 <1 16 1 Hypokalemia 24 5 18 2 Hematology Anemia 42 5 25 2 Thrombocytopenia 41 3 12 3 Neutropenia 33 7 21 4 CYRAMZA Administered in Combination with Docetaxel (REVEL) The safety of CYRAMZA was evaluated in REVEL [see Clinical Studies ( 14.2 )]. Patients had NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease and ECOG PS 0 or 1. REVEL excluded patients with bilirubin greater than the ULN, uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously in combination with docetaxel 75 mg/m 2 intravenously every 21 days. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, REVEL was amended and 24 patients (11 patients receiving CYRAMZA with docetaxel, 13 patients receiving placebo with docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m 2 every three weeks. Patients randomized to CYRAMZA received a median of 4.5 doses; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions (all grades) observed in CYRAMZA with docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Table 6 provides the frequency and severity of adverse reactions (NCI CTCAE, version 4.0) in REVEL. Table 6: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in REVEL a Neutropenia, thrombocytopenia, and hypertension are consolidated terms. Adverse Reactions CYRAMZA + Docetaxel (N=627) Placebo + Docetaxel (N=618) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Hematology Neutropenia a 55 49 46 40 Febrile neutropenia 16 16 10 10 Thrombocytopenia a 13 3 5 <1 General Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Gastrointestinal Stomatitis/Mucosal inflammation 37 7 19 2 Respiratory, Thoracic, and Mediastinal Epistaxis 19 <1 7 <1 Eye Lacrimation increased 13 <1 5 0 Vascular Hypertension a 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were: Hyponatremia (4.8%) Proteinuria (3.3%) Colorectal Cancer The safety of CYRAMZA was evaluated in RAISE [see Clinical Studies ( 14.3 )] . Patients had mCRC with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine and ECOG PS 0 or 1. RAISE excluded patients with uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding event; or bowel perforation. Patients received either CYRAMZA 8 mg/kg or placebo intravenously in combination with FOLFIRI intravenously every two weeks. Patients randomized to CYRAMZA received a median of 8 doses (range 1-68); the median duration of exposure was 4.4 months, and 169 (32% of 529) patients received CYRAMZA for at least six months. The most common serious adverse reactions with CYRAMZA with FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%). Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA with FOLFIRI as compared to placebo with FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%). The most common adverse reactions (all grades) observed in CYRAMZA with FOLFIRI-treated patients at a rate of ≥30% and ≥2% higher than placebo with FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony-stimulating factors. Table 7 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAISE. Table 7: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RAISE a Gastrointestinal hemorrhage events, neutropenia, thrombocytopenia, hypertension, proteinuria, and hypoalbuminemia, are consolidated terms. b Includes 3 fatal events in the CYRAMZA arm. c Includes 3 patients with nephrotic syndrome in the CYRAMZA arm. Adverse Reactions CYRAMZA + FOLFIRI (N=529) Placebo + FOLFIRI (N=528) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Gastrointestinal Diarrhea 60 11 51 10 Decreased appetite 37 2 27 2 Stomatitis 31 4 21 2 Gastrointestinal hemorrhage events a,b 12 2 7 1 Hematology Neutropenia a 59 38 46 23 Thrombocytopenia a 28 3 14 <1 Respiratory, Thoracic, and Mediastinal Epistaxis 33 0 15 0 Vascular Hypertension a 26 11 9 3 General Peripheral edema 20 <1 9 0 Renal and Urinary Proteinuria a,c 17 3 5 <1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 13 1 5 <1 Metabolism and Nutrition Hypoalbuminemia a 6 1 2 0 Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with FOLFIRI were: Gastrointestinal perforation (1.7%) including 4 fatal events Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo with FOLFIRI-treated patients) with normal baseline TSH levels. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated with placebo with FOLFIRI. Hepatocellular Carcinoma The safety of CYRAMZA was evaluated in REACH-2 [see Clinical Studies ( 14.4 )] . Patients had Barcelona Clinic Liver Cancer (BCLC) stage B HCC who were no longer amenable to locoregional therapy, or BCLC stage C HCC, Child-Pugh score A, and baseline AFP ≥400 ng/mL. Patients had ECOG PS 0 or 1. REACH-2 excluded patients with clinically meaningful ascites, history of or current hepatic encephalopathy, uncontrolled hypertension, major surgery within 28 days, bilirubin >1.5 times ULN, severe variceal bleeding in the 3 months prior to treatment or with varices at high risk of bleeding, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients received a median of 6 doses (range 1-51) of CYRAMZA; the median duration of exposure was 12 weeks (range 2-107 weeks) and 48 patients (24% of 197) received CYRAMZA for at least six months. The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%). Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%). The most common adverse reactions reported in ≥15% of patients and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities ≥30% and ≥2% higher than placebo were thrombocytopenia, hypoalbuminemia, and hyponatremia. Table 8 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 9 provides the incidence and severity of laboratory abnormalities in REACH-2. Table 8: Adverse Reactions Occurring in ≥10% of Patients with a ≥2% Difference Between Arms in REACH-2 a Fatigue, hypertension, abdominal pain, and proteinuria are consolidated terms. b Includes 1 fatal event in the CYRAMZA arm. c Includes 1 patient with nephrotic syndrome in the CYRAMZA arm. Adverse Reactions CYRAMZA (N=197) Placebo (N=95) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) General Fatigue a 36 5 20 3 Peripheral edema 25 2 14 0 Decreased appetite 23 2 20 1 Insomnia 11 0 6 1 Pyrexia 10 0 3 0 Vascular Hypertension a 25 13 13 5 Gastrointestinal Abdominal Pain a 25 2 16 2 Nausea 19 0 12 0 Ascites b 18 4 7 1 Vomiting 10 0 7 0 Renal and Urinary Proteinuria a , c 20 2 4 0 Nervous System Headache 14 0 5 1 Respiratory, Thoracic, and Mediastinal Epistaxis 14 <1 3 0 Musculoskeletal Back Pain 10 <1 7 1 Clinically relevant adverse drug reactions reported in ≥1% and <10% of CYRAMZA-treated patients in REACH-2 were: IRR (9%) Hepatic encephalopathy (5%) including 1 fatal event Hepatorenal syndrome (2%) including 1 fatal event Table 9: Laboratory Abnormalities Worsening from Baseline in ≥15% (All Grades) of Patients Receiving CYRAMZA with a Difference Between Arms of ≥2% in REACH-2 a Laboratory abnormalities were not included if the ≥ Grade 3 percentage was less than placebo-treated patients. b The denominator used to calculate the incidence varied based on the number of patients with a baseline and at least one on study laboratory measurement: CYRAMZA-treated patients (range 179-193 patients) and placebo-treated patients (range 84-92 patients). Laboratory Abnormality a CYRAMZA b Placebo b All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Hematology Thrombocytopenia 46 8 15 1 Neutropenia 24 8 12 3 Chemistry Hypoalbuminemia 33 <1 16 0 Hyponatremia 32 16 25 5 Hypocalcemia 16 2 5 0 6.2 Immunogenicity As with all therapeutic proteins, there is the 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 incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CYRAMZA. Because such 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. Blood and lymphatic system: Thrombotic microangiopathy Neoplasms benign, malignant and unspecified: Hemangioma Respiratory, thoracic, and mediastinal: Dysphonia Vascular: Arterial (including aortic) aneurysms, dissections, and rupture Cardiac: Heart failure