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Ramucirumab

Pronunciation

(ra mue SIR ue mab)

Index Terms

  • IMC-1121B

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Cyramza: 100 mg/10 mL (10 mL); 500 mg/50 mL (50 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Cyramza

Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitor

Pharmacology

Ramucirumab is a recombinant monoclonal antibody which inhibits vascular endothelial growth factor receptor 2 (VEGFR2). Ramucirumab has a high affinity for VEGFR2 (Spratlin, 2010), binding to it and blocking binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D to inhibit activation of VEGFR2, thereby inhibiting ligand-induced proliferation and migration of endothelial cells. VEGFR2 inhibition results in reduced tumor vascularity and growth (Fuchs, 2014).

Half-Life Elimination

14 days

Use: Labeled Indications

US labeling:

Colorectal cancer, metastatic: Treatment (in combination with FOLFIRI [irinotecan, leucovorin, and fluorouracil]) of metastatic colorectal cancer (mCRC) in patients with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Gastric cancer, advanced or metastatic: Treatment (single-agent or in combination with paclitaxel) of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients with disease progression on or following fluoropyrimidine- or platinum-containing chemotherapy

Non-small cell lung cancer, metastatic: Treatment (in combination with docetaxel) of metastatic non-small cell lung cancer (NSCLC) in patients with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab.

Canadian labeling: Gastric cancer, advanced or metastatic: Treatment (single-agent or in combination with paclitaxel) of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients with disease progression on or following fluoropyrimidine- or platinum-containing chemotherapy.

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to ramucirumab or any component of the formulation.

Dosing: Adult

Note: Premedicate prior to infusion with an IV H1 antagonist (for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone or equivalent and acetaminophen).

US labeling:

Colorectal cancer, metastatic: IV: 8 mg/kg every 2 weeks in combination with FOLFIRI (irinotecan, leucovorin, and fluorouracil); continue until disease progression or unacceptable toxicity.

Gastric cancer, advanced or metastatic: IV: 8 mg/kg every 2 weeks as a single agent or in combination with paclitaxel; continue until disease progression or unacceptable toxicity.

Non-small cell lung cancer, metastatic: IV: 10 mg/kg on day 1 every 21 days in combination with docetaxel; continue until disease progression or unacceptable toxicity

Canadian labeling: Gastric cancer, advanced or metastatic: Adults: IV: 8 mg/kg every 2 weeks as a single agent or in combination with paclitaxel; continue until disease progression or unacceptable toxicity.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild impairment (normal bilirubin with AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate impairment (total bilirubin >1.5 to 3 times ULN and any AST): No dosage adjustment necessary.

Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Use in patients with Child-Pugh class B or C cirrhosis only if the potential benefits outweigh the potential risks.

Dosing: Adjustment for Toxicity

Infusion-related reaction:

Grade 1 or 2: Reduce infusion rate by 50%

Grade 3 or 4: Permanently discontinue

Hypertension:

Severe hypertension: Interrupt infusion until controlled with medical management

Severe hypertension, uncontrolled: Permanently discontinue

Proteinuria:

Urine protein ≥2 g/24 hours (first dose reduction): Withhold treatment; when urine protein returns to <2 g/24 hours, reinitiate at a reduced dose of 6 mg/kg (if initial dose was 8 mg/kg) or 8 mg/kg (if initial dose was 10 mg/kg)

Recurrent urine protein ≥2 g/24 hours (second dose reduction): Withhold treatment; when urine protein returns to <2 g/24 hours, reinitiate at a reduced dose of 5 mg/kg (if first dose reduction was to 6 mg/kg) or 6 mg/kg (if first dose reduction was to 8 mg/kg)

Urine protein >3 g/24 hours: Discontinue permanently

Nephrotic syndrome: Discontinue permanently

Arterial thrombotic events: Discontinue permanently

Bleeding, grade 3 or 4: Discontinue permanently

Gastrointestinal perforation: Discontinue permanently

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue permanently for confirmed diagnosis

Wound healing complications: Withhold treatment prior to surgery; do not reinitiate until the surgical wound is fully healed. If wound healing complications develop during treatment, withhold ramucirumab until the wound is fully healed.

Reconstitution

Dilute total dose in NS 250 mL prior to administration (the manufacturer recommends a final volume of 250 mL). Do not use dextrose containing solutions. Invert gently to mix thoroughly; do not shake. Discard unused portion of the vial.

Administration

Premedicate prior to infusion with an IV H1 antagonist; for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone (or equivalent) and acetaminophen.

Infuse over 60 minutes through a separate infusion line using an infusion pump; the use of a 0.22 micron protein sparing filter is recommended. Do not administer as an IV push or bolus. Flush the line with NS after infusion is complete. Do not infuse in the same IV line with electrolytes or other medications. Administer ramucirumab prior to docetaxel, paclitaxel, or FOLFIRI if administering in combination. Monitor for infusion reaction; reduce infusion rate (by 50%) for grade 1 or 2 infusion reaction; discontinue permanently for grade 3 or 4 infusion reaction.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Retain in original carton to protect from light. Do not shake. Solutions diluted in NS for infusion may be stored at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours (do not freeze) or may be stored for 4 hours at room temperature (below 25°C [77°F]); do not shake diluted product.

Drug Interactions

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Adverse Reactions

As reported with monotherapy. Frequency not always defined.

Cardiovascular: Hypertension (16%; grades 3/4: 8%), arterial thrombosis (including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia; 2%)

Central nervous system: Headache (9%)

Dermatologic: Skin rash (4%)

Endocrine & metabolic: Hyponatremia (6%)

Gastrointestinal: Diarrhea (14%), intestinal obstruction (2%)

Genitourinary: Proteinuria (8% to 17%; grade ≥3: 1%)

Hematologic & oncologic: Decreased red blood cells (requiring transfusion; 11%), neutropenia (5%), anemia (4%), hemorrhage (2% to 4%)

Immunologic: Antibody development (3%; neutralizing: 1%)

Respiratory: Epistaxis (5%)

Miscellaneous: Infusion related reaction (≤16%; reactions minimized with premedications)

<1% and frequency not defined (Limited to important or life-threatening): Gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome

ALERT: U.S. Boxed Warning

Hemorrhage:

Ramucirumab increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue ramucirumab in patients who experience severe bleeding.

Gastrointestinal perforation:

Ramucirumab can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue ramucirumab in patients who experience a gastrointestinal perforation.

Wound healing impairment:

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue ramucirumab therapy in patients with impaired wound healing. Withhold ramucirumab prior to surgery and discontinue ramucirumab if a patient develops wound healing complications.

Warnings/Precautions

Concerns related to adverse effects:

• Arterial thrombotic events: Serious and fatal arterial thrombotic events, including MI, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have occurred with ramucirumab. Discontinue permanently in patients who experience serious arterial thrombotic events.

• Bone marrow suppression: A higher incidence of neutropenia and thrombocytopenia were observed when ramucirumab was used in combination with paclitaxel (compared to paclitaxel with placebo); monitor CBC with differential when used in combination with paclitaxel.

• Gastrointestinal perforation: [US Boxed Warning]: Ramucirumab may increase the risk of gastrointestinal perforation, a potentially fatal event. Discontinue permanently in patients who experience a gastrointestinal perforation.

• Hemorrhage: [US Boxed Warning]: Ramucirumab is associated with an increased risk of hemorrhage and gastrointestinal hemorrhage, which may be severe or sometimes fatal. Discontinue ramucirumab permanently in patients who experience serious bleeding. Patients receiving NSAIDs were excluded from some clinical trials; the risk of gastric hemorrhage in patients with gastric tumors receiving NSAIDs is not known. In addition, NSCLC patients receiving therapeutic anticoagulation or chronic NSAID or other antiplatelet therapy (other than aspirin), or with radiograph evidence of major airway or blood vessel involvement or intratumor cavitation were also excluded from the clinical study; the risk of pulmonary hemorrhage in such patients is not known.

• Hypertension: May cause and/or worsen hypertension; the incidence of severe hypertension is increased with ramucirumab. Blood pressure (BP) should be controlled prior to treatment initiation. Monitor BP every 2 weeks (more frequently if indicated) during treatment. If severe hypertension occurs, temporarily withhold until medically controlled. Discontinue permanently if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

• Infusion reaction: Ramucirumab is associated with infusion-related reactions (may be severe), generally occurring with the first or second dose. Symptoms of infusion reactions have included chills, flushing, hypotension, bronchospasm, dyspnea, hypoxia, wheezing, chest pain/tightness, supraventricular tachycardia, back pain/spasms, rigors/tremors, and/or paresthesia. Monitor for infusion reaction symptoms during infusion; discontinue immediately and permanently for grade 3 or 4 infusion reactions. Administer in a facility equipped to manage infusion reactions.

• Proteinuria/nephrotic syndrome: Ramucirumab is associated with proteinuria (may be severe). Monitor proteinuria during treatment by urine dipstick and/or urinary protein creatinine ratio for the development of and/or worsening of proteinuria. Withhold treatment for urine protein levels ≥2 g/24 hours. Discontinue permanently for urine protein >3 g/24 hours or for nephrotic syndrome.

• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported (may be fatal). Symptoms of RPLS include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances. Confirm diagnosis of RPLS with MRI; discontinue ramucirumab with confirmed RPLS diagnosis. Resolution of symptoms may occur within days after discontinuation, although neurologic sequelae may remain in some patients.

• Thyroid dysfunction: Hypothyroidism has been observed. Monitor thyroid function during treatment.

• Wound healing impairment: [US Boxed Warning]: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue ramucirumab in patients with impaired wound healing. Withhold ramucirumab prior to surgery and discontinue in patients who develop wound healing complications. Following surgery, use clinical judgment to resume based on adequate wound healing. If wound healing complications develop during treatment, withhold ramucirumab until wound is fully healed. Ramucirumab was not studied in patients with serious or nonhealing wounds.

Disease-related concerns:

• Cardiovascular disease: Antiangiogenic medications may increase the risk for heart failure (HF); events consistent with HF have been reported with ramucirumab. Use with caution in patients with known (or at risk of) coronary artery disease. Ramucirumab may enhance the cardiotoxicity of other chemotherapy with cardiotoxic potential (Cyramza Canadian labeling 2015).

• Hepatic impairment: Clinical deterioration, including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome has been reported in patients with Child-Pugh class B or C cirrhosis receiving ramucirumab. Use in patients with Child-Pugh class B or C cirrhosis only if the potential benefits outweigh the potential risks.

Monitoring Parameters

Liver function tests; urine protein (by urine dipstick and/or urinary protein creatinine ratio); thyroid function; CBC with differential (when used as a part of combination chemotherapy); blood pressure (every 2 weeks; more frequently if indicated); signs/symptoms of infusion-related reactions (during infusion); signs/symptoms of arterial thromboembolic events, bleeding/hemorrhage, gastrointestinal perforation, wound healing impairment, and reversible posterior leukoencephalopathy syndrome

Pregnancy Considerations

Ramucirumab inhibits angiogenesis, which is of critical importance to human fetal development. Based on the mechanism of action, ramucirumab may cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during and for at least 3 months after the last ramucirumab dose. Ramucirumab may impair fertility in women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience more tears or lack of appetite. Have patient report immediately to prescriber signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), swelling of arms or legs, back pain, tremors, burning or numbness feeling, angina, passing out, arrhythmia, chills, flushing, mood changes, severe dizziness, severe headache, severe constipation, severe diarrhea, severe nausea, vomiting, severe abdominal pain, shortness of breath, wound healing impairment, mouth sores, redness or irritation of palms or soles of feet, loss of strength and energy, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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