Data from FDA - Curated by EPG Health - Last updated 04 April 2018

Indication(s)

1 INDICATIONS AND USAGE 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 advanced gastric or gastro-esophageal junction adenocarcinoma, with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. (1.1) in combination with docetaxel, for treatment of 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 metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. (1.3) 1.1 Gastric Cancer CYRAMZA® as a single agent, or in combination with paclitaxel, is indicated 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. 1.2 Non-Small Cell Lung Cancer CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) 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. 1.3 Colorectal Cancer CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Fluid Management

Fluid Management

Are you up-to-date with the latest evidence of effective procedures for fluid management?

+ 2 more

Hereditary ATTR amyloidosis

Hereditary ATTR amyloidosis

Explore the pathophysiology, epidemiology and multi-system symptoms associated with hereditary ATTR amyloidosis, as well as how to achieve an early and accurate diagnosis.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS None None (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: Hemorrhage [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Arterial Thromboembolic Events [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Hypertension [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)]. Infusion-Related Reactions [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]. Gastrointestinal Perforation [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Impaired Wound Healing [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)]. Patients with Child-Pugh B or C Cirrhosis [see Warnings and Precautions (5.7)]. Reversible Posterior Leukoencephalopathy 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 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 plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. (6.1) The most common adverse reactions observed in patients treated with CYRAMZA plus docetaxel at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. (6.1) The most common adverse reactions observed in patients treated with CYRAMZA plus FOLFIRI at a rate of ≥30% and ≥2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. (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. 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 White, 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 (2.3) and Warnings and Precautions (5.1, 5.2)]. 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 (2.2, 2.3) and Warnings and Precautions (5.4, 5.5)]. 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 White 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 a Includes 3 patients with nephrotic syndrome in the CYRAMZA plus FOLFIRI treatment group. 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 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. 6.2 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. For intravenous infusion only. Do not administer as an intravenous push or bolus. (2) Gastric Cancer The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks. (2.1, 2.2, 2.3) Non-Small Cell Lung Cancer Administer CYRAMZA at 10 mg/kg intravenously on day 1 of a 21-day cycle prior to docetaxel infusion. (2.1, 2.2, 2.3) Colorectal Cancer Administer CYRAMZA at 8 mg/kg intravenously every 2 weeks, prior to FOLFIRI administration. (2.1, 2.2, 2.3) 2.1 Recommended Dose and Schedule Gastric Cancer The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel. Non-Small Cell Lung Cancer The recommended dose 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. Continue CYRAMZA until disease progression or unacceptable toxicity. Colorectal Cancer The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease progression or unacceptable toxicity. 2.2 Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion [see Dosage and Administration (2.3)]. 2.3 Dose Modifications Infusion-Related Reactions (IRR) Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. Hypertension Interrupt CYRAMZA for severe hypertension until controlled with medical management. Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy [see Warnings and Precautions (5.3)]. Proteinuria Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 1) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose (see Table 1) once the urine protein level returns to <2 g/24 hours. Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)]. Table 1: CYRAMZA Dose Reductions for Proteinuria Initial CYRAMZA Dose First Dose Reduction to: Second Dose Reduction to: 8 mg/kg 6 mg/kg 5 mg/kg 10 mg/kg 8 mg/kg 6 mg/kg Wound Healing Complications Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed [see Warnings and Precautions (5.6)]. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding Permanently discontinue CYRAMZA [see Warnings and Precautions (5.1, 5.2, 5.5)]. For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information. 2.4 Preparation for Administration Inspect vial contents for particulate matter and discoloration prior to dilution [see Description (11)]. Discard the vial, if particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. Calculate the dose and the required volume of CYRAMZA needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of CYRAMZA. 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. Gently invert the container to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications. Store diluted infusion 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 vial with any unused portion of CYRAMZA. 2.5 Administration Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution. Administer diluted CYRAMZA infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not advised. (8.2) 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)], CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug–associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Data Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. 8.2 Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. 8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. 8.5 Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. [see Clinical Studies (14.1)] Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over [see Clinical Studies (14.2)]. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). [see Clinical Studies (14.2)] Of the 529 patients who received CYRAMZA plus FOLFIRI in Study 4, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects. [see Clinical Studies (14.3)] 8.6 Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38 [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number BLA125477
Agency product number D99YVK4L0X
Orphan designation No
Product NDC 0002-7678,0002-7669
Date Last Revised 01-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1657777
Storage and handling 16.2 Storage and Handling Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial.
Marketing authorisation holder Eli Lilly and Company
Warnings WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.3), Warnings and Precautions (5.5)]. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications [see Dosage and Administration (2.3), Warnings and Precautions (5.6)]. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING See full prescribing information for complete boxed warning. Hemorrhage: CYRAMZA increased the risk of hemorrhage, and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. (2.3, 5.1) Gastrointestinal Perforation: Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. (2.3, 5.5) Impaired Wound Healing: Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications (2.3, 5.6)