Ramucirumab, a recombinant human IgG1 monoclonal antibody, is a vascular endothelial growth factor receptor (VEGFR)-2 antagonist.1
Ramucirumab is used alone or in combination with paclitaxel for the treatment of advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, that has progressed during or following fluoropyrimidine- or platinum-based chemotherapy;1, 2, 11 ramucirumab is designated an orphan drug by FDA for the treatment of this cancer.7
The current indication for ramucirumab in the treatment of gastric cancer is based principally on the results of 2 randomized, double-blind, placebo-controlled phase 3 studies (REGARD and RAINBOW)1, 2, 8, 11 in patients with locally advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had received platinum- and/or fluoropyrimidine-containing regimens.1, 2, 8, 11 In both studies, the primary measure of efficacy was overall survival.1, 2, 8, 11
In the REGARD study, 355 patients were randomized in a 2:1 ratio to receive either ramucirumab (8 mg/kg by IV infusion) or placebo every 2 weeks; all patients received best supportive care.1, 2 Treatment was continued until disease progression, unacceptable toxicity, or death occurred.2 The median age of patients was 60 years; all except one of the enrolled patients had a baseline ECOG performance status of 0 or 1.1, 2 Most patients (81%) enrolled in the study had received prior combined chemotherapy with a platinum compound and a fluoropyrimidine; 15% of patients had received fluoropyrimidine-containing regimens without a platinum compound, and 4% had received platinum-containing regimens without a fluoropyrimidine.1 At the time of the primary analysis, patients receiving ramucirumab had longer median overall survival (5.2 versus 3.8 months) and progression-free survival (2.1 versus 1.3 months) compared with patients receiving placebo.1 Results of an exploratory subgroup analysis (based on age, gender, race, and geographic region) suggested a lack of an overall survival benefit in women; patients in North America, Europe, Australia, and New Zealand; and patients categorized as “other” race.2, 8
In the RAINBOW study, 665 patients were randomized in a 1:1 ratio to receive either ramucirumab (8 mg/kg by IV infusion over 1 hour on days 1 and 15 of each 28-day cycle) in combination with paclitaxel (80 mg/m2 by IV infusion over 1 hour on days 1, 8, and 15 of each 28-day cycle) or placebo in combination with paclitaxel.1, 8, 11 The median age of patients was 61 years; all patients enrolled in the study had a baseline ECOG performance status of 0 or 1.1, 8 Most patients (81%) enrolled in the study had received prior combined chemotherapy with a platinum compound and a fluoropyrimidine; 15% of patients had received fluoropyrimidine-containing chemotherapy without a platinum compound, and 4% had received platinum-containing regimens without a fluoropyrimidine.8 Final analysis of overall survival, using derived data, indicated that patients receiving ramucirumab in combination with paclitaxel had longer median overall survival (9.6 versus 7.4 months) and median progression-free survival (4.4 versus 2.9 months) compared with patients receiving placebo in combination with paclitaxel.1, 8, 11 The objective response rate (complete and partial responses) was 28% for patients receiving ramucirumab in combination with paclitaxel compared with 16% for those receiving placebo in combination with paclitaxel.1 Data from this study indicate that effects of ramucirumab on survival were consistent across various patient subgroups (including women and patients in Europe, North America, and Australia)8, 9 and support the hypothesis that results of the exploratory subgroup analysis of the REGARD study were likely limited by small sample size and random effects.9
Ramucirumab is used in combination with docetaxel for the treatment of metastatic non-small cell lung cancer (NSCLC) that has progressed during or following platinum-based chemotherapy.1, 12 Patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumors also should have documented disease progression during or following an FDA-labeled anti-EGFR or anti-ALK therapy prior to initiating therapy with ramucirumab.1
The current indication for ramucirumab in the treatment of metastatic NSCLC is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (REVEL) in patients with locally advanced or metastatic NSCLC that had progressed during or following platinum-based chemotherapy.1, 12 The primary measure of efficacy was overall survival.1, 12 In this study, 1253 patients were randomized in a 1:1 ratio to receive either ramucirumab (10 mg/kg by IV infusion on day 1 of each 21-day cycle) in combination with docetaxel (75 mg/m2 by IV infusion on day 1 of each 21-day cycle) or placebo in combination with docetaxel; because an increased incidence of neutropenia and febrile neutropenia was noted in patients in East Asia, these patients received a reduced docetaxel dosage (60 mg/m2 every 21 days).1, 12 Treatment was continued until disease progression, death, or unacceptable toxicity occurred, or treatment was discontinued for other reasons.12 The median duration of treatment was 3.5 months for patients receiving ramucirumab in combination with docetaxel.1 The median age of patients was 62 years.1 All patients enrolled in the study had a baseline ECOG performance status of 0 or 1, and 73% had nonsquamous histology.1 The majority (99%) of patients had received previous platinum-based chemotherapy.1 In addition to platinum-based chemotherapy, 38% of patients also had received pemetrexed; 25% had received gemcitabine; 24% had received a taxane; and 14% had received bevacizumab.1
Patients randomized to receive ramucirumab in combination with docetaxel had a longer median overall survival (10.5 versus 9.1 months) and progression-free survival (4.5 versus 3 months) compared with patients receiving placebo in combination with docetaxel.1, 12 In addition, patients receiving ramucirumab in combination with docetaxel appeared to have a higher investigator-assessed objective response rate (complete and partial responses) (23 versus 14%) and higher disease control rate (64 versus 53%) compared with those receiving placebo in combination with docetaxel.12
Ramucirumab is used in combination with fluorouracil, leucovorin (folinic acid), and irinotecan (the combination of fluorouracil, leucovorin, and irinotecan is hereafter referred to as FOLFIRI in this monograph) for the treatment of metastatic colorectal cancer that has progressed during or following combination therapy with oxaliplatin, bevacizumab, and a fluoropyrimidine.1, 14 Results of a randomized, placebo-controlled study (RAISE) demonstrated improved overall and progression-free survival with such second-line ramucirumab therapy; an increase in the frequency of certain adverse effects with ramucirumab therapy generally was manageable with appropriate dosage adjustments and supportive therapy.1, 14
In the RAISE study, 1072 patients were randomly assigned to receive either ramucirumab 8 mg/kg by IV infusion over 1 hour or placebo in combination with FOLFIRI.1, 14 The FOLFIRI regimen consisted of irinotecan 180 mg/m2 by IV infusion over 90 minutes concurrent with (or followed by) leucovorin 400 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by IV injection over 2-4 minutes, then fluorouracil 2.4 g/m2 by IV infusion over 46-48 hours.1, 14 Treatment was repeated every 2 weeks and continued until radiographically confirmed disease progression or unacceptable toxicity occurred; if one or more components of treatment were discontinued for toxicity, patients were permitted to continue therapy with the remaining treatment component(s) until disease progression or unacceptable toxicity occurred.1 The median duration of treatment was 4.4 months for patients receiving ramucirumab in combination with FOLFIRI.1 The median age of patients was 62 years; 76% of patients were white, 49% had a baseline ECOG performance status of 0, 49% had KRAS mutations, and 24% had experienced disease progression within less than 6 months after beginning first-line therapy.1
Patients receiving the ramucirumab-FOLFIRI regimen had a longer median overall survival (13.3 versus 11.7 months) and a longer progression-free survival (5.7 versus 4.5 months) than patients receiving the placebo-FOLFIRI regimen.1, 14 In addition, results of a subgroup analysis (based on age, disease stage, ECOG performance status, KRAS mutation status, time to disease progression, number of metastatic sites, presence of metastasis only in the liver, site of primary tumor, and baseline carcinoembryonic antigen [CEA] concentration) suggested that the drug's effect on overall and progression-free survival was consistent across all subgroups.14 Ramucirumab therapy was associated with a higher incidence of grade 3 or worse treatment-emergent adverse effects (e.g., neutropenia, hypertension).1, 14 (See Cautions.)
Ramucirumab should be administered only in settings where adequate monitoring can be performed and appropriate medical support is available for management of potential infusion-related reactions.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
To minimize the risk of infusion-related reactions associated with ramucirumab, premedication with an antihistamine (e.g., IV diphenhydramine hydrochloride) is recommended prior to each infusion.1 Patients who have experienced a grade 1 or 2 infusion-related reaction also should receive dexamethasone (or equivalent) and acetaminophen prior to subsequent infusions.1
Ramucirumab can only be obtained through a limited network of specialty pharmacies.10 Clinicians may contact the manufacturer (Eli Lilly) by telephone at 800-545-5979 or consult the Cyramza® website for specific ordering and availability information ([Web]).10
Ramucirumab is administered by IV infusion over 1 hour.1 The drug should not be administered by rapid IV injection, such as IV “push” or “bolus.” 1
Ramucirumab injection concentrate must be diluted prior to administration.1
Diluted ramucirumab solution should be inspected visually for particulate matter and discoloration prior to administration; if particulate matter or discoloration is evident, the diluted solution should be discarded.1
Diluted ramucirumab solution should be administered using an infusion pump.1 The manufacturer recommends administering the drug through a low-protein-binding 0.22-µm inline filter.1 Diluted ramucirumab solution should not be administered in the same IV line with any other drug or electrolyte solution.1 The IV line should be flushed with 0.9% sodium chloride injection at the end of the infusion.1
Unopened vials of ramucirumab injection concentrate should be protected from light, stored at 2-8°C, and should not be frozen or shaken.1
Prior to dilution, ramucirumab injection concentrate should be inspected visually for particulate matter and discoloration; if particulate matter or discoloration is evident, the solution should be discarded.1
Ramucirumab is diluted by withdrawing the appropriate dose (8 mg/kg) of ramucirumab injection concentrate from the vial labeled as containing 10 mg/mL and diluting in 0.9% sodium chloride injection to yield a final volume of 250 mL.1 The diluted ramucirumab solution for infusion should be mixed by gentle inversion and should not be shaken.1 Ramucirumab injection concentrate should not be diluted in diluents containing dextrose.1 Ramucirumab should not be admixed with any other drug or electrolytes.1 Commercially available ramucirumab injection concentrate contains no preservatives and is intended for single use; any partially used vials should be discarded.1
Diluted ramucirumab solution may be stored at room temperature (below 25°C) for up to 4 hours or under refrigeration (2-8°C) for up to 24 hours; the diluted solution should not be frozen.1
For the treatment of advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, that has progressed during or following fluoropyrimidine- or platinum-based chemotherapy, the recommended adult dosage of ramucirumab (as a single agent or in combination with paclitaxel) is 8 mg/kg administered by IV infusion every 2 weeks.1
When used in combination with paclitaxel, ramucirumab should be administered before administration of paclitaxel.1 In the RAINBOW study, patients received ramucirumab (8 mg/kg by IV infusion over 1 hour) on days 1 and 15 of each 28-day cycle and paclitaxel (80 mg/m2 by IV infusion over 1 hour) on days 1, 8, and 15 of each 28-day cycle.1, 8, 11
Treatment with ramucirumab should be continued until disease progression or unacceptable toxicity occurs.1 In the REGARD study in which ramucirumab was used as a single agent, patients received a median of 4 doses of ramucirumab.1 In the RAINBOW study in which ramucirumab was used in combination with paclitaxel, patients received a median of 9 doses of ramucirumab.1
For the treatment of metastatic non-small cell lung cancer (NSCLC) that has progressed during or following platinum-based chemotherapy, the recommended adult dosage of ramucirumab is 10 mg/kg administered by IV infusion every 3 weeks in combination with docetaxel.1
Ramucirumab should be administered before administration of docetaxel.1
Treatment with ramucirumab should be continued until disease progression or unacceptable toxicity occurs.1 In the REVEL study, patients received a median of 4.5 doses of ramucirumab.1
For the treatment of metastatic colorectal cancer that has progressed during or following combination therapy with oxaliplatin, bevacizumab, and a fluoropyrimidine, the recommended dosage of ramucirumab in adults is 8 mg/kg administered by IV infusion every 2 weeks in combination with FOLFIRI (i.e., fluorouracil, leucovorin [folinic acid], and irinotecan).1
Ramucirumab should be administered before FOLFIRI.1
Treatment with ramucirumab should be continued until disease progression or unacceptable toxicity occurs.1 In the RAISE study, patients received a median of 8 doses of ramucirumab over a median of 4.4 months.1, 14
Dosage Modification for Toxicity
If toxicities occur, temporary or permanent discontinuance of ramucirumab may be required based on causality.1
Ramucirumab should be permanently discontinued in patients who develop severe (grade 3 or 4) bleeding, arterial thromboembolic events, clinically important hypertension that is not controlled with antihypertensive therapy, hypertensive crisis, hypertensive encephalopathy, grade 3 or 4 infusion-related effects, GI perforation, nephrotic syndrome, proteinuria exceeding 3 g per 24 hours, or reversible posterior leukoencephalopathy syndrome (RPLS).1 (See Cautions: Warnings/Precautions.)
Ramucirumab therapy should be temporarily suspended prior to surgery or if wound healing complications develop during therapy.1 Therapy also should be temporarily interrupted in patients who develop severe hypertension or proteinuria.1 (See Hypertension and also Proteinuria under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
If grade 1 or 2 infusion-related reactions occur, the infusion rate should be reduced by 50%.1 If grade 3 or 4 infusion-related reactions occur, ramucirumab should be permanently discontinued.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If severe hypertension occurs, ramucirumab therapy should be interrupted until hypertension is controlled.1 Ramucirumab should be permanently discontinued in patients with clinically important hypertension that is not controlled with antihypertensive therapy or in patients who develop hypertensive crisis or hypertensive encephalopathy.1 (See Hypertension under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Ramucirumab therapy should be interrupted for proteinuria of 2 g or more per 24 hours; when proteinuria declines below this level, ramucirumab may be resumed at a reduced dosage of 6 mg/kg every 2 weeks (in patients receiving ramucirumab for advanced or metastatic gastric adenocarcinoma or metastatic colorectal cancer) or 8 mg/kg every 3 weeks (in patients receiving ramucirumab for metastatic NSCLC).1 If proteinuria recurs, therapy should be withheld again; when proteinuria declines below 2 g per 24 hours, ramucirumab may then be resumed at a reduced dosage of 5 mg/kg every 2 weeks (in patients receiving ramucirumab for advanced or metastatic gastric adenocarcinoma or metastatic colorectal cancer) or 6 mg/kg every 3 weeks (in patients receiving ramucirumab for metastatic NSCLC).1 If nephrotic syndrome or proteinuria exceeding 3 g per 24 hours occurs, treatment with ramucirumab should be permanently discontinued.1 (See Proteinuria under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentration within the upper limit of normal [ULN] and AST concentration exceeding the ULN, or total bilirubin concentration ranging from more than 1 to 1.5 times the ULN and any AST concentration).1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
No dosage adjustment is necessary in patients with renal impairment.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states there are no known contraindications to the use of ramucirumab.1
Ramucirumab is associated with an increased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhage.1
In the REGARD study, severe bleeding was reported in 3.4% of patients receiving ramucirumab compared with 2.6% of those receiving placebo, and red blood cell transfusions were required in 11% of patients receiving ramucirumab compared with 8.7% of those receiving placebo.1 In the RAINBOW study, severe bleeding was reported in 4.3% of patients receiving ramucirumab in combination with paclitaxel compared with 2.4% of those receiving placebo plus paclitaxel.1 Patients with gastric cancer receiving nonsteroidal anti-inflammatory agents (NSAIAs) were excluded from the REGARD and RAINBOW studies; therefore, the risk of gastric hemorrhage associated with ramucirumab is unknown in such patients.1
In the REVEL study, severe bleeding was reported in 2.4% of patients with metastatic non-small cell lung cancer (NSCLC) receiving ramucirumab in combination with docetaxel compared with 2.3% of those receiving placebo plus docetaxel.1 Pulmonary hemorrhage was reported in 7% of patients with nonsquamous histology receiving ramucirumab in combination with docetaxel compared with 6% of those receiving placebo plus docetaxel; among patients with squamous histology, pulmonary hemorrhage was reported in 10% of patients receiving ramucirumab in combination with docetaxel compared with 12% of those receiving placebo plus docetaxel.1 Patients with NSCLC receiving therapeutic anticoagulation, long-term therapy with NSAIAs, or antiplatelet therapy other than once-daily aspirin, and those with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation, were excluded from the REVEL study;1, 12 therefore, the risk of pulmonary hemorrhage associated with ramucirumab is unknown in such patients.1
In the RAISE study, severe bleeding was reported in 2.5% of patients with metastatic colorectal cancer receiving ramucirumab in combination with FOLFIRI (i.e., fluorouracil, leucovorin [folinic acid], and irinotecan) compared with 1.7% of those receiving placebo plus FOLFIRI.1
Ramucirumab should be permanently discontinued if severe (grade 3 or 4) hemorrhage occurs during therapy with the drug.1
GI perforation, potentially fatal, has been reported with antiangiogenic agents that are inhibitors of vascular endothelial growth factor receptor (VEGFR), including ramucirumab.1, 2 In clinical trials, GI perforation was reported in 4 of 570 patients (0.7%) receiving ramucirumab as a single agent.1 In the RAINBOW study, GI perforation was reported in 1.2% of patients receiving ramucirumab in combination with paclitaxel compared with 0.3% of patients receiving placebo plus paclitaxel.1 In the REVEL study, GI perforation was reported in 1% of patients receiving ramucirumab in combination with docetaxel compared with 0.3% of patients receiving placebo plus docetaxel.1 In the RAISE study, GI perforation was reported in 1.7% of patients receiving ramucirumab in combination with FOLFIRI compared with 0.6% of those receiving placebo plus FOLFIRI.1
Ramucirumab should be permanently discontinued in patients who develop GI perforation.1
Data are lacking on the effects of ramucirumab in patients with serious or non-healing wounds;1 however, inhibitors of VEGFR may impair wound healing.1, 3 Ramucirumab should be discontinued in patients with impaired wound healing.1
The manufacturer recommends that ramucirumab be discontinued prior to scheduled surgery.1 The decision to resume therapy postoperatively should be based on clinical assessment of the adequacy of wound healing.1 If wound healing complications develop during ramucirumab therapy, the drug should be discontinued until the wound is fully healed.1
Other Warnings and Precautions
Arterial Thromboembolic Events
Severe, sometimes fatal, arterial thromboembolic events (including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia) have been reported in patients receiving ramucirumab.1, 2 In the REGARD study, arterial thromboembolic events were reported in 1.7% of patients receiving ramucirumab compared with none of those receiving placebo.1
Ramucirumab should be permanently discontinued if a severe arterial thromboembolic event occurs during therapy with the drug.1
Ramucirumab is associated with an increased risk of severe hypertension.1, 2, 14 In the REGARD study, grade 3 or 4 hypertension was reported in 8% of patients receiving ramucirumab compared with 3% of those receiving placebo.1 In the RAINBOW study, grade 3 or greater hypertension was reported in 15% of patients receiving ramucirumab in combination with paclitaxel compared with 3% of those receiving placebo plus paclitaxel.1, 11 In the REVEL study, grade 3 or greater hypertension was reported in 6% of patients receiving ramucirumab in combination with docetaxel compared with 2% of those receiving placebo plus docetaxel.1, 12 In the RAISE study, grade 3 or greater hypertension was reported in 11% of patients receiving ramucirumab in combination with FOLFIRI compared with 3% of those receiving placebo plus FOLFIRI.1, 14
Hypertension should be controlled prior to initiating therapy with ramucirumab.1 Blood pressure should be monitored every 2 weeks or more frequently as clinically indicated during therapy with the drug.1 If severe hypertension occurs, ramucirumab therapy should be interrupted until hypertension is controlled.1 Ramucirumab should be permanently discontinued in patients with clinically important hypertension that is not controlled with antihypertensive therapy or in patients who develop hypertensive crisis or hypertensive encephalopathy.1
Infusion-related reactions, sometimes severe, have been reported in patients receiving ramucirumab.1 In clinical studies, infusion-related reactions occurred in 16% of patients receiving ramucirumab without premedication.1 Infusion-related reactions generally occurred more frequently during or following the first 2 infusions.1 Infusion-related reactions may include bronchospasm, supraventricular tachycardia, hypotension, rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.1
Premedication with an antihistamine (e.g., IV diphenhydramine hydrochloride) should be administered prior to each infusion of ramucirumab.1 (See Dosage and Administration: General.) Patients should be monitored during infusions of the drug for manifestations of infusion-related reactions.1 If infusion-related reactions occur, reduction in the infusion rate or permanent discontinuance of ramucirumab may be required.1 (See Infusion-related Effects under Dosage: Dosage Modification for Toxicity, under Dosage and Administration.)
New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome has been reported in patients with preexisting Child-Pugh class B or C cirrhosis receiving ramucirumab as a single agent.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in less than 0.1% of patients receiving ramucirumab in clinical studies.1
If signs or symptoms of RPLS develop, diagnosis of RPLS should be confirmed by magnetic resonance imaging (MRI), and ramucirumab therapy should be discontinued.1 Symptoms of RPLS may resolve or improve within days, but some patients can experience ongoing neurologic sequelae or death.1
Proteinuria has been reported in patients receiving ramucirumab.1 In the RAINBOW study, proteinuria of any grade occurred in 17% of patients receiving ramucirumab in combination with paclitaxel compared with 6% of those receiving placebo plus paclitaxel.1 In the RAISE study, grade 3 or greater proteinuria occurred in 3% of patients receiving ramucirumab in combination with FOLFIRI compared with 0.2% of those receiving placebo plus FOLFIRI; among these patients, nephrotic syndrome occurred in 0.6% of patients receiving ramucirumab in combination with FOLFIRI versus none of those receiving placebo plus FOLFIRI.1
Urine dipstick proteinuria and/or urinary protein-to-creatinine ratio should be monitored for development or worsening of proteinuria during therapy.1
Ramucirumab therapy should be interrupted in patients with urine protein levels of 2 g or more per 24 hours and resumed at a reduced dosage when proteinuria declines below this level.1 If urine protein levels exceed 3 g per 24 hours or if nephrotic syndrome occurs, treatment with ramucirumab should be permanently discontinued.1 (See Proteinuria under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Hypothyroidism has been reported in patients receiving ramucirumab in combination with FOLFIRI.1 In the RAISE study, hypothyroidism occurred in 2.6% of patients receiving ramucirumab in combination with FOLFIRI compared with 0.9% of those receiving placebo plus FOLFIRI.1 Among patients with normal baseline thyroid-stimulating hormone (TSH) concentrations, increases in TSH concentrations were reported in 46% of patients receiving ramucirumab in combination with FOLFIRI compared with 4% of those receiving placebo plus FOLFIRI.1
Thyroid function should be monitored during ramucirumab therapy.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of ramucirumab in pregnant women; however, based on its mechanism of action, ramucirumab can cause fetal harm.1 In animals, angiogenesis, vascular endothelial growth factors (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR-2) have a critical role in female reproduction, embryofetal development, and postnatal development.1 Teratogenicity (i.e., poor development of cranial region, forelimbs, forebrain, heart, blood vessels) has been observed in animals following disruption of VEGF signaling.1
Pregnancy should be avoided during ramucirumab therapy.1 Women of childbearing potential should be advised to use an effective method of contraception while receiving ramucirumab and for at least 3 months after discontinuance of therapy.1 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1
Antibodies to ramucirumab have been detected in patients receiving the drug.1 In clinical studies, anti-ramucirumab antibodies were detected in 86 of 2890 patients (3%) receiving ramucirumab.1 Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for anti-ramucirumab antibodies.1
Results of animal studies suggest that inhibitors of VEGFR, such as ramucirumab, may impair female fertility or ability to maintain pregnancy.1
Based on its mechanism of action, ramucirumab may cause fetal harm if administered to pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether ramucirumab is distributed into human milk.1 Human immunoglobulin G (IgG) is distributed into milk; however, published data suggest that antibodies contained in breast milk do not enter the neonatal and infant circulation in substantial amounts.1 Nevertheless, because of the potential for serious adverse reactions to ramucirumab in nursing infants, the manufacturer states that nursing during ramucirumab therapy is not recommended.1 Data are lacking on the effects of the drug in nursing infants or on the production of milk.1
Safety and efficacy of ramucirumab have not been established in pediatric patients younger than 18 years of age.1, 2
In animals, exposure to ramucirumab at concentrations 0.2 times that of human clinical exposure resulted in toxicities in bone (i.e., thickening of epiphyseal growth plates, osteochondropathy).1
In the REGARD and RAINBOW studies, 36% of patients with advanced or metastatic gastric adenocarcinoma receiving ramucirumab were 65 years of age or older, and 7% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric and younger adults.1
In the REVEL study, 36% of patients with metastatic NSCLC receiving ramucirumab in combination with docetaxel were 65 years of age or older, and 7% were 75 years of age or older.1, 12 In an exploratory subgroup analysis, survival benefit was not observed in patients 65 years of age or older receiving ramucirumab in combination with docetaxel (hazard ratio 1.10).1
In the RAISE study, 40% of patients with metastatic colorectal cancer receiving ramucirumab in combination with FOLFIRI were 65 years of age or older, and 10% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric and younger adults in this study.1
In a population pharmacokinetic analysis, no clinically meaningful differences in the average steady-state concentrations of ramucirumab were observed between patients with mild (total bilirubin concentration within the upper limit of normal [ULN] and AST concentration exceeding the ULN, or total bilirubin concentration ranging from more than 1 to 1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration ranging from 1.5 to 3 times the ULN and any AST concentration) hepatic impairment and those with normal hepatic function.1 Formal pharmacokinetic studies have not been conducted in patients with severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment.1 (See Dosage and Administration: Special Populations.)
New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome has been reported in patients with preexisting Child-Pugh class B or C cirrhosis receiving ramucirumab as a single agent.1 Ramucirumab should be used in patients with Child-Pugh class B or C cirrhosis only if the potential benefit outweighs the risk of clinical deterioration.1
In a population pharmacokinetic analysis, no clinically meaningful differences in the average steady-state concentrations of ramucirumab were observed between patients with mild (creatinine clearance of 60-89 mL/minute), moderate (creatinine clearance of 30-59 mL/minute), or severe (creatinine clearance of 15-29 mL/minute) renal impairment and those with normal renal function.1 (See Dosage and Administration: Special Populations.)
Adverse effects reported in 5% or more of patients with advanced or metastatic gastric adenocarcinoma receiving ramucirumab as a single agent in the REGARD study and occurring at an incidence at least 2% higher than that reported with placebo include hypertension,1, 2 diarrhea,1 bleeding or hemorrhage,2 headache,1, 8 proteinuria,1, 8 and hyponatremia.1 Clinically important adverse effects reported in less than 5% of patients receiving ramucirumab as a single agent in the REGARD study include neutropenia,1, 8 epistaxis,1, 8 rash,1, 8 anemia,1 intestinal obstruction,1, 8 arterial thromboembolic events,1, 8 GI perforation,1 and infusion-related reactions.1
Adverse effects reported in 5% or more of patients with advanced or metastatic gastric adenocarcinoma receiving ramucirumab in combination with paclitaxel in the RAINBOW study and occurring at an incidence at least 2% higher than that reported with placebo plus paclitaxel include fatigue or asthenia,1, 11 neutropenia,1, 11 diarrhea,1, 11 epistaxis,1, 11 peripheral edema,1, 11 hypertension,1, 11 stomatitis,1, 11 proteinuria,1, 11 thrombocytopenia,1, 11 hypoalbuminemia,1, 11 and GI hemorrhage.1 Clinically important adverse effects reported in less than 5% of patients receiving ramucirumab in combination with paclitaxel in the RAINBOW study include sepsis1 and GI perforation.1
Adverse effects reported in 5% or more of patients with metastatic NSCLC receiving ramucirumab in combination with docetaxel in the REVEL study and occurring at an incidence at least 2% higher than that reported with placebo plus docetaxel include neutropenia,1, 12 fatigue or asthenia,1, 12 stomatitis or mucosal inflammation,1, 12 epistaxis,1, 12 febrile neutropenia,1, 12 peripheral edema,1, 12 thrombocytopenia,1, 12 increased lacrimation,1, 12 hypertension,1, 12 diarrhea,12 decreased appetite,12 neuropathy,12 leukopenia,12 pyrexia,12 myalgia,12 arthralgia,12 back pain,12 dysgeusia,12 and insomnia.12 Clinically important adverse effects reported in less than 5% of patients receiving ramucirumab in combination with docetaxel in the REVEL study include hyponatremia1 and proteinuria.1
Adverse effects reported in the RAISE study in 5% or more of patients with metastatic colorectal cancer receiving ramucirumab in combination with FOLFIRI and at an incidence at least 2% higher than that reported with placebo plus FOLFIRI include diarrhea,1, 14 neutropenia,1, 14 fatigue,14 hemorrhage,14 decreased appetite,1, 14 epistaxis,1, 14 stomatitis,1, 14 vomiting,14 constipation,14 abdominal pain,14 thrombocytopenia,1, 14 hypertension,1, 14 peripheral edema,1, 14 mucosal inflammation,14 proteinuria,1, 14 pyrexia,14 headache,14 decreased weight,14 cough,14 liver injury or liver failure,14 palmar-plantar erythrodysesthesia (hand-foot syndrome),1, 14 GI hemorrhage,1, 14 venous thromboembolic event,14 hypoalbuminemia,1 and infusion-related reactions.14 Clinically important adverse effects reported in less than 5% of patients receiving ramucirumab in combination with FOLFIRI include GI perforation.1
Concomitant administration of ramucirumab (10 mg/kg) with docetaxel (75 mg/m2) in patients with solid tumors did not substantially alter systemic exposure to ramucirumab or docetaxel.1, 13
Concomitant administration of ramucirumab with irinotecan in patients with solid tumors did not substantially alter systemic exposure to ramucirumab or irinotecan (including its active metabolite SN-38).1
Concomitant administration of ramucirumab (8 mg/kg) with paclitaxel (80 mg/m2) in patients with solid tumors did not substantially alter systemic exposure to ramucirumab or paclitaxel.1, 13
Ramucirumab, a recombinant human IgG1 monoclonal antibody, is a vascular endothelial growth factor receptor (VEGFR)-2 antagonist.1 Ramucirumab binds specifically to VEGFR-2 and blocks the interaction of VEGFR-2 with its ligands (VEGF-A, VEGF-C, and VEGF-D), resulting in inhibition of VEGF-stimulated activation of both VEGFR-2 and downstream signaling pathways.1, 8, 9 The VEGFR signaling pathway plays an important role in the pathogenesis and progression of several types of tumors since it is a pivotal mediator of tumor angiogenesis; the pathway also regulates tumor growth and metastatic spread.4, 5, 6 In vitro assays have shown that binding of ramucirumab to VEGFR-2 blocks ligand-induced phosphorylation and activation of the receptor.1, 4 Ramucirumab has been shown to inhibit VEGF-induced endothelial cell proliferation and migration in vitro.4 Ramucirumab also has been shown to inhibit angiogenesis in vivo.1
Following administration of 8 mg/kg every 2 weeks in patients with advanced or metastatic gastric adenocarcinoma, the mean elimination half-life of ramucirumab was 15 days.1 Following administration of 10 mg/kg every 21 days in patients with metastatic non-small cell lung cancer [NSCLC]), the mean elimination half-life of ramucirumab was 23 days.1 Data from a population pharmacokinetic analysis indicate that age, gender, and race do not have clinically important effects on the pharmacokinetics of ramucirumab.1, 9
Risk of severe bleeding.1 Importance of informing clinician of any episodes or symptoms of bleeding (e.g., lightheadedness).1
Risk of arterial thromboembolic events.1
Risk of hypertension.1 Importance of receiving routine monitoring of blood pressure and informing clinician if blood pressure is elevated or if manifestations of hypertension (e.g., severe headache, lightheadedness, neurologic symptoms) occur.1
Importance of informing clinician if severe diarrhea, vomiting, or severe abdominal pain occurs.1
Risk of wound healing complications.1 Importance of informing clinician of any scheduled surgery.1
Risk of fetal or neonatal toxicity and miscarriage.1 Necessity of advising women receiving ramucirumab to use an effective method of contraception during and for at least 3 months after the last dose of ramucirumab.1 Importance of immediately informing clinician if the patient becomes pregnant during therapy.1 If pregnancy occurs, apprise patient of potential hazard to the fetus.1
Importance of discontinuing nursing while receiving ramucirumab therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]), as well as any concomitant illnesses (e.g., hypertension, hepatic disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 7, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Eli Lilly. Cyramza® (ramucirumab) injection for intravenous infusion prescribing information. Indianapolis, IN; 2015 Apr.
2. Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet . 2014; 383:31-9. [PubMed 24094768]
3. GlaxoSmithKline. Votrient® (pazopanib hydrochloride) tablets prescribing information. Research Triangle Park, NC: 2014 Jun.
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Pharmacology review(s). From FDA website. [Web]
5. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D . 2011; 11:113-26. [PubMed 21679004]
6. Hu-Lowe DD, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res . 2008; 14:7272-83. [PubMed 19010843]
7. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Jun 23. [Web]
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Summary review. From FDA website. [Web]
9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Medical review(s). From FDA website. [Web]
10. Eli Lilly. How to order Cyramza® (ramucirumab). Indianapolis, IN. Accessed 2014 Jun 18. [Web]
11. Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol . 2014; 15:1224-35. [PubMed 25240821]
12. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet . 2014; 384:665-73. [PubMed 24933332]
13. Eli Lilly. Cyramza® (ramucirumab) injection for intravenous infusion prescribing information. Indianapolis, IN; 2014 Dec.
14. Tabernero J, Yoshino T, Cohn AL et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol . 2015; 16:499-508. [PubMed 25877855]