Version May 2024
Note: Premedicate prior to infusion with an IV H1 antagonist (eg, diphenhydramine); for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone (or equivalent) and acetaminophen.
Colorectal cancer, metastatic:
IV: 8 mg/kg once every 2 weeks in combination with FOLFIRI (irinotecan, leucovorin, and fluorouracil); continue ramucirumab until disease progression or unacceptable toxicity (Ref).
Gastric cancer, advanced or metastatic:
IV: 8 mg/kg once every 2 weeks as a single agent or in combination with weekly paclitaxel; continue ramucirumab until disease progression or unacceptable toxicity (Ref).
Hepatocellular carcinoma (advanced, relapsed/refractory):
IV: 8 mg/kg once every 2 weeks (as a single agent); continue ramucirumab until disease progression or unacceptable toxicity (Ref).
Non–small cell lung cancer, metastatic:
First-line treatment in tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations: IV: 10 mg/kg once every 2 weeks (in combination with erlotinib) until disease progression or unacceptable toxicity (Ref).
Disease progression on or after platinum-based therapy: I V: 10 mg/kg on day 1 every 21 days in combination with docetaxel; continue ramucirumab until disease progression or unacceptable toxicity (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling. However, no clinically meaningful effect was noted in ramucirumab pharmacokinetics in patients with CrCl 15 to 89 mL/minute.
Mild (normal bilirubin with AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment: No dosage adjustment necessary.
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Use in patients with Child-Pugh class B or C cirrhosis only if the potential benefits of treatment outweigh the potential risks of clinical deterioration.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Arterial thrombotic events (all grades): Discontinue ramucirumab permanently.
GI perforation (all grades): Discontinue ramucirumab permanently.
Hemorrhage, grade 3 or 4: Discontinue ramucirumab permanently.
Hypertension: If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications (ASCO [Armenian 2017]; ESC [Lyon 2022]). If ramucirumab is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (ESC [Lyon 2022]).
Severe hypertension: Interrupt ramucirumab infusion until controlled with medical management.
Severe hypertension, uncontrolled with antihypertensive therapy: Permanently discontinue ramucirumab.
Hypertensive crisis or hypertensive encephalopathy: Permanently discontinue ramucirumab.
Infusion-related reaction:
Grade 1 or 2: Reduce ramucirumab infusion rate by 50%.
Grade 3 or 4: Permanently discontinue ramucirumab.
Posterior reversible encephalopathy syndrome (all grades): Discontinue ramucirumab permanently.
Proteinuria:
Urine protein ≥2 g/24 hours (first occurrence): Withhold ramucirumab treatment; when urine protein returns to <2 g/24 hours, reinitiate at a reduced dose of 6 mg/kg (if initial dose was 8 mg/kg) or 8 mg/kg (if initial dose was 10 mg/kg).
Recurrent urine protein ≥2 g/24 hours: Withhold ramucirumab treatment; when urine protein returns to <2 g/24 hours, reinitiate at a reduced dose of 5 mg/kg (if first dose reduction was to 6 mg/kg) or 6 mg/kg (if first dose reduction was to 8 mg/kg).
Urine protein >3 g/24 hours: Discontinue ramucirumab permanently.
Nephrotic syndrome: Discontinue ramucirumab permanently.
Wound healing complications (all grades): Withhold ramucirumab treatment for 28 days prior to elective surgery; do not reinitiate for at least 2 weeks after major surgery and until the surgical wound is adequately healed.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with monotherapy in adults.
>10%:
Cardiovascular: Hypertension (16% to 25%, can be severe hypertension), peripheral edema (25%)
Endocrine & metabolic: Hypoalbuminemia (33%), hypocalcemia (16%), hyponatremia (6% to 32%)
Gastrointestinal: Abdominal pain (25%), decreased appetite (23%), diarrhea (14%; grade 3/4: 1%), nausea (19%)
Genitourinary: Proteinuria (8% to 20%)
Hematologic & oncologic: Neutropenia (5% to 24%; grade ≥3: 8%), thrombocytopenia (46%; grade ≥3: 8%)
Hepatic: Ascites (18%)
Nervous system: Fatigue (36%), headache (9% to 14%), insomnia (11%)
Respiratory: Epistaxis (5% to 14%)
1% to 10%:
Cardiovascular: Arterial thromboembolism (2%)
Dermatologic: Skin rash (4%)
Gastrointestinal: Intestinal obstruction (2%), vomiting (10%)
Hematologic & oncologic: Anemia (4%)
Hepatic: Hepatic encephalopathy (5%), hepatorenal syndrome (2%)
Hypersensitivity: Infusion-related reaction (≤9%)
Immunologic: Antibody development (3%; neutralizing: <1%)
Neuromuscular & skeletal: Back pain (10%)
Respiratory: Pneumonia (3%)
Miscellaneous: Fever (10%)
<1%: Gastrointestinal: Gastrointestinal perforation
Frequency not defined:
Cardiovascular: Acute myocardial infarction
Endocrine & metabolic: Hypothyroidism
Gastrointestinal: Gastrointestinal hemorrhage
Hematologic & oncologic: Hemorrhage, major hemorrhage
Nervous system: Cerebral ischemia, cerebrovascular accident, reversible posterior leukoencephalopathy syndrome
Renal: Nephrotic syndrome
Postmarketing:
Cardiovascular: Aneurysm (arterial, including aortic), coronary artery dissection (including aortic), heart failure, vascular injury (rupture)
Hematologic & oncologic: Hemangioma, thrombotic microangiopathy
Nervous system: Voice disorder
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to ramucirumab or any component of the formulation.
Concerns related to adverse effects:
• Arterial thrombotic events: Serious and sometimes fatal arterial thrombotic events, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have occurred with ramucirumab, including ≥ grade 3 events. Discontinue ramucirumab permanently in patients who experience arterial thrombotic events.
• Gastrointestinal perforation: Ramucirumab may increase the risk of GI perforation, a potentially fatal event. Discontinue ramucirumab permanently in patients who experience a GI perforation.
• Hemorrhage: Ramucirumab is associated with an increased risk of hemorrhage and GI hemorrhage, including ≥ grade 3 events, which may be severe or sometimes fatal. Discontinue ramucirumab permanently in patients who experience serious (grade 3 or 4) bleeding. Patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from some clinical trials; the risk of gastric hemorrhage in patients with gastric tumors receiving NSAIDs is not known. In addition, various exclusion criteria in some non-small cell lung cancer trials included a recent history of gross hemoptysis, use of therapeutic anticoagulation or chronic NSAID or other antiplatelet therapy (other than once-daily aspirin), or evidence (including radiographic evidence) of major airway or blood vessel involvement or intratumor cavitation; the risk of pulmonary hemorrhage in patients with such criteria is not known.
• Hepatotoxicity: Clinical deterioration, including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome has been reported in patients with Child-Pugh class B or C cirrhosis receiving ramucirumab. Use in patients with Child-Pugh class B or C cirrhosis only if the potential benefits outweigh the potential risks. Based on clinical trial data for the treatment of hepatocellular carcinoma, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was increased in patients with Child Pugh class A liver cirrhosis receiving ramucirumab compared to patients who received placebo.
• Hypertension: May cause and/or worsen hypertension; the incidence of severe hypertension is increased with ramucirumab. In a non-small cell lung cancer study, new or worsening hypertension requiring initiation of ≥3 antihypertensive medications occurred at a higher incidence in patients receiving ramucirumab in combination with erlotinib, versus patients receiving placebo plus erlotinib. Control hypertension prior to treatment initiation. Monitor BP every 2 weeks (more frequently if indicated) during treatment. If severe hypertension occurs, temporarily withhold ramucirumab until medically controlled. Permanently discontinue ramucirumab if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
• Infusion reaction: Ramucirumab is associated with infusion-related reactions (may be severe), generally occurring with the first or second dose. Symptoms of infusion reactions have included chills, flushing, hypotension, bronchospasm, dyspnea, hypoxia, wheezing, chest pain/tightness, supraventricular tachycardia, back pain/spasms, rigors/tremors, and/or paresthesia. Premedication(s) are recommended prior to infusion. Monitor for infusion reaction symptoms during infusion. Reduce infusion rate for grade 1 or 2 infusion reaction; discontinue ramucirumab immediately and permanently for grade 3 or 4 infusion reactions. Administer in a facility equipped to manage infusion reactions.
• Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome) have been reported (may be fatal). Symptoms of PRES include headache, nausea/vomiting, seizure, blindness, or altered consciousness, with or without associated hypertension. Confirm diagnosis of PRES with MRI; permanently discontinue ramucirumab in patients who develop PRES. Resolution of symptoms may occur within days after discontinuation, although neurologic sequelae may remain in some patients.
• Proteinuria/Nephrotic syndrome: Ramucirumab is associated with proteinuria (including ≥ grade 3 proteinuria and cases of nephrotic syndrome). Monitor proteinuria during treatment by urine dipstick and/or urinary protein creatinine ratio for the development of and/or worsening of proteinuria. Withhold ramucirumab treatment for urine protein levels ≥2 g/24 hours; reduce dose upon therapy reinitiation. Discontinue ramucirumab permanently for urine protein >3 g/24 hours or for nephrotic syndrome.
• Thyroid dysfunction: Hypothyroidism (grade 1 or 2) has been observed. Monitor thyroid function during treatment.
• Wound healing impairment: Impaired wound healing can occur with vascular endothelial growth factor (VEGF) or VEGF receptor pathway inhibitors. Withhold ramucirumab for 28 days prior to elective surgery, and for at least 2 weeks following a major surgical procedure (and until the wound is adequately healed). The safety of resuming ramucirumab treatment after resolution of wound healing complications has not been established. Ramucirumab was not studied in patients with serious or nonhealing wounds.
Special populations:
• Older adult: Patients ≥65 years of age who received ramucirumab in combination with erlotinib in a non-small cell lung cancer trial had increased incidences of diarrhea, hypertension, elevated ALT/AST, stomatitis, decreased appetite, dysgeusia, and weight loss compared to patients <65 years of age.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Cyramza: 100 mg/10 mL (10 mL); 500 mg/50 mL (50 mL) [contains polysorbate 80]
No
Solution (Cyramza Intravenous)
100 mg/10 mL (per mL): $171.39
500 mg/50 mL (per mL): $171.39
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Cyramza: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Premedicate prior to infusion with an IV H1 antagonist (eg, diphenhydramine); for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone (or equivalent) and acetaminophen.
IV: Administer initial infusion over 60 minutes; if tolerated, may administer subsequent infusions over 30 minutes. Infuse through a separate infusion line using an infusion pump; the use of a 0.22-micron protein-sparing filter is recommended. Do not administer as an IV push or bolus. Flush the line with NS after infusion is complete. Do not infuse in the same IV line with solutions other than NS, or with electrolytes or other medications. Monitor for infusion reaction; reduce infusion rate (by 50%) for grade 1 or 2 infusion reaction; discontinue permanently for grade 3 or 4 infusion reaction.
Administer ramucirumab prior to docetaxel, paclitaxel, or FOLFIRI if administering in combination.
Colorectal cancer, metastatic: Treatment (in combination with FOLFIRI [irinotecan, leucovorin, and fluorouracil]) of metastatic colorectal cancer in patients with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Gastric cancer, advanced or metastatic: Treatment (single agent or in combination with paclitaxel) of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients with disease progression on or following fluoropyrimidine- or platinum-containing chemotherapy.
Hepatocellular carcinoma, advanced or relapsed/refractory: Treatment (as a single agent) of hepatocellular carcinoma (HCC) in patients who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.
According to guidelines from the American Society of Clinical Oncology for systemic therapy for advanced HCC, ramucirumab is a second-line therapy option in patients with AFP ≥400 ng/mL who received first-line therapy with sorafenib or lenvatinib (ASCO [Gordan 2020]).
Non-small cell lung cancer, metastatic:
First-line treatment (in combination with erlotinib) of metastatic non-small cell lung cancer in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
Treatment (in combination with docetaxel) of metastatic non-small cell lung cancer in patients with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on approved therapy for these aberrations prior to receiving ramucirumab.
Cyramza may be confused with Cimzia
Ramucirumab may be confused with necitumumab, ranibizumab, ravulizumab, raxibacumab, regorafenib, rituximab, rizankizumab, romosozumab
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Verify pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during and for 3 months after the last ramucirumab dose.
Based on the mechanism of action, ramucirumab may cause fetal harm if administered during pregnancy.
It is not known if ramucirumab is present in breast milk. Immunoglobulins are excreted in breast milk, and it is assumed that ramucirumab may appear in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 2 months after the final ramucirumab dose.
LFTs; urine protein (by urine dipstick and/or urinary protein creatinine ratio); thyroid function; CBC with differential (when used as a part of combination chemotherapy). Verify pregnancy status prior to treatment (in females of reproductive potential). Monitor BP (every 2 weeks; more frequently if indicated). Monitor for signs/symptoms of infusion-related reactions (during infusion). Monitor for signs/symptoms of arterial thromboembolic events, bleeding/hemorrhage, GI perforation, wound healing impairment, and posterior reversible encephalopathy syndrome.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months during the first year and every 6 to 12 months thereafter for moderate-risk patients) (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Ramucirumab is a recombinant monoclonal antibody which inhibits vascular endothelial growth factor receptor 2 (VEGFR2). Ramucirumab has a high affinity for VEGFR2 (Spratlin 2010), binding to it and blocking binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D to inhibit activation of VEGFR2, thereby inhibiting ligand-induced proliferation and migration of endothelial cells. VEGFR2 inhibition results in reduced tumor vascularity and growth (Fuchs 2014).
Half-life elimination: 14 days
Distribution: Vdss: 5.4 L
Excretion: Clearance: 0.015 L/hour
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