CYRAMZA SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Hemorrhage
• Gastrointestinal Perforations
• Impaired Wound Healing
• Arterial Thromboembolic Events
• Hypertension
• Infusion-Related Reactions
• Worsening of Pre-existing Hepatic Impairment
• Posterior Reversible Encephalopathy Syndrome
• Proteinuria Including Nephrotic Syndrome
• Thyroid Dysfunction

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 . Patients in both trials had locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) and had previously received platinumor 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 1: 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 placebotreated 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 colonystimulating 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 2 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAINBOW.

Table 2: 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. 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 antiplatelet 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 3 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 4 provides the incidence and severity of laboratory abnormalities in RELAY.

Table 3: 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
Infectionsab	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 4: 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 + Erlotinib
	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 onstudy 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.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 antiplatelet 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 5: 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. 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 6 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAISE.

Table 6: 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. 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 7 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 7: 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 8: 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

 

SRC: NLM .