Dosing and uses of Cyramza (ramucirumab)
Adult dosage forms and strengths
IV solution
- 10mg/mL (10mL and 50mL vials)
Non-Small Cell Lung Cancer
Indicated in combination with docetaxel for 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 ramucirumaB
10 mg/kg IV infused over ~1 hr prior to docetaxel (75 mg/m²) IV infusion on Day 1 of a 21-day cycle
Continue until disease progression or unacceptable toxicity
Gastric Cancer
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
Single agent or in combination with paclitaxel: 8 mg/kg IV q2wk; infuse over 1 hr
Paclitaxel dose (if given in combination): 80 mg/m² once weekly for 3 weeks of every 28-day cycle
When given in combination, administer ramucirumab prior to administration of paclitaxeL
Continue until disease progression or unacceptable toxicity
Colorectal Cancer
Indicated for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen
8 mg/kg IV q2wk; administer by IV infusion over 60 minutes prior to FOLFIRI administration
Continue until disease progression or unacceptable toxicity
Dosage modifications
Wound healing: Interrupt prior to scheduled surgery until wound is fully healed
Arterial thromboembolic events, GI perforation, or grade 3 or 4 bleeding: Permanently discontinue
Infusion-related reactions
- Reduce the infusion rate by 50% for grade 1 or 2; add dexamethasone (or equivalent) and acetaminophen to diphenhydramine premedication regimen before each ramucirumab dose
- Permanently discontinue for grade 3 or 4
Hypertension
- Interrupt therapy for severe hypertension until controlled with medical management
- Permanently discontinue for severe hypertension that cannot be controlled with antihypertensive therapy
Proteinuria
- Interrupt therapy for urine protein levels ≥2 g/24 hr; reinitiate treatment at reduced dose of 6 mg/kg q2wk (gastric cancer) or 8 mg/kg q3wk (NSCLC) when urine protein level returns to <2 g/24 hr
- If the protein level ≥2 g/24 hr reoccurs, interrupt therapy and reduce dose to 5 mg/kg q2wk(gastric cancer) or 6 mg/kg q3wk (NSCLC) when urine protein level returns to <2 g/24 hr
- Permanently discontinue for urine protein level >3 g/24 hr or in the setting of nephrotic syndrome
Dosing Considerations
Premedicate with IV diphenhydramine before each ramucirumab infusion
For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each ramucirumab infusion
Blood pressure should be controlled prior to treatment and monitored every 2 weeks or more frequently if indicated
Available exclusively from Biologics, a specialty pharmacy
Hepatocellular Carcinoma (Orphan)
Orphan designation for treatment of hepatocellular carcinoma
Sponsor
- Eli Lilly and Company; Lilly Corporate Center; Indianapolis, IN 46285
Pediatric dosage forms and strengths
Safety and efficacy not established
Cyramza (ramucirumab) adverse (side) effects
>10%
All grades unless otherwise states
GI cancer (plus paclitaxel)
- Fatigue/asthenia (57%)
- Neutropenia (54%)
- Diarrhea (32%)
- Epistaxis (31%)
- Peripheral edema (25%)
- Stomatitis (20%)
- Proteinuria (17%)
- Hypertension (25%)
- Infusion-related reactions (16%)
- Hypertension grade 3-4 (15%)
- Thrombocytopenia (13%)
- Hypoalbuminemia (11%)
NSCLC (plus docetaxel)
- Neutropenia (55%)
- Fatigue/asthenia (55%)
- Stomatitis/mucosal inflammation (37%)
- Epistaxis (19%)
- Febrile neutropenia (16%)
- Peripheral edema (16%)
- Thrombocytopenia (13%)
- Lacrimation increased (13%)
- Hypertension (11%)
1-10%
GI hemorrhage events, gastric cancer (10%)
<1%
Gastrointestinal perforation (single agent) (0.7%)
Reversible posterior leukoencephalopathy syndrome (<0.1%)
Warnings
Black box warnings
Hemorrhage
- Increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events Permanently discontinue patients who experience severe bleeding
Gastrointestinal perforation
- Can increase the risk of gastrointestinal perforation, a potentially fatal event
- Permanently discontinue in patients who experience a gastrointestinal perforation
Impaired wound healing
- Impaired wound healing can occur with antibodies inhibiting the VEGF pathway
- Discontinue in patients with impaired wound healing
- Withhold drug prior to surgery and discontinue if a patient develops wound healing complications
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 (see Black box warnings)
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 (see Black box warnings)
Impaired wound healing can occur with antibodies inhibiting the VEGF pathway; withhold drug before surgery and discontinue if patient develops wound healing complications (see Black box warnings)
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
Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare); discontinue ramucirumaB
Severe proteinuria reported, particularly when administered with FOLFIRI (see Dosage modifications)
May cause hypothyroidism; monitor thyroid function during treatment
Based on its mechanism of action, ramucirumab can cause fetal harm when administered to pregnant women
Pregnancy and lactation
Pregnancy
Based on its mechanism of action, ramucirumab 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 ramucirumab 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 Advise females of reproductive potential to use effective contraception while receiving ramucirumab and for at least 3 months after the last dose
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 of Cyramza (ramucirumab)
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
Minimum concentration levels: 50 mcg/mL (range: 6-228 mcg/mL) after 3rd dose; 74 mcg/mL (range: 14-234 mcg/mL) after 6th dose
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
Inspect vial contents for particulate matter and discoloration prior to dilution
Discard the vial if particulate matter or discolorations are identified
Calculate the dose and the required volume needed to prepare the infusion solution
Further dilute with only 0.9% NaCl injection in an IV infusion container to a final volume of 250 mL
Do not dilute with solutions other than 0.9% NaCl or co-infuse with other electrolytes or medications
Gently invert the container to ensure adequate mixing
IV Administration
Premedicate all patients with diphenhydramine IV
If grade 1 or 2 infusion reaction occurs, also premedicate with dexamethasone and acetaminophen
Use protein sparing 0.22-micron filter
Administer diluted solution by IV infusion via infusion pump over 60 minutes through a separate infusion line
Do NOT administer as IV push or bolus
Flush the line with sterile 0.9% NaCl at the end of the infusion
Storage
Unopened vials
- Refrigerate at 2-8°C (36-46°F)
- Keep the vial in the outer carton to protect from light
Diluted infusion
- Administer within 24 hr of dilution
- Store refrigerated at 2-8°C (36-46°F) or 4 hr at room temperature (ie, below 25°C [77°F])
- Do not freeze
- Discard partially used vials
