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Description for Cyramza

CYRAMZA (ramucirumab) is a recombinant human IgG1 monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2. CYRAMZA has an approximate molecular weight of 147 kDa. CYRAMZA is produced in genetically engineered mammalian NS0 cells.

CYRAMZA is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion following dilution and preparation. 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.

ADVERSE REACTIONS

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)].

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

Adverse Reactions	CYRAMZA (N=236)		Placebo (N=115)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Vascular
Hypertensiona	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
a Hypertension is a consolidated term.

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/m2 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

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
Neutropeniaa	54	41	31	19
Thrombocytopenia	13	2	6	2
Gastrointestinal
Diarrhea	32	4	23	2
Stomatitis	20	1	7	1
Gastrointestinal hemorrhage eventsa,b	10	4	6	2
Respiratory, Thoracic, and Mediastinal
Epistaxis	31	0	7	0
Vascular
Hypertensiona	25	15	6	3
Renal and Urinary
Proteinuriaa	17	1	6	0
Metabolism and Nutrition
Hypoalbuminemiaa	11	1	5	1
a Neutropenia, gastrointestinal hemorrhage events, hypertension, proteinuria, and hypoalbuminemia are consolidated terms. b Includes 1 fatal event in the CYRAMZA arm.

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

Adverse Reactions	CYRAMZA + Erlotinib (N=221)		Placebo + Erlotinib (N=225)
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Infections
Infectionsa,b	81	17	76	7
Vascular
Hypertension	45	24	12	5
Gastrointestinal
Diarrhea	70	7	71	1
Stomatitis	42	2	36	1
Gastrointestinal hemorrhagec	10	1	3	<1
Gingival bleeding	9	0	1	0
Renal and Urinary
Proteinuriac	34	3	8	0
Skin and Subcutaneous Tissue
Alopecia	34	N/Ad	20	N/Ad
Respiratory, Thoracic, and Mediastinal
Epistaxis	34	0	12	0
Pulmonary hemorrhagec,e	7	<1	2	<1
General
Peripheral edema	23	<1	4	0
Nervous System
Headache	15	<1	7	0
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.

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

Laboratory Abnormality	CYRAMZA + Erlotiniba		Placebo + Erlotiniba
	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
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).

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/m2 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/m2 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

Adverse Reactions	CYRAMZA + Docetaxel (N=627)		Placebo + Docetaxel (N=618)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Hematology
Neutropeniaa	55	49	46	40
Febrile neutropenia	16	16	10	10
Thrombocytopeniaa	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
Hypertensiona	11	6	5	2
a Neutropenia, thrombocytopenia, and hypertension are consolidated terms.

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

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 eventsa,b	12	2	7	1
Hematology
Neutropeniaa	59	38	46	23
Thrombocytopeniaa	28	3	14	<1
Respiratory, Thoracic, and Mediastinal
Epistaxis	33	0	15	0
Vascular
Hypertensiona	26	11	9	3
General
Peripheral edema	20	<1	9	0
Renal and Urinary
Proteinuriaa,c	17	3	5	<1
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	13	1	5	<1
Metabolism and Nutrition
Hypoalbuminemiaa	6	1	2	0
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.

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

Adverse Reactions	CYRAMZA (N=197)		Placebo (N=95)
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
General
Fatiguea	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
Hypertensiona	25	13	13	5
Gastrointestinal
Abdominal Paina	25	2	16	2
Nausea	19	0	12	0
Ascitesb	18	4	7	1
Vomiting	10	0	7	0
Renal and Urinary
Proteinuriaa,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
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.

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

Laboratory Abnormalitya	CYRAMZAb		Placebob
	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
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).

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.

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

Drug Interactions for Cyramza

No information provided.

Warnings for Cyramza

Included as part of the PRECAUTIONS section.

Precautions for Cyramza

Hemorrhage

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5% [see Adverse Reactions (6.1)].

Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.

Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin, or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding [see Dosage and Administration (2.6)].

Gastrointestinal Perforations

CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2% [see Adverse Reactions (6.1)].

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.6)].

Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.

Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established [see Dosage and Administration (2.6)].

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2% [see Adverse Reactions (6.1)].

Permanently discontinue CYRAMZA in patients who experience an ATE [see Dosage and Administration (2.6)].

Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15% [see Adverse Reactions (6.1)]. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled.

Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.6)].

Infusion-Related Reactions

Infusion-related reactions (IRR), including severe and life-threatening IRR, occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1-9%. Grade 3-5 IRR incidence was <1% [see Adverse Reactions (6.1)].

Premedicate prior to each CYRAMZA infusion [see Dosage and Administration (2.1)]. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR [see Dosage and Administration (2.6)].

Worsening of Pre-existing Hepatic Impairment

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%) [see Adverse Reactions (6.1)].

Posterior Reversible Encephalopathy Syndrome

Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients enrolled in six clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.

Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death [see Dosage and Administration (2.6)].

Proteinuria Including Nephrotic Syndrome

Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3% [see Adverse Reactions (6.1)].

Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome [see Dosage and Administration (2.6)].

Thyroid Dysfunction

Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism [see Adverse Reactions (6.1)]. Monitor thyroid function during treatment with CYRAMZA.

Embryo-Fetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

OVERDOSES

No information provided.

Contraindications for Cyramza

No information provided.

Clinical Pharmacology for Cyramza

Mechanism Of Action

Ramucirumab is a VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

Pharmacokinetics

The pharmacokinetics (PK) of ramucirumab were studied in patients with various cancers over a dose range of 6-12 mg/kg administered every two or three weeks. The PK characteristics of ramucirumab are similar for patients across cancer types based on a population PK analysis. Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above and steady state concentrations were achieved at approximately 12 weeks.

Distribution

The mean (% coefficient of variation [CV%]) volume of distribution of ramucirumab at steady-state (Vss) was 5.4 L (15%).

Elimination

The mean (CV%) clearance of ramucirumab was 0.015 L/hour (30%) and the mean elimination half-life was 14 days (20%).

Specific Populations

Age (19-88 years), sex (68% male), race (70% White, 24% Asian), renal impairment (creatinine clearance [CLcr] calculated by Cockcroft-Gault, 15-89 mL/min, mild hepatic impairment (total bilirubin within ULN and AST>ULN or total bilirubin >1 to 1.5 times ULN and any AST), or moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN) had no clinically meaningful effect on the PK of ramucirumab. The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on the PK of ramucirumab is unknown.

Drug Interaction Studies

No clinically meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the approved combinations, including paclitaxel, docetaxel, irinotecan (or its active metabolite, SN-38), and erlotinib were observed in patients with solid tumors.

Animal Toxicology and/or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the human exposure at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

Patient Information for Cyramza

Hemorrhage

Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness [see Warnings and Precautions (5.1)].

Gastrointestinal Perforations

Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.2)].

Impaired Wound Healing

Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions (5.3)].

Arterial Thromboembolic Events

Advise patients of an increased risk of an arterial thromboembolic event [see Warnings and Precautions (5.4)].

Hypertension

Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5)].

Posterior Reversible Encephalopathy Syndrome

Advise patients to inform their health care provider if they develop neurological symptoms consistent with PRES (seizure, headache, nausea/vomiting, blindness, or altered consciousness) [see Warnings and Precautions (5.8)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their health care provider of a known or suspected pregnancy and to use effective contraception during CYRAMZA treatment and for 3 months after the last dose [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during CYRAMZA treatment and for 2 months after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that CYRAMZA may impair fertility [see Use in Specific Populations (8.3)]. 

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