Ramucirumab is a fully human monoclonal antibody that binds with high affinity to the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR2; kinase insert domain-containing receptor; KDR), preventing the binding of VEGF-A, VEGF-C, and VEGF-D. The mechanism of binding to VEGFR2 rather than VEGF may lead to less resistance since endothelial cells are genetically stable. Ramucirumab is indicated as monotherapy for the treatment of advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer as well as previously treated hepatocellular cancer in patients with an alpha-fetoprotein of 400 ng/mL or more. It is also indicated in combination with paclitaxel for advanced or metastatic gastric/GEJ cancer, in combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) after progression on platinum-based therapy, and in combination with FOLFIRI for metastatic colorectal cancer in patients previously treated with bevacizumab, oxaliplatin, and a fluoropyrimidine. An increased incidence of severe hypertension has been reported in clinical trials; monitor blood pressure and treat as appropriate. Severe infusion reactions have also occurred; all patients should receive premedication with IV diphenhydramine or equivalent; patients with a previous grade 1 or 2 infusion reaction should also receive premedication with acetaminophen and dexamethasone (or equivalent).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if it is discolored or if foreign particulate matter is present.
Intravenous Administration
Reconstitution:
-Withdraw the appropriate volume from a single-use vial of ramucirumab (10 mg/mL) and add to a bag of 0.9% Sodium Chloride Injection to a final volume of 250 mL.
-Do not dilute ramucirumab with other medications or electrolytes. Do not use dextrose-containing solutions.
-Mix diluted solution by gentle inversion. Do not shake.
-The diluted solution is stable for no more than 24 hours at 2 to 8 degrees C (36 to 46 degrees F) or for 4 hours at room temperature (below 25 degrees C or 77 degrees F). Do not freeze.
Infusion:
-Administer using an infusion pump through a separate infusion line. Use of a protein-sparing 0.22-micron filter is recommended.
-Infuse the first dose over 60 minutes. If the first infusion is tolerated, subsequent doses may be infused over 30 minutes.
-Do not administer as an IV push or bolus.
-Flush the IV line with 0.9% Sodium Chloride Injection at the end of each infusion.
Back pain was reported in 10% (grade 3 or 4, less than 1%) of patients with hepatocellular cancer treated with ramucirumab monotherapy (n = 197) compared with 7% (grade 3 or 4, 1%) of those who received placebo in a randomized clinical trial.
Infusion-related reactions including rigors/tremor, back pain/spasms, chest pain (unspecified) and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesias have been reported in less than 9% (grade 3 to 5, less than 1%) of patients treated with ramucirumab across 6 clinical trials (n = 2,137); in severe cases, symptoms included bronchospasm, supraventricular tachycardia (SVT), and hypotension. Monitor patients for infusion-related reactions. Reduce the rate of infusion by 50% for grade 1 or 2 infusion-related reactions; permanently discontinue therapy for grade 3 or 4 reactions.
Bleeding events occurred in between 13% to 55% (grade 3 to 5, 2% to 5%) of patients with various cancers who received ramucirumab across 5 clinical trials (n = 2,137). Epistaxis was reported in 4.7% to 14% (grade 3 or 4, less than 1%) of patients who received ramucirumab monotherapy in two randomized clinical trials; it occurred with a similar frequency (19%; grade 3 or 4, less than 1%) in patients treated with ramucirumab plus docetaxel in a separate clinical trial. The incidence of epistaxis was higher (31% to 34%) in patients who received ramucirumab in combination with paclitaxel, FOLFIRI, or bevacizumab in three other clinical trials; 10% to 12% of ramucirumab-treated patients in these trials also developed GI bleeding (grade 3 or 4, 1% to 4%; grade 5, 0.6% or less). Pulmonary hemorrhage was occurred in 7% (grade 3 or higher, 1%) of patients with non-squamous NSCLC treated with ramucirumab plus docetaxel; this incidence was not meaningfully higher than patients who received placebo plus docetaxel (6%; grade 3 or higher, 1%). In patients with squamous histology, pulmonary hemorrhage occurred in fewer patients who received ramucirumab plus docetaxel compared with placebo plus docetaxel (10% vs. 12%; grade 3 or higher, 2% vs. 2%). Pulmonary hemorrhage also occurred in 7% of NSCLC patients treated with ramucirumab in combination with erlotinib (grade 3 or 4, less than 1%); gingival bleeding occurred in 9% of these patients.
Serious and sometimes fatal arterial thrombosis including myocardial infarction, cardiac arrest, cerebrovascular accident (stroke), and cerebral ischemia occurred in 1% to 3% (grade 3 or 4, 1% to 2%) of patients with various cancers treated with ramucirumab across 6 clinical trials (n = 2,137). Permanently discontinue ramucirumab in patients who experience an arterial thrombotic event. Thrombotic microangiopathy and heart failure have also been reported in postmarketing experience with ramucirumab.
An increased incidence of severe hypertension (11% to 26%; grade 3 to 5, 6% to 15%) has been reported in patients with various cancers treated with ramucirumab across 5 clinical trials (n = 1,916). In a sixth study of non-small cell lung cancer (NSCLC) patients receiving ramucirumab in combination with erlotinib (the RELAY study), the incidence of new or worsening hypertension was higher compared to other ramucirumab studies, and also higher compared to patients treated with placebo plus erlotinib in RELAY (45% vs. 12%; grade 3 or higher, 24% vs. 5%); 13% of patients in the ramucirumab arm required initiation of 3 or more antihypertensive medications compared to 4% of those in the placebo arm. In the RELAY study, hypertension was more common in elderly patients (older than 65 years) compared to younger patients (50% vs. 40%). Control blood pressure prior to initiating ramucirumab therapy and monitor blood pressure during treatment; an interruption or discontinuation of therapy may be necessary.
Ramucirumab can increase the risk of GI perforation. Grade 3 to 5 GI perforation occurred in 2% or fewer patients with various cancers who received ramucirumab across 6 clinical trials (n = 2,137); permanently discontinue ramucirumab in patients who experience GI perforation. GI obstruction has also been reported in 2.1% to 3% of patients with gastric cancer receiving ramucirumab monotherapy or colorectal cancer receiving ramucirumab in combination with FOLFIRI in 2 randomized clinical trials.
Abdominal pain (25% vs. 16%; grade 3 or 4, 2% vs. 2%), nausea (19% vs. 12%), and vomiting (10% vs. 7%) were more common in patients with hepatocellular cancer who received ramucirumab monotherapy (n = 197) compared with placebo (n = 95) in a randomized clinical trial.
Anorexia/decreased appetite occurred in 23% (grade 3 or 4, 2%) of patients with hepatocellular cancer treated with ramucirumab monotherapy and in 37% (grade 3 or 4, 2%) of patients with metastatic colorectal cancer who received ramucirumab in combination with FOLFIRI in 2 separate randomized clinical trials. In patients with non-small cell lung cancer (NSCLC) treated with ramucirumab plus erlotinib, decreased appetite was more common in elderly patients (65 years or older) compared to younger patients (32% vs. 19%).
Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) was reported in less than 0.1% of patients treated with ramucirumab across 6 clinical trials (n = 2,137). If suspected, confirm the diagnosis with MRI and permanently discontinue ramucirumab therapy. Symptoms may improve or resolve within days; some patients can experience ongoing neurologic sequelae or death.
In a randomized clinical trial of patients with hepatocellular cancer, 18% of patients treated with ramucirumab monotherapy developed ascites compared with 7% of those who received placebo (grade 3 or 4, 4% vs. 1%). Hepatic encephalopathy occurred in 5% (grade 5, 0.5%) and hepatorenal syndrome in 2% (grade 5, 0.5%) of ramucirumab-treated patients. Clinical deterioration, manifested by new onset or worsening hepatic encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C liver disease who received ramucirumab monotherapy in clinical trials. Based on safety data in patients with hepatocellular cancer and Child-Pugh A liver disease, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received ramucirumab compared to those who received placebo (6% vs. 0%).
Hyponatremia occurred in 6% (grade 3 or 4, 3%) of patients with advanced gastric cancer treated with ramucirumab monotherapy and in 4.8% of patients with metastatic non-small cell lung cancer (NSCLC) who received ramucirumab plus docetaxel in separate clinical trials. Hyponatremia occurred in 32% (grade 3 or 4, 16%) and hypocalcemia in 16% (grade 3 or 4, 2%) of patients with hepatocellular cancer treated with ramucirumab monotherapy. Hypokalemia occurred in 24% of patients with NSCLC treated with ramucirumab plus erlotinib, (grade 3 or 4, 5%).
Fatigue was reported in 36% (grade 3 or 4, 5%) of patients with hepatocellular cancer treated with ramucirumab monotherapy in a randomized clinical trial. The incidence of fatigue/asthenia was higher 55% to 57% (grade 3 or 4, 12% to 14%) in patients with gastric cancer or non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with either paclitaxel or docetaxel in 2 randomized clinical trials.
Neutropenia has been reported in patients treated with ramucirumab, although the incidence varies in clinical trials. Neutropenia occurred in 4.7% of patients with advanced gastric cancer receiving ramucirumab monotherapy, although the incidence was higher (24%; grade 3 or 4, 8%) in another randomized clinical trial of patients with hepatocellular cancer receiving ramucirumab monotherapy. Neutropenia occurred more often in non-small cell lung cancer (NSCLC) patients treated with ramucirumab plus erlotinib compared with those receiving placebo plus erlotinib in one trial (33% vs. 21%; grade 3 or 4, 7% vs. 4%). Neutropenia occurred in 54% to 59% (grade 3 or 4, 38% to 49%) of patients with various advanced cancers treated with ramucirumab in combination with paclitaxel, docetaxel, or FOLFIRI compared with 31% to 46% (grade 3 or 4, 19% to 40%) of patients receiving placebo plus chemotherapy. Febrile neutropenia occurred in 2.8% and 16% of patients receiving ramucirumab in combination with FOLFIRI and docetaxel, respectively.
Dermatologic effects have infrequently been reported with the use of ramucirumab in clinical trials. Rash occurred in 4.2% of patients with advanced gastric cancer treated with ramucirumab monotherapy (n = 236) in a randomized clinical trial. Palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 13% (grade 3 or 4, 1%) of patients with metastatic colorectal cancer who received FOLFIRI in combination with ramucirumab (n = 529) compared with 5% (grade 3 or 4, less than 1%) of those receiving FOLFIRI plus placebo (n = 528). Hemangioma has been reported in postmarketing experience with ramucirumab.
Proteinuria occurred in 3% to 34% (grade 3 or higher, 3% or less) of patients with various cancers treated with ramucirumab across 6 clinical trials (n = 2,137), including 4 patients with nephrotic syndrome. Monitor proteinuria during treatment; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
Peripheral edema occurred in 25% (grade 3 or 4, 2%) of patients with hepatocellular cancer treated with ramucirumab monotherapy compared with 14% of those treated with placebo in a randomized clinical trial. In combination with paclitaxel, docetaxel, FOLFIRI, or erlotinib, peripheral edema occurred in 16% to 23% (grade 3 or 4, 2% or less) of those treated ramucirumab compared with 4% to 14% (grade 3 or 4, 1% or less) of those who received placebo.
Hypoalbuminemia occurred in 33% (grade 3 or 4, less than 1%) of patients with hepatocellular cancer treated with ramucirumab monotherapy (n = 197) compared with 16% of those receiving placebo (n = 95) in a randomized clinical trial. Hypoalbuminemia occurred in 6% to 11% (grade 3 or 4, 1%) of patients receiving ramucirumab in combination with FOLFIRI or paclitaxel in separate clinical trials.
As with all therapeutic proteins, there is the potential for antibody formation. Treatment-emergent anti-ramucirumab antibodies were detected in 3% of patients treated with ramucirumab in clinical trials (n = 2,890); neutralizing antibodies were detected in 16% of these patients. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, the timing of sample collection, concomitant medications, and underlying disease. Comparison of the incidence of antibodies to ramucirumab with the incidences of antibodies to other products may be misleading.
Grade 1 or 2 fever was reported in 10% of patients with hepatocellular cancer treated with ramucirumab monotherapy compared with 3% of those who received placebo in a randomized clinical trial. Serious infection including sepsis occurred in 3.1% of patients with advanced gastric cancer treated with ramucirumab in combination with paclitaxel in a randomized clinical trial, including 5 deaths. Infections occurred in 81% of patients with non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with erlotinib, compared with 76% of those receiving placebo plus erlotinib (grade 3 or 4, 17% vs. 7%); the most common infections in the ramucirumab arm included paronychia (4%), pneumonia (3%), cellulitis (1%), skin infection (1%), and urinary tract infection (1%).
In a multinational, randomized, double-blind study, 13% of patients treated with ramucirumab in combination with docetaxel experienced increased lacrimation (n = 627; grade 3 or 4, less than 1%) compared with 5% of patients who received docetaxel and placebo (n = 618).
Mild (grade 1 or 2) hypothyroidism occurred in 3% or fewer patients with various cancers who received ramucirumab treatment across 6 clinical trials (n = 2,137); there were no reports of grade 3 to 5 hypothyroidism. Increased TSH levels were observed in 46% of patients with metastatic colorectal cancer and normal baseline TSH levels who were treated with FOLFIRI in combination with ramucirumab (n = 115), compared with 4% of those treated with FOLFIRI plus placebo (n = 109). Monitor thyroid function during treatment.
Impaired wound healing has been reported with antibodies that inhibit the VEGF pathway. Interrupt ramucirumab therapy 28 days prior to elective surgery. Do not administer ramucirumab for at least 28 days after a major surgical procedure and until the wound is fully healed. If a patient develops wound healing complications that require medical intervention, discontinue ramucirumab. Ramucirumab has not been studied in patients with serious or non-healing wounds.
Grade 1 or 2 insomnia was reported in 11% of patients with hepatocellular cancer treated with ramucirumab monotherapy (n = 197) compared with 6% (grade 1 or 2, 1%) of those who received placebo (n = 95) in a randomized clinical trial.
Dysphonia has been reported in patients treated with ramucirumab in postmarketing experience.
The incidence of diarrhea with ramucirumab varies depending on concomitant chemotherapy. Diarrhea was reported in 14% (grade 3 or 4, 1%) of patients with gastric cancer receiving ramucirumab monotherapy; it occurred in 32% (grade 3 or 4, 4%) of patients with gastric cancer who received ramucirumab in combination with paclitaxel in another clinical trial. In yet another clinical trial of patients with metastatic colorectal cancer, diarrhea occurred in 60% (grade 3 or 4, 11%) of patients receiving ramucirumab plus FOLFIRI. Diarrhea occurred in 70% of patients with metastatic non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with erlotinib (grade 3 or 4, 7%); it was more common in elderly patients (older than 65 years) compared to younger patients (75% vs. 65%).
Stomatitis occurred in 20% of patients with gastric cancer who received ramucirumab in combination with paclitaxel in one clinical trial (grade 3 or 4, 1%). Stomatitis/mucosal inflammation was reported in 37% (grade 3 or 4, 7%) of patients with advanced non-small cell lung cancer (NSCLC) who received ramucirumab plus docetaxel, and in 42% (grade 3 or 4, 2%) of NSCLC patients treated with ramucirumab in combination with erlotinib. In those treated with ramucirumab plus erlotinib, stomatitis was more common in elderly patients (65 years or older) compared to younger patients (46% vs. 36%).
Alopecia occurred in 34% of patients with non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with erlotinib compared with 20% of those receiving placebo plus erlotinib in a randomized clinical trial.
Mild (grade 1 or 2) headache was reported in 9% to 14% of patients treated with ramucirumab monotherapy in clinical trials. The incidence was similar when administered in combination with erlotinib for the treatment of non-small cell lung cancer (NSCLC) (15%; grade 3 or 4, less than 1%).
Pneumothorax occurred in 1.8% of patients with non-small cell lung cancer treated with ramucirumab in combination with erlotinib in a randomized clinical trial.
Elevated hepatic enzymes occurred more often in non-small cell lung cancer (NSCLC) patients treated with ramucirumab in combination with erlotinib compared with placebo plus erlotinib, including increased ALT (74% vs. 60%; grade 3 or 4, 11% vs. 13%), increased AST (71% vs. 47%; grade 3 or 4, 6% vs. 4%), and increased alkaline phosphatase (25% vs. 16%; grade 3 or 4, less than 1% vs. 1%). Increased ALT (49% vs. 35%) and increased AST (49% vs. 33%) were more common in elderly patients (65 years or older) compared to younger patients.
Thrombocytopenia was not reported in patients with advanced gastric cancer treated with ramucirumab monotherapy but occurred in 46% (grade 3 or 4, 8%) of patients with hepatocellular cancer who received ramucirumab monotherapy. In combination with chemotherapy, thrombocytopenia occurred in 13% to 28% (grade 3 or 4, 2% to 3%) of patients receiving ramucirumab compared with 5% to 14% (grade 3 or 4, 2% or less) of those receiving placebo. Thrombocytopenia occurred in 41% of patients who received ramucirumab plus erlotinib compared with 12% of those receiving placebo with erlotinib (grade 3 or 4, 3% vs. 3%).
Anemia occurred in 42% of non-small cell lung cancer (NSCLC) patients treated with ramucirumab in combination with erlotinib compared with 25% of those who received placebo plus erlotinib (grade 3 or 4, 5% vs. 2%).
In patients with non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with erlotinib, dysgeusia was more common in elderly patients (65 years or older) compared to younger patients (23% vs. 12%).
In patients with non-small cell lung cancer (NSCLC) treated with ramucirumab in combination with erlotinib, weight loss was more common in elderly patients (65 years or older) compared to younger patients (19% vs. 6%).
Arterial (including aortic) aneurysms, dissections (aortic dissection), and rupture have occurred in postmarketing experience with ramucirumab.
Ramucirumab increased the risk of hemorrhage and GI bleeding, including severe and sometimes fatal bleeding events. Patients with gastric cancer receiving non-steroidal anti-inflammatory drugs (NSAIDS) were excluded from ramucirumab clinical studies; therefore, the risk of GI bleeding in this population is unknown. Patients with non-small cell lung cancer (NSCLC) receiving concomitant chronic NSAID therapy, anti-platelet therapy (other than once-daily aspirin), or therapeutic anticoagulant therapy, those with a recent history of gross hemoptysis, and patients with evidence of major airway invasion by cancer or intratumor cavitation were excluded from clinical studies; therefore, the risk of pulmonary hemorrhage in these patients is unknown. Permanently discontinue ramucirumab in patients who experience severe (grade 3 or 4) bleeding. Anti-angiogenic therapy, including ramucirumab, can also increase the risk of GI perforation; permanently discontinue ramucirumab if this occurs.
Impaired wound healing can occur in patients treated with vascular endothelial growth factor (VEGF) receptor inhibitors such as ramucirumab. Therefore, ramucirumab therapy should be suspended 28 days prior to elective surgery; do not administer ramucirumab for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming ramucirumab after the resolution of wound healing complications has not been established.
Infusion-related reactions have been reported with the use of ramucirumab in clinical trials including rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesias; in severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Premedicate all patients with an IV histamine-1 receptor antagonist (e.g., diphenhydramine) prior to each infusion; add dexamethasone (or equivalent) and acetaminophen prior to each infusion in patients who have experienced a prior grade 1 or 2 infusion-related reactions. Monitor patients during the infusion for signs and symptoms of infusion-related reactions; have resuscitation equipment available. Reduce the infusion rate by 50% for grade 1 or 2 infusion-related reactions; permanently discontinue ramucirumab for grade 3 or 4 infusion-related reactions.
Serious and sometimes fatal arterial thromboembolic events including myocardial infarction, cardiac arrest, and stroke have been reported in ramucirumab clinical trials. Permanently discontinue ramucirumab in patients who experience an arterial thromboembolic event.
Use ramucirumab with caution in patients with pre-existing hypertension. Severe hypertension has been reported in patients receiving treatment with ramucirumab in clinical trials. Blood pressure should be controlled prior to initiation of treatment, and monitored every 2 weeks during treatment, or more frequently as indicated. If patients experience severe hypertension, hold ramucirumab therapy until blood pressure is controlled. Permanently discontinue ramucirumab in patients with hypertensive crisis, hypertensive encephalopathy, or if clinically significant hypertension is unable to be controlled with medical therapy.
Use ramucirumab in patients with caution in patients with mild to moderate hepatic disease (total bilirubin within the upper limit of normal (ULN) and AST greater than ULN, OR total bilirubin 1.1 to 3 times ULN and any AST). Clinical deterioration, manifested by new or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C biliary cirrhosis treated with ramucirumab monotherapy; use ramucirumab in these patients only if the potential benefits of treatment outweigh the risks of clinical deterioration. Based on safety data in patients with hepatocellular cancer, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was also higher for patients with Child-Pugh A liver disease who received ramucirumab compared to patients who received placebo.
Treatment-emergent human anti-human antibody (HAHA) was detected in 3% of patients treated with ramucirumab in clinical trials (n = 2,890); neutralizing antibodies were detected in 16% of these patients. Results may be influenced by several factors, including sample handling, the timing of sample collection, drug interference, concomitant medication, and the underlying disease. Comparison of the incidence of antibodies to ramucirumab with the incidence of antibodies to other products may be misleading.
Use ramucirumab with caution in patients with renal disease; severe proteinuria including nephrotic syndrome has been reported with ramucirumab therapy. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. An interruption of therapy, dose reduction, or discontinuation of therapy may be needed for proteinuria or in the setting of nephrotic syndrome.
Posterior Reversible Encephalopathy Syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), has been reported with ramucirumab use. Symptoms of PRES include seizures, headache, nausea/vomiting, blindness, and altered mental status. Permanently discontinue ramucirumab therapy if PRES is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging.
Use ramucirumab with caution in patients with a history of pre-existing thyroid disease; mild (grade 1 or 2) hypothyroidism has been reported with ramucirumab treatment. Monitor thyroid function during treatment with ramucirumab.
Pregnancy should be avoided by females of reproductive potential during ramucirumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, ramucirumab can cause fetal harm or death when administered during pregnancy based on its mechanism of action. In mice, loss of the VEGFR gene resulted in embryofetal death, and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with the development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies, including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.
Counsel patients about the reproductive risk and contraception requirements during ramucirumab treatment. Ramucirumab can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with ramucirumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of ramucirumab. Women who become pregnant while receiving ramucirumab should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of ramucirumab on human fertility, infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from ramucirumab, advise women to discontinue breast-feeding during treatment and for 2 months after the final dose. It is not known whether ramucirumab is present in human milk, although many drugs are excreted in human milk.
For the treatment of gastric cancer or gastro-esophageal junction adenocarcinoma:
-for the treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy, as monotherapy:
Intravenous dosage:
Adults: 8 mg/kg IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. In a multinational, randomized, double-blind study (REGARD), treatment with ramucirumab significantly improved overall survival (5.2 months vs. 3.8 months) and progression-free survival (2.1 months vs. 1.3 months) compared with placebo plus best supportive care in patients with locally advanced or metastatic gastric cancer.
-for the treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy, in combination with paclitaxel:
Intravenous dosage:
Adults: 8 mg/kg IV infusion over 60 minutes every 2 weeks in combination with paclitaxel (80 mg/m2 IV on days 1, 8, and 15 every 28 days) until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. Administer ramucirumab prior to paclitaxel. In a randomized, double-blind clinical trial (RAINBOW), treatment with ramucirumab plus paclitaxel significantly improved overall survival (9.6 months vs. 7.4 months), progression-free survival (4.4 months vs. 2.9 months), and objective response rate (28% vs. 16%) compared with paclitaxel plus placebo in patients with locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer who had previously been treated with platinum- and fluoropyrimidine- containing chemotherapy.
For the treatment non-small cell lung cancer (NSCLC):
-for the treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy, in combination with docetaxel:
NOTE: Patients with EGFR-positive or ALK-positive tumors should have disease progression on FDA-approved therapy for these mutations prior to treatment with ramucirumab.
Intravenous dosage:
Adults: 10 mg/kg IV infusion over 60 minutes in combination with docetaxel (75 mg/m2 IV) on day 1, every 21 days until disease progression or unacceptable toxicity; study sites in East Asia administered docetaxel at a reduced dose (60 mg/m2) due to an increased incidence of neutropenia and febrile neutropenia. Administer ramucirumab prior to docetaxel. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. In a randomized, double-blind clinical trial (REVEL), treatment with ramucirumab in combination with docetaxel significantly improved overall survival (10.5 months vs. 9.1 months) and progression-free survival (4.5 months vs. 3 months) compared with docetaxel plus placebo in patients with NSCLC that progressed on or after one platinum-based therapy for locally advanced or metastatic disease; the objective response was 23% versus 14%, respectively.
-for the first-line treatment of metastatic NSCLC in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, in combination with erlotinib:
NOTE: If EGFR exon 19 deletions or exon 21 (L858R) substitution mutations are not detected in a plasma specimen, test tumor tissue if available. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 10 mg/kg IV over 60 minutes every 2 weeks in combination with erlotinib (150 mg PO once daily) until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind clinical trial (the RELAY study), treatment with ramucirumab in combination with erlotinib significantly improved the median progression-free survival (PFS) compared with erlotinib plus placebo in patients with previously untreated metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations (19.4 months vs. 12.4 months). The objective response rate was 76% for a median duration of 18 months in the ramucirumab arm compared with 75% for a median duration of 11.1 months in the placebo arm. At the time of the final PFS analysis, data for overall survival were not mature.
For the treatment of metastatic colorectal cancer (mCRC):
-for the treatment of metastatic colorectal cancer (mCRC) in patients with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, in combination with irinotecan, folinic acid (leucovorin), and fluorouracil (FOLFIRI):
Intravenous dosage:
Adults: 8 mg/kg IV over 60 minutes on day 1 prior to FOLFIRI administration, every 2 weeks until disease progression or unacceptable toxicity. FOLFIRI consists of irinotecan 180 mg/m2 IV over 90 minutes and folinic acid (leucovorin) 400 mg/m2 IV administered simultaneously over 120 minutes on day 1, followed by fluorouracil 400 mg/m2 IV bolus over 2 to 4 minutes on day 1, followed by fluorouracil 2,400 mg/m2 by continuous IV infusion over 46 to 48 hours. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. In a randomized, double-blind clinical trial (RAISE), treatment with ramucirumab plus FOLFIRI significantly improved overall survival (13.3 months vs. 11.7 months) and progression-free survival (5.7 months vs. 4.5 months) compared with placebo plus FOLFIRI in patients with mCRC who had progressed on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
For the treatment of hepatocellular cancer:
-for the treatment of advanced hepatocellular cancer in patients with an alpha-fetoprotein (AFP) of 400 ng/mL or more and have previously been treated with sorafenib:
Intravenous dosage:
Adults: 8 mg/kg IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. All patients should receive premedication with an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine); for patients who have had a prior grade 1 or 2 infusion-related reaction, premedicate with an H1-receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab infusion. In a randomized, double-blind clinical trial (REACH-2), treatment with ramucirumab significantly improved median overall survival (8.5 months vs. 7.3 months) and progression-free survival (2.8 months vs. 1.6 months) compared with placebo in patients with advanced hepatocellular cancer and AFP 400 ng/mL or more, who had disease progression on or after prior sorafenib therapy or were intolerant to sorafenib. The overall response rate was 4.6% versus 1.1%, respectively; all responses were partial responses.
Therapeutic Drug Monitoring:
Dose Adjustments for Treatment-Related Toxicity
Arterial thromboembolic events
-Permanently discontinue ramucirumab therapy.
GI perforation
-Permanently discontinue ramucirumab therapy.
Hemorrhage
-Grade 3 or 4: Permanently discontinue ramucirumab therapy.
Hypertension
-Severe hypertension: Hold ramucirumab until controlled with medical management. Permanently discontinue ramucirumab for patients with severe hypertension that is unable to be controlled with antihypertensive therapy.
-Hypertensive crisis: Permanently discontinue ramucirumab therapy.
-Hypertensive encephalopathy: Permanently discontinue ramucirumab therapy.
Infusion-related reactions
-Grade 1 or 2: Reduce the rate of infusion by 50%.
-Grade 3 or 4: Permanently discontinue ramucirumab therapy.
Posterior Reversible Encephalopathy Syndrome (PRES)
-All grades: Permanently discontinue ramucirumab therapy.
Proteinuria
-Urine protein 2 g or more per 24 hours: Hold ramucirumab therapy. When urine protein is less than 2 g per 24 hours, for the first occurrence reduce the dose of ramucirumab to 6 mg/kg (from 8 mg/kg) or 8 mg/kg (from 10 mg/kg); for a re-occurrence, reduce the dose of ramucirumab to 5 mg/kg (from 6 mg/kg) or 6 mg/kg (from 8 mg/kg).
-Urine protein greater than 3 g per 24 hours: Permanently discontinue ramucirumab therapy.
-Nephrotic syndrome: Permanently discontinue ramucirumab therapy.
Maximum Dosage Limits:
-Adults
10 mg/kg IV per single dose.
-Geriatric
10 mg/kg IV per single dose.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-Mild to moderate hepatic impairment (Child-Pugh A; total bilirubin 1.1 to 3 times the upper limit of normal [ULN] and any AST, OR or total bilirubin within ULN and AST greater than ULN): No dosage adjustment needed.
-Severe hepatic impairment (Child-Pugh B or C): Use ramucirumab only if the potential benefits of treatment outweigh the risks of clinical deterioration. Specific recommendations for dosage adjustment are not available, but clinical deterioration was reported in patients with Child Pugh B or C hepatic impairment treated with ramucirumab monotherapy.
Patients with Renal Impairment Dosing
-No dosage adjustment is necessary in patients with renal impairment.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Ramucirumab binds with high affinity to the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR2; kinase insert domain-containing receptor; KDR), preventing the binding of ligands VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimuluated activation of VEGFR2, inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model. Ramucirumab works differently than bevacizumab, another VEGF inhibitor, in that bevacizumab binds to the ligand, VEGF, preventing it from binding to VEGFR2/KDR; bevacizumab also decreases VEGF levels after binding. Ramucirumab binds to VEGF2, preventing the VEGF ligands from binding, and does not affect initial levels of VEGF. The mechanism of binding to VEGFR2 rather than VEGF may also induce less resistance, since endothelial cells are genetically stable.
Ramucirumab is administered by intravenous infusion. Ramucirumab is administered by intravenous infusion. Based on a population pharmacokinetic analysis, the mean volume of distribution at steady state was 5.4 L (CV, 15%). The mean clearance of ramucirumab is 0.015 L/hour (CV, 30%) and the mean elimination half-life is 14 days (CV, 20%). Steady-state concentrations were achieved at approximately 12 weeks. The pharmacokinetic characteristics of ramucirumab are similar for patients across cancer types. The drug is eliminated by saturable receptor-mediated clearance.
Affected Cytochrome P450 (CYP450) enzymes and drug transporters: None reported.
-Route-Specific Pharmacokinetics
Intravenous Route
Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above.
-Special Populations
Hepatic Impairment
Mild to moderate hepatic impairment (total bililrubin within the upper limit of normal (ULN) and AST greater than ULN, OR total bilrubin 1.1 to 3 times ULN and any AST) did not have a clinically meaningful effect on the pharmacokinetics of ramucirumab. The effect of severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) on the pharmacokinetics of ramucirumab is unknown.
Renal Impairment
Renal impairment (CrCl 15 to 89 mL/min) did not have a clinically meaningful effect on the pharmacokinetics of ramucirumab.
Geriatric
Age (range, 19 to 88 years) did not have a clinically meaningful effect on the pharmacokinetics of ramucirumab.
Gender Differences
Gender (68% male) did not have a clinically meaningful effect on the pharmacokinetics of ramucirumab.
Ethnic Differences
Race (Caucasian, 70%; Asian, 24%) did not have a clinically meaningful effect on the pharmacokinetics of ramucirumab.