)].
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)].
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
The pharmacokinetic (PK) characteristics of ramucirumab are similar for patients with gastric cancer, NSCLC, and mCRC based on a population PK analysis. The mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 L/hour (30%) and the mean terminal half-life was 14 days (20%).
Specific Populations
Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis.
Renal Impairment: Based on a population PK analysis, no clinically meaningful differences in the average concentration of ramucirumab at steady state (Css) were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n=687), moderate (CLcr 30-59 mL/min, n=244) or severe (CLcr 15-29 mL/min, n=6) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n=697).
Hepatic Impairment: Based on a population PK analysis, no clinically meaningful differences in the average Css of ramucirumab were observed 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=525), or moderate (total bilirubin >1.5-3.0 times ULN n=23) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST ≤ULN, n=1055). No PK data are available from patients with severe hepatic dysfunction (total bilirubin >3.0 times ULN and any AST).
Drug Interaction Studies
No clinicall |
