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——美国FDA扩展Cyramza的批准使用治疗侵袭性非小细胞肺癌
CYRAMZA® is a human vascular endothelial growth factor receptor 2 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) DOSAGE AND ADMINISTRATION 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) DOSAGE FORMS AND STRENGTHS Injection: 100 mg/10 mL (10 mg per mL) solution, single-dose vial (3) 500 mg/50 mL (10 mg per mL) solution, single-dose vial (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Arterial Thromboembolic Events (ATEs): Serious, sometimes fatal ATEs have been reported in clinical trials. Discontinue CYRAMZA for severe ATEs. (5.2) Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend CYRAMZA for severe hypertension. Discontinue CYRAMZA for hypertension that cannot be medically controlled. (5.3) Infusion-Related Reactions: Monitor for signs and symptoms during infusion. (5.4) Gastrointestinal Perforation: Discontinue CYRAMZA. (5.5) Impaired Wound Healing: Withhold CYRAMZA prior to surgery. (5.6) Clinical Deterioration in Patients with Cirrhosis: New onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. (5.7) Reversible Posterior Leukoencephalopathy Syndrome: Discontinue CYRAMZA. (5.8) ADVERSE REACTIONS 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) 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. USE IN SPECIFIC POPULATIONS Pregnancy: Based on its mechanism of action, CYRAMZA may cause fetal harm. (8.1) Nursing Mothers: Discontinue nursing or discontinue CYRAMZA. (8.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 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 CancerCYRAMZA, 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. 2 DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. 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 approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. 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 Adverse Reactions (6.1)]. Table 1: CYRAMZA Dose Reductions for Proteinuria
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 or docetaxel, 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. 3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/10 mL (10 mg per mL) solution, single-dose vial 500 mg/50 mL (10 mg per mL) solution, single-dose vial Close 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding [see Dosage and Administration (2.3)]. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. 5.2 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE [see Dosage and Administration (2.3)]. 5.3 Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.3)]. 5.4 Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs 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. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs [see Dosage and Administration (2.3)]. 5.5 Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.3)]. 5.6 Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed [see Dosage and Administration (2.3)]. 5.7 Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis 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. 5.8 Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. 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)]. 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
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 60 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
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
6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 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. 7 DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and paclitaxel or between ramucirumab and docetaxel [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may 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 adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. 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. 8.3 Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA's impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 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)] 8.6 Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (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) based on population PK 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)]. 8.8 Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility [see Nonclinical Toxicology (13.1)]. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. 10 OVERDOSAGE There are no data on overdose in humans. CYRAMZA was administered at doses up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. 11 DESCRIPTION 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. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model. 12.3 Pharmacokinetics With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastro-esophageal junction cancer, the geometric means of the minimum ramucirumab concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose. Similar Cmin values of ramucirumab were observed when ramucirumab was administered with paclitaxel. Based on a population PK analysis, the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%). With the dosing regimen of 10 mg/kg every 21 days in patients with NSCLC, the geometric means (ranges) of the minimum ramucirumab concentrations (Cmin) were 28 μg/mL (3-108 μg/mL) after the second dose and 38 μg/mL (3-128 μg/mL) after the fourth dose. Based on a population PK analysis in NSCLC patients, the mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 L/hour (27%), the mean volume of distribution at steady state (Vss) was 7.1 L (13%), and the mean elimination half-life was 23 days (24%). Specific Populations Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis. Renal Impairment: The effect of renal impairment on the average concentration of ramucirumab at steady state (Css) was evaluated in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n=368), moderate (CLcr 30-59 mL/min, n=160) or severe (CLcr 15 -29 mL/min, n=4) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n=360) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were observed between patients with renal impairment and patients with normal renal function. Hepatic Impairment: The effect of hepatic impairment on the average Css of ramucirumab was evaluated in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN or total bilirubin >1.0-1.5 times ULN and any AST, n=143) compared to patients with normal hepatic function (total bilirubin and AST ≤ULN, n=735) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were found between patients with mild hepatic impairment and patients with normal hepatic function. No PK data were available from patients with moderate (total bilirubin >1.5-3.0 times ULN and any AST) or severe hepatic dysfunction (total bilirubin >3.0 times ULN and any AST). Drug Interaction Studies No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when CYRAMZA 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors. No clinically meaningful changes in docetaxel exposure were observed when CYRAMZA 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumors. 13 NONCLINICAL TOXICOLOGY 13.1 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. 13.2 Animal Toxicology and/or Pharmacology Adverse effects in the kidney (glomerulonephritis) occurred with 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 exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model. 14 CLINICAL STUDIES 14.1 Gastric Cancer Study 1 was a multinational, randomized, double-blind, multicenter study of CYRAMZA plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients received either an intravenous infusion of CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ). Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo. Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA as compared to patients randomized to receive placebo. Efficacy results are shown in Table 5 and Figure 1. Table 5: Randomized Trial of CYRAMZA plus BSC versus Placebo plus BSC in Gastric Cancer
Figure 1: Kaplan-Meier Curves of Overall Survival - CYRAMZA plus BSC versus Placebo plus BSC in Gastric Cancer
Figure 2: Kaplan-Meier Curves of Overall Survival - CYRAMZA plus Paclitaxel versus Placebo plus Paclitaxel in Gastric Cancer
Figure 3: Kaplan-Meier Curves of Overall Survival - CYRAMZA plus Docetaxel versus Placebo plus Docetaxel in NSCLC
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雷莫芦单抗注射剂|CYRAMZA (ramucirumab) injection,简介：
——美国FDA扩展Cyramza的批准使用治疗侵袭性非小细胞肺癌2014年12月12日，美国FDA批准Cyramza (ramucirumab)治疗转移性非小细胞癌(NSCLC)新适应症。NSCLC是最常见形式的肺癌，当癌细胞在肺部组织形成时 ... 责任编辑：admin |
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