Dosing & Uses
Dosage Forms & Strengths
IV solution
- 10mg/mL (10mL and 50mL vials)
Non-Small Cell Lung Cancer
Combination therapy with docetaxel
- Indicated in combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy
- Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression before receiving ramucirumab
- Ramucirumab 10 mg/kg IV on Day 1, PLUS
- Docetaxel 75 mg/m2 IV on Day 1
- Repeat cycle every 21 days
- Continue until disease progression or unacceptable toxicity
Combination therapy with erlotinib
- Indicated in combination with erlotinib, for first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
- Ramucirumab 10 mg/kg IV q2Weeks, PLUS
- Erlotinib 150 mg PO qDay
- Continue until disease progression or unacceptable toxicity
- Refer to prescribing information for erlotinib for dosage information
Gastric Cancer
As a single agent or in combination with paclitaxel for advanced gastric or gastro-esophageal junction adenocarcinoma in patients with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy
Single agent: Ramucirumab 8 mg/kg IV q2wk
Combination with paclitaxel
- Days 1 and 15: Ramucirumab 8 mg/kg IV
- Days 1, 8, and 15: Paclitaxel 80 mg/m2
- Repeat cycle every 28 days
- Continue until disease progression or unacceptable toxicity
Colorectal Cancer
Indicated for use in combination with FOLFIRI for patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen
Ramucirumab 8 mg/kg IV q2wk in combination with FOLFIRI
Continue until disease progression or unacceptable toxicity
Hepatocellular Carcinoma
Indicated as a single agent for hepatocellular carcinoma (HCC) in patients with alpha fetoprotein (AFP) of ≥400 ng/mL who have been treated with sorafenib
8 mg/kg IV q2wk
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Posterior reversible encephalopathy syndrome (PRES), arterial thromboembolic events, GI perforation, or grade 3 or 4 hemorrhage: Permanently discontinue
Wound healing (all grades)
- Withhold for 28 days before elective surgery; resume no sooner than 2 weeks after surgery and until adequate wound healing
- Safety of resumption of ramucirumab after resolution of wound healing complications has not been established
Infusion-related reactions
- Grade 1 or 2: Reduce infusion rate by 50%
- Grade 3 or 4: Permanently discontinue
Hypertension
- Severe hypertension: Interrupt therapy until controlled with medical management
- Uncontrolled severe hypertension despite antihypertensive therapy: Permanently discontinue
Proteinuria
- First occurrence of increased urine protein levels ≥2 g/24 hr: Withhold dose until urine protein levels <2 g/24 hr; resume at reduced dose (eg, reduce 8 mg to 6 mg, 10 mg to 8 mg)
- Reoccurrence of protein level ≥2 g/24 hr: Withhold dose until urine protein <2 g/24 hr; resume at reduced dose (eg, reduce 6 mg to 5 mg, 8 mg to 6 mg)
- Urine protein level >3 g/24 hr or nephrotic syndrome: Permanently discontinue
Hepatic impairment
- Mild-to-moderate (total bilirubin ≤3x ULN and any AST): No dosage adjustment necessary
- Severe (total bilirubin >3x ULN and any AST): Pharmacokinetics unknown
- Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single agent ramucirumab
Renal impairment
- Mild-to-severe (CrCl 15-89 mL/min): No clinically meaningful effect on pharmacokinetics
Dosing Considerations
Blood pressure should be controlled before initiating treatment and monitored every 2 weeks or more frequently if indicated
Safety and efficacy not established
Adverse Effects
All grades unless otherwise states
>10% (Gastric Cancer)
Single agent
- Hypertension (16%)
- Diarrhea (14%)
Combination therapy
- Fatigue/asthenia (57%)
- Neutropenia (54%)
- Neutropenia, Grade 3-4 (41%)
- Diarrhea (32%)
- Epistaxis (31%)
- Peripheral edema (25%)
- Hypertension (25%)
- Stomatitis (20%)
- Proteinuria (17%)
- Hypertension, Grade 3-4 (15%)
- Thrombocytopenia (13%)
- Fatigue/asthenia, Grade 3-4 (12%)
- Hypoalbuminemia (11%)
>10% (Non-small Lung Cancer)
Combination with erlotinib
- Infections (81%)
- ALT increased (74%)
- AST increased (71%)
- Diarrhea (70%)
- Hypertension (45%)
- Anemia (42%)
- Stomatitis (42%)
- Thrombocytopenia (41%)
- Proteinuria (34%)
- Alopecia (34%)
- Epistaxis (34%)
- Neutropenia (33%)
- Alkaline phosphatase increased (25%)
- Hypokalemia (24%)
- Hypertension, Grade 3-4 (24%)
- Peripheral edema (23%)
- Infections, Grade 3-4 (17%)
- Headache (15%)
- ALT increased, Grade 3-4 (11%)
Combination with docetaxel
- Neutropenia (55%)
- Fatigue/asthenia (55%)
- Neutropenia, Grade 3-4 (49%)
- Stomatitis/mucosal inflammation (37%)
- Epistaxis (19%)
- Febrile neutropenia (16%)
- Peripheral edema (16%)
- Fatigue/asthenia, Grade 3-4 (14%)
- Thrombocytopenia (13%)
- Lacrimation increased (13%)
- Hypertension (11%)
>10% (Hepatocellular Carcinoma)
Thrombocytopenia (46%)
Fatigue (36%)
Hypoalbuminemia (33%)
Hyponatremia (32%)
Peripheral edema (25%)
Hypertension (25%)
Abdominal pain (25%)
Neutropenia (24%)
Decreased appetite (23%)
Proteinuria (20%)
Nausea (19%)
Ascites (18%)
Hypocalcemia (16%)
Hyponatremia, Grade 3-4 (16%)
Headache (14%)
Epistaxis (14%)
Hypertension, Grade 3-4 (13%)
Insomnia (11%)
>10% (Colorectal Cancer)
Diarrhea (60%)
Neutropenia (59%)
Decreased appetite (37%)
Epistaxis (33%)
Stomatitis (31%)
Thrombocytopenia (28%)
Hypertension (26%)
Peripheral edema (20%)
Proteinuria (17%)
Palmoplantar erythrodysesthesia syndrome (13%)
Gastrointestinal hemorrhage events (12%)
1-10% (Gastric Cancer)
Single agent
- Headache (9%)
- Proteinuria, Grade 3-4 (8%)
- Hypertension, Grade 3-4 (8%)
- Hyponatremia (6%)
- Neutropenia (4.7%)
- Epistaxis (4.7%)
- Rash (4.2%)
- Hyponatremia, Grade 3-4 (3%)
- Intestinal obstruction (2.1%)
- Arterial thromboembolic events (1.7%)
Combination therapy
- Gastrointestinal hemorrhage events (10%)
- Diarrhea, Grade 3-4 (4%)
- Gastrointestinal hemorrhage events, Grade 3-4 (4%)
- Sepsis (3.1%)
- Peripheral edema, Grade 3-4 (2%)
- Thrombocytopenia, Grade 3-4 (2%)
- Gastrointestinal perforations (1.2%)
- Stomatitis, Grade 3-4 (1%)
- Proteinuria, Grade 3-4 (1%)
- Hypoalbuminemia, Grade 3-4 (1%)
1-10% (Non-small Lung Cancer)
Combination with erlotinib
- Gastrointestinal hemorrhage (10%)
- Gingival bleeding (9%)
- Pulmonary hemorrhage (7%)
- Diarrhea, Grade 3-4 (7%)
- Neutropenia, Grade 3-4 (7%)
- AST increased, Grade 3-4 (6%)
- Hypokalemia, Grade 3-4 (5%)
- Anemia, Grade 3-4 (5%)
- Thrombocytopenia, Grade 3-4 (3%)
- Proteinuria, Grade 3-4 (3%)
- Stomatitis, Grade 3-4 (2%)
- Gastrointestinal hemorrhage, Grade 3-4 (1%)
- Pneumonia (3.2%)
- Cellulitis (1.8%)
- Pneumothorax (1.8%)
- Increased ALT (1.4%)
- Paronychia (1.4%)
Combination with docetaxel
- Stomatitis/mucosal inflammation, Grade 3-4 (7%)
- Hypoalbuminemia (6%)
- Hypertension, Grade 3-4 (6%)
- Hyponatremia (4.8%)
- Stomatitis, Grade 3-4 (4%)
- Proteinuria (3.3%)
- Thrombocytopenia, Grade 3-4 (3%)
- Decreased appetite, Grade 3-4 (2%)
- Gastrointestinal hemorrhage events, Grade 3-4 (2%)
- Palmoplantar erythrodysesthesia syndrome, Grade 3-4 (1%)
- Hypoalbuminemia, Grade 3-4 (1%)
1-10% (Hepatocellular Carcinoma)
- Pyrexia (10%)
- Vomiting (10%)
- Back pain (10%)
- Infusion-related reactions (9%)
- Thrombocytopenia, Grade 3-4 (8%)
- Neutropenia, Grade 3-4 (8%)
- Hepatic encephalopathy (5%)
- Fatigue, Grade 3-4 (5%)
- Ascites, Grade 3-4 (4%)
- Hypocalcemia, Grade 3-4 (2%)
- Hepatorenal syndrome (2%)
- Peripheral edema, Grade 3-4 (2%)
- Decreased appetite, Grade 3-4 (2%)
- Abdominal pain, Grade 3-4 (2%)
<1% (Gastric Cancer)
Single agent
- Gastrointestinal perforation, Grade 3-4 (0.8%)
- Infusion-related reactions, Grade 3-4 (0.4%)
<1% (Non-small Lung Cancer)
Combination with erlotinib
- Alkaline phosphate increased, Grade 3-4 (<1%)
- Pulmonary hemorrhage, Grade 3-4 (<1%)
- Peripheral edema, Grade 3-4 (<1%)
- Headache, Grade 3-4 (<1%)
Combination with docetaxel
- Epistaxis, Grade 3-4 (<1%)
- Lacrimation increased, Grade 3-4 (<1%)
<1% (Hepatocellular Carcinoma)
- Epistaxis, Grade 3-4 (<1%)
- Back pain, Grade 3-4 (<1%)
- Hypoalbuminemia, Grade 3-4 (<1%)
- Postmarketing Reports H3
- Blood and lymphatic system: Thrombotic microangiopathy
- Neoplasms benign, malignant and unspecified: Hemangioma
- Respiratory, thoracic, and mediastinal: Dysphonia
Postmarketing Reports
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
Cardiac: Heart failure
Warnings
Contraindications
None
Cautions
Increased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhagic events; permanently discontinue in patients who experience severe bleeding
Serious, sometimes fatal, arterial thromboembolic events including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia reported during clinical trials
Increased incidence of severe hypertension reported; control hypertension before initiating treatment and monitor blood pressure q2weeks or more frequently as indicated; temporarily suspend therapy for severe hypertension
Infusion-related reactions observed that include 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
Ramucirumab is an antiangiogenic therapy that can increase the risk of GI perforation and affect wound healing; withhold prior to surgery; permanently discontinue ramucirumab in patients who experience a gastrointestinal perforation
Impaired wound healing can occur with antibodies inhibiting the VEGF or VEGFR pathway; VEGFR2 antagonist has the potential to adversely affect wound healing; not studied in patients with serious or non-healing wounds
Withhold for 28 days prior to elective surgery; do not administer for at least 2 weeks following a major surgical procedure and until adequate wound healing; safety of resumption after resolution of wound healing complications not established
Clinical deterioration, manifested by new-onset or worsening encephalopathy, ascites, or hepatorenal syndrome, reported in patients with Child-Pugh B or C cirrhosis; use only if the benefits outweigh the risks
Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), reported; confirm diagnosis with magnetic resonance imaging; permanently discontinue in patients who develop PRES; symptoms may resolve or improve within days; some patients can experience ongoing neurologic sequelae or death
Severe proteinuria, including nephrotic syndrome, reported, monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio; if result of urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement; withhold drug for urine protein levels that are 2 or more grams over 24 hours; reinitiate drug at a reduced dose once urine protein level returns to < 2 grams over 24 hours; permanently discontinue therapy for urine protein levels > 3 grams over 24 hours or in setting of nephrotic syndrome
May cause hypothyroidism; monitor thyroid function during treatment
May cause fetal harm when administered to pregnant women
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman
There are no available data on use in pregnant women
Animal data
- Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development
- Advise a pregnant woman of the potential risk to a fetus
Pregnancy testing
- Verify pregnancy status of females of reproductive potential before initiating therapy
Contraception
- Females: Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose
Infertility
- Advise females of reproductive potential that based on animal data, fertility may be impaired
Lactation
Unknown if distributed in human breast milk; a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother
Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Vascular endothelial growth factor receptor 2 (VEGFR2) 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 VEGF2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells
Absorption
Steady-state achieved at ~ 12 weeks
Distribution
Vd (steady-state): 5.4L
Elimination
Clearance: 0.015 L/hr
Half-life: 14 days
Pharmacogenomics
NSCLC: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
Administration
IV Compatibilities
0.9% NaCl
IV Incompatibilities
Dextrose-containing solutions
IV Preparation
Visually inspect vials for particulate matter and discoloration
Discard if particulate matter or discolorations identified
Calculate dose and withdraw required volume
Further dilute with only 0.9% NaCl in IV infusion container to final volume of 250 mL
Do not shake; gently invert container to ensure adequate mixing
Do not dilute with other solutions or infuse with other electrolytes or medications; do not freeze
Discard any unused portion
Premedication
Before each infusion, premedicate all patients with an IV histamine-1 receptor antagonist (eg, diphenhydramine)
For patients who have experienced a grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen before each infusion
IV Administration
Visually inspect diluted solution for particulate matter and discoloration before administration
Discard if particulate matter or discolorations are identified; do not administer as an IV push or bolus
Administer diluted solution via infusion pump through a separate infusion line; use a protein sparing 0.22 micron filter
Infuse IV infusion over 60 min; if first infusion is tolerated, all subsequent infusion may be administered over 30 min
When given in combination therapy, administer ramucirumab first 1 hr prior to other therapies (eg, paclitaxel, docetaxel, or FOLFIRI)
Flush line with sterile 0.9% NaCl at the end of infusion
Storage
Unopened vials
- Refrigerate at 2-8ºC (36-46ºF)
- Keep the vial in the outer carton to protect from light
Diluted infusion
- Administer within 24 hr of dilution
- Store refrigerated at 2-8ºC (36-46ºF) or 4 hr at room temperature (ie, below 25ºC [77ºF])
- Do not freeze
- Discard partially used vials
Images
| BRAND | FORM. | UNIT PRICE | PILL IMAGE |
|---|---|---|---|
| Cyramza intravenous - | 10 mg/mL vial |  |
Copyright © 2010 First DataBank, Inc.
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