May 27, 2016
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Cyramza

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Cyramza




Cyramza Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Cyramza (ramucirumab) is a recombinant human IgG1 monoclonal antibody used a single-agent is for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. Common side effects include high blood pressure, diarrhea, headache, and low levels of sodium in the blood.

The recommended dose of Cyramza Is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Cyramza may interact with other drugs. Tell your doctor all medications and supplements you use. During pregnancy, Cyramza should be used only if prescribed. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.

Our Cyramza (ramucirumab) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Cyramza FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

The following adverse drug reactions are discussed in greater detail in other sections of the label:

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.

Gastric Cancer

Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m² on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥ 1.5 mg/dL and Study 2 excluded patients with bilirubin > 1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent

Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were W hite, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, 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. The most common serious adverse events 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.

Table 2 provides the frequency and severity of adverse reactions in Study 1.

Table 2: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1

Adverse Reactions (MedDRA) System Organ Class CYRAMZA (8 mg/kg)
N=236
Placebo
N=115
All Grades (Frequency %) Grade 3-4 (Frequency %) All Grades (Frequency %) Grade 3-4 (Frequency %)
Gastrointestinal Disorders
  Diarrhea 14 1 9 2
Metabolism and Nutrition Disorders
  Hyponatremia 6 3 2 1
Nervous System Disorders
  Headache 9 0 3 0
Vascular Disorders
  Hypertension 16 8 8 3

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo) [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

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 infusion-related reactions.

In Study 1, 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 Study 1 was 0.8% and the rate of infusion-related reactions was 0.4% [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

CYRAMZA Administered in Combination with Paclitaxel

Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 61 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥ 30% and ≥ 2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 3 provides the frequency and severity of adverse reactions in Study 2.

Table 3: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2

Adverse Reactions (MedDRA) System Organ Class CYRAMZA plus Paclitaxel
(N=327)
Placebo plus Paclitaxel
(N=329)
All Grades (Frequency %) Grade ≥ 3 (Frequency %) All Grades (Frequency %) Grade ≥ 3 (Frequency %)
Blood and Lymphatic System Disorders
  Neutropenia 54 41 31 19
  Thrombocytopenia 13 2 6 2
Gastrointestinal Disorders
  Diarrhea 32 4 23 2
  Gastrointestinal hemorrhage events 10 4 6 2
  Stomatitis 20 1 7 1
General Disorders and Administration Site Disorders
  Fatigue/Asthenia 57 12 44 6
  Peripheral edema 25 2 14 1
Metabolism and Nutrition Disorders
  Hypoalbuminemia 11 1 5 1
Renal and Urinary Disorders
  Proteinuria 17 1 6 0
Respiratory, Thoracic, and Mediastinal Disorders
  Epistaxis 31 0 7 0
Vascular Disorder
  Hypertension 25 15 6 3

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Non-Small Cell Lung Cancer

CYRAMZA Administered in Combination with Docetaxel

Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m² intravenously every 3 weeks or placebo plus docetaxel 75 mg/m² intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m² every 3 weeks.

Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (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. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor.

The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were W hite and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months.

In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥ 30% and ≥ 2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (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 plus docetaxel compared to 6% overall incidence and 1% for ≥ Grade 3 pulmonary hemorrhage for placebo plus 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 plus docetaxel compared to 12% overall incidence and 2% for ≥ Grade 3 pulmonary hemorrhage for placebo plus docetaxel.

The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥ 65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

Adverse Reactions (MedDRA) System Organ Class CYRAMZA plus docetaxel
(N=627)
Placebo plus docetaxel
(N=618)
All Grades (Frequency %) Grade 3-4 (Frequency %) All Grades (Frequency %) Grade 3-4 (Frequency %)
Blood and Lymphatic System Disorders
  Febrile neutropenia 16 16 10 10
  Neutropenia 55 49 46 40
  Thrombocytopenia 13 3 5 < 1
Gastrointestinal Disorders
  Stomatitis/Mucosal inflammation 37 7 19 2
Eye Disorders
  Lacrimation increased 13 < 1 5 0
General Disorders and Administration Site Disorders
  Fatigue/Asthenia 55 14 50 11
  Peripheral edema 16 0 9 < 1
Respiratory, Thoracic, and Mediastinal Disorders
  Epistaxis 19 < 1 7 < 1
Vascular Disorders
  Hypertension 11 6 5 2

Clinically relevant adverse drug reactions reported in ≥ 1% and < 5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Colorectal Cancer

CYRAMZA Administered in Combination with FOLFIRI

Study 4 was a multinational, randomized, double-blind study conducted in patients with metastatic colorectal cancer with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients received either CYRAMZA 8 mg/kg intravenously plus FOLFIRI intravenously every 2 weeks or placebo plus FOLFIRI intravenously every 2 weeks.

Study 4 excluded patients with an ECOG PS of 2 or greater, 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.

Demographics and baseline characteristics for the treated population were similar between treatment arms (n=1057). Median age was 62 years; 57% of patients were men; 76% were White and 20% were Asian; 48% had ECOG PS 0.

The data described in this section reflect exposure to CYRAMZA plus FOLFIRI in 529 patients in Study 4. Patients received a median of 8 doses (range 1-68) of CYRAMZA; 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 adverse reactions (all grades) observed in CYRAMZA plus FOLFIRI-treated patients at a rate of ≥ 30% and ≥ 2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors. Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%).

The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus 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 serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

Table 5 provides the frequency and severity of adverse reactions in Study 4.

Table 5: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving CYRAMZA in Study 4

Adverse Reactions (MedDRA) System Organ Class CYRAMZA plus FOLFIRI
N=529
Placebo plus FOLFIRI
N=528
All Grades (Frequency %) Grade ≥ 3 (Frequency %) All Grades (Frequency %) Grade ≥ 3 (Frequency %)
Blood and Lymphatic System Disorders
  Neutropenia 59 38 46 23
  Thrombocytopenia 28 3 14 < 1
Gastrointestinal Disorders
  Decreased appetite 37 2 27 2
  Diarrhea 60 11 51 10
  Gastrointestinal hemorrhage events 12 2 7 1
  Stomatitis 31 4 21 2
General Disorders and Administration Site Disorders
  Peripheral edema 20 < 1 9 0
Metabolism and Nutrition Disorders
  Hypoalbuminemia 6 1 2 0
Renal and Urinary Disorders
  Proteinuriaa 17 3 5 < 1
Respiratory, Thoracic, and Mediastinal Disorders
  Epistaxis 33 0 15 0
Skin and Subcutaneous Tissue Disorders
  Palmar-plantar erythrodysesthesia syndrome 13 1 5 < 1
Vascular Disorders
  Hypertension 26 11 9 3
aIncludes 3 patients with nephrotic syndrome in the CYRAMZA plus FOLFIRI treatment group.

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in Study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).

Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus 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 plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) 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.

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.

Read the entire FDA prescribing information for Cyramza (Ramucirumab Solution for Intravenous Infusion)

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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