Cyramza

Antineoplastic Monoclonal Antibodies Targeting VEGF

Emetic Risk
Minimal

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.

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.[57042]
 
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.[57042]

hypertension / Early / 6.0-24.0
hyponatremia / Delayed / 3.0-16.0
asthenia / Delayed / 0-14.0
fatigue / Early / 5.0-14.0
diarrhea / Early / 1.0-11.0
neutropenia / Delayed / 0-8.0
stomatitis / Delayed / 0-7.0
bleeding / Early / 2.0-5.0
hypokalemia / Delayed / 0-5.0
GI bleeding / Delayed / 2.6-4.3
ascites / Delayed / 0-4.0
GI obstruction / Delayed / 0-3.0
proteinuria / Delayed / 0-3.0
GI perforation / Delayed / 0-2.0
abdominal pain / Early / 0-2.0
anorexia / Delayed / 0-2.0
hypocalcemia / Delayed / 0-2.0
peripheral edema / Delayed / 0-2.0
back pain / Delayed / 0-1.0
infusion-related reactions / Rapid / 0-1.0
epistaxis / Delayed / 0-1.0
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-1.0
hypoalbuminemia / Delayed / 0-1.0
lacrimation / Early / 0-1.0
headache / Early / 0-1.0
hepatic encephalopathy / Delayed / 0-0.5
nephrotic syndrome / Delayed / 0.2-0.2
leukoencephalopathy / Delayed / 0-0.1
bronchospasm / Rapid / Incidence not known
cardiac arrest / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
thrombotic microangiopathy / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
stroke / Early / Incidence not known
pneumothorax / Early / Incidence not known
aortic dissection / Delayed / Incidence not known

antibody formation / Delayed / 0.5-3.0
hypothyroidism / Delayed / 0-3.0
encephalopathy / Delayed / 0-0.1
wheezing / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
hypoxia / Early / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not known
dyspnea / Early / Incidence not known
impaired wound healing / Delayed / Incidence not known
dysphonia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known

alopecia / Delayed / 0-34.0
nausea / Early / 0-19.0
insomnia / Early / 0-11.0
vomiting / Early / 0-10.0
fever / Early / 0-10.0
rash / Early / 0-4.2
chills / Rapid / Incidence not known
flushing / Rapid / Incidence not known
paresthesias / Delayed / Incidence not known
tremor / Early / Incidence not known
infection / Delayed / Incidence not known
dysgeusia / Early / Incidence not known
weight loss / Delayed / Incidence not known

Cyramza

Rx

Intravenous human monoclonal antibody that inhibits VEGFR2
Used for advanced gastric or gastro-esophageal junction adenocarcinoma, metastatic NSCLC, and hepatocellular cancer
Severe infusion reactions have occurred; premedicate all patients with IV diphenhydramine or equivalent; add acetaminophen and dexamethasone (or equivalent) for patients with a previous grade 1 or 2 infusion reaction

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.[57042]

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.[57042]

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.[57042] [64217]

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.

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.[57042]

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.[57042]

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.

No dosage adjustment is necessary in patients with renal impairment.

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.
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.
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.

Cyramza Intravenous Inj Sol: 1mL, 10mg

10 mg/kg IV per single dose.

10 mg/kg IV per single dose.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[57042] The drug is eliminated by saturable receptor-mediated clearance.[57057]
 
Affected Cytochrome P450 (CYP450) enzymes and drug transporters: None reported.[57042]

Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above.

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.[57042]

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.