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Ramucirumab

Medically reviewed by Drugs.com. Last updated on Sep 14, 2020.

Pronunciation

(ra mue SIR ue mab)

Index Terms

  • IMC-1121B
  • Ramucirumab

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).

Distribution

Vdss: 5.4 L

Excretion

Clearance: 0.015 L/hour

Half-Life Elimination

14 days

Use: Labeled Indications

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

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

Hepatocellular carcinoma, advanced or relapsed/refractory: Treatment (as a single agent) of hepatocellular carcinoma in patients who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib.

Non-small cell lung cancer, metastatic:

First-line treatment (in combination with erlotinib) of metastatic non-small cell lung cancer in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Treatment (in combination with docetaxel) of metastatic non-small cell lung cancer in patients with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on approved therapy for these aberrations prior to receiving ramucirumab.

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 (eg, diphenhydramine); for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone (or equivalent) and acetaminophen.

Colorectal cancer, metastatic:

IV: 8 mg/kg once every 2 weeks in combination with FOLFIRI (irinotecan, leucovorin, and fluorouracil); continue ramucirumab until disease progression or unacceptable toxicity (Tabernero 2015).

Gastric cancer, advanced or metastatic:

IV: 8 mg/kg once every 2 weeks as a single agent or in combination with weekly paclitaxel; continue ramucirumab until disease progression or unacceptable toxicity (Fuchs 2014; Wilke 2014).

Hepatocellular carcinoma (advanced, relapsed/refractory):

IV: 8 mg/kg once every 2 weeks (as a single agent); continue ramucirumab until disease progression or unacceptable toxicity (Zhu 2019).

Non-small cell lung cancer, metastatic:

IV:

First-line treatment in tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations: 10 mg/kg once every 2 weeks (in combination with erlotinib) until disease progression or unacceptable toxicity (Nakagawa 2019).

Disease progression on or after platinum-based therapy: 10 mg/kg on day 1 every 21 days in combination with docetaxel; continue ramucirumab until disease progression or unacceptable toxicity (Garon 2014).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Arterial thrombotic events (all grades): Discontinue ramucirumab permanently.

GI perforation (all grades): Discontinue ramucirumab permanently.

Hemorrhage, grade 3 or 4: Discontinue ramucirumab permanently.

Hypertension:

Severe hypertension: Interrupt ramucirumab infusion until controlled with medical management.

Severe hypertension, uncontrolled with antihypertensive therapy: Permanently discontinue ramucirumab.

Hypertensive crisis or hypertensive encephalopathy: Permanently discontinue ramucirumab.

Infusion-related reaction:

Grade 1 or 2: Reduce ramucirumab infusion rate by 50%.

Grade 3 or 4: Permanently discontinue ramucirumab.

Posterior reversible encephalopathy syndrome (all grades): Discontinue ramucirumab permanently.

Proteinuria:

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

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

Urine protein >3 g/24 hours: Discontinue ramucirumab permanently.

Nephrotic syndrome: Discontinue ramucirumab permanently.

Wound healing complications (all grades): Withhold ramucirumab treatment for 28 days prior to elective surgery; do not reinitiate for at least 2 weeks after major surgery and until the surgical wound is adequately healed.

Reconstitution

Dilute total dose in NS 250 mL prior to administration (the manufacturer recommends a final volume of 250 mL). Do not dilute with dextrose containing solutions or other 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 (eg, diphenhydramine); for patients who experienced a grade 1 or 2 infusion reaction with a prior infusion, also premedicate with dexamethasone (or equivalent) and acetaminophen.

IV: Administer initial infusion over 60 minutes; if tolerated, may administer subsequent infusions over 30 minutes. Infuse through a separate infusion line using an infusion pump; the use of a 0.22-micron protein-sparing filter is recommended. Do not administer as an IV push or bolus. Flush the line with NS after infusion is complete. Do not infuse in the same IV line with solutions other than NS, or with electrolytes or other medications. Monitor for infusion reaction; reduce infusion rate (by 50%) for grade 1 or 2 infusion reaction; discontinue permanently for grade 3 or 4 infusion reaction.

Administer ramucirumab prior to docetaxel, paclitaxel, or FOLFIRI if administering in combination.

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

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

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

As reported with monotherapy.

>10%:

Cardiovascular: Hypertension (16% to 25%, can be severe hypertension), peripheral edema (25%)

Endocrine & metabolic: Hypoalbuminemia (33%), hypocalcemia (16%), hyponatremia (6% to 32%)

Gastrointestinal: Abdominal pain (25%), decreased appetite (23%), diarrhea (14%), nausea (19%)

Genitourinary: Proteinuria (8% to 20%)

Hematologic & oncologic: Neutropenia (5% to 24%; grade ≥3: 8%), thrombocytopenia (46%; grade ≥3: 8%)

Hepatic: Ascites (3% to 18%)

Nervous system: Fatigue (36%), headache (9% to 14%), insomnia (11%)

Respiratory: Epistaxis (5% to 14%)

1% to 10%:

Cardiovascular: Arterial thromboembolism (2%)

Dermatologic: Skin rash (4%)

Gastrointestinal: Intestinal obstruction (2%), vomiting (10%)

Hematologic & oncologic: Anemia (4%)

Hepatic: Hepatic encephalopathy (≤6%), hepatorenal syndrome (≤6%)

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

Neuromuscular & skeletal: Back pain (10%)

Respiratory: Pneumonia (3%)

Miscellaneous: Fever (10%), infusion related reaction (≤9%; reactions minimized with premedications)

<1%: Gastrointestinal: Gastrointestinal perforation

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cerebral ischemia, cerebrovascular accident

Endocrine & metabolic: Hypothyroidism

Gastrointestinal: Gastrointestinal hemorrhage

Genitourinary: Nephrotic syndrome

Hematologic & oncologic: Hemorrhage, major hemorrhage

Nervous system: Reversible posterior leukoencephalopathy syndrome

Postmarketing:

Cardiovascular: Aneurysm (arterial, including aortic), coronary artery dissection (including aortic), vascular injury (rupture)

Hematologic & oncologic: Hemangioma, thrombotic microangiopathy

Nervous system: Voice disorder

Warnings/Precautions

Concerns related to adverse effects:

• Arterial thrombotic events: Serious and sometimes fatal arterial thrombotic events, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have occurred with ramucirumab, including ≥ grade 3 events. Discontinue ramucirumab permanently in patients who experience arterial thrombotic events.

• Bone marrow suppression: A higher incidence of neutropenia and thrombocytopenia were observed when ramucirumab was used as a part of combination therapy (compared to the combination therapy with placebo); monitor CBC with differential when used as a part of combination treatment.

• Gastrointestinal perforation: Ramucirumab may increase the risk of GI perforation, a potentially fatal event. Discontinue ramucirumab permanently in patients who experience a GI perforation.

• Hemorrhage: Ramucirumab is associated with an increased risk of hemorrhage and GI hemorrhage, including ≥ grade 3 events, which may be severe or sometimes fatal. Discontinue ramucirumab permanently in patients who experience serious (grade 3 or 4) bleeding. Patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from some clinical trials; the risk of gastric hemorrhage in patients with gastric tumors receiving NSAIDs is not known. In addition, various exclusion criteria in some non-small cell lung cancer trials included a recent history of gross hemoptysis, use of therapeutic anticoagulation or chronic NSAID or other antiplatelet therapy (other than once-daily aspirin), or evidence (including radiographic evidence) of major airway or blood vessel involvement or intratumor cavitation; the risk of pulmonary hemorrhage in patients with such criteria is not known.

• Hepatotoxicity: Clinical deterioration, including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome has been reported in patients with Child-Pugh class B or C cirrhosis receiving ramucirumab. Use in patients with Child-Pugh class B or C cirrhosis only if the potential benefits outweigh the potential risks. Based on clinical trial data for the treatment of hepatocellular carcinoma, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was increased in patients with Child Pugh class A liver cirrhosis receiving ramucirumab compared to patients who received placebo.

• Hypertension: May cause and/or worsen hypertension; the incidence of severe hypertension is increased with ramucirumab. In a non-small cell lung cancer study, new or worsening hypertension requiring initiation of ≥3 antihypertensive medications occurred at a higher incidence in patients receiving ramucirumab in combination with erlotinib, versus patients receiving placebo plus erlotinib. Control hypertension prior to treatment initiation. Monitor BP every 2 weeks (more frequently if indicated) during treatment. If severe hypertension occurs, temporarily withhold ramucirumab until medically controlled. Permanently discontinue ramucirumab if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

• Infusion reaction: Ramucirumab is associated with infusion-related reactions (may be severe), generally occurring with the first or second dose. Symptoms of infusion reactions have included chills, flushing, hypotension, bronchospasm, dyspnea, hypoxia, wheezing, chest pain/tightness, supraventricular tachycardia, back pain/spasms, rigors/tremors, and/or paresthesia. Premedication(s) are recommended prior to infusion. Monitor for infusion reaction symptoms during infusion. Reduce infusion rate for grade 1 or 2 infusion reaction; discontinue ramucirumab immediately and permanently for grade 3 or 4 infusion reactions. Administer in a facility equipped to manage infusion reactions.

• Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome) have been reported (may be fatal). Symptoms of PRES include headache, nausea/vomiting, seizure, blindness, or altered consciousness, with or without associated hypertension. Confirm diagnosis of PRES with MRI; permanently discontinue ramucirumab in patients who develop PRES. Resolution of symptoms may occur within days after discontinuation, although neurologic sequelae may remain in some patients.

• Proteinuria/Nephrotic syndrome: Ramucirumab is associated with proteinuria (including ≥ grade 3 proteinuria and cases of nephrotic syndrome). Monitor proteinuria during treatment by urine dipstick and/or urinary protein creatinine ratio for the development of and/or worsening of proteinuria. Withhold ramucirumab treatment for urine protein levels ≥2 g/24 hours; reduce dose upon therapy reinitiation. Discontinue ramucirumab permanently for urine protein >3 g/24 hours or for nephrotic syndrome.

• Thyroid dysfunction: Hypothyroidism (grade 1 or 2) has been observed. Monitor thyroid function during treatment.

• Wound healing impairment: Impaired wound healing can occur with vascular endothelial growth factor (VEGF) or VEGF receptor pathway inhibitors. Withhold ramucirumab for 28 days prior to elective surgery, and for at least 2 weeks following a major surgical procedure (and until the wound is adequately healed). The safety of resuming ramucirumab treatment after resolution of wound healing complications has not been established. Ramucirumab was not studied in patients with serious or nonhealing wounds.

Special populations:

• Elderly: Patients ≥65 years of age who received ramucirumab in combination with erlotinib in a non-small cell lung cancer trial had increased incidences of diarrhea, hypertension, elevated ALT/AST, stomatitis, decreased appetite, dysgeusia, and weight loss compared to patients <65 years of age.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

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); verify pregnancy status prior to treatment (in females of reproductive potential). Monitor BP (every 2 weeks; more frequently if indicated); signs/symptoms of infusion-related reactions (during infusion); signs/symptoms of arterial thromboembolic events, bleeding/hemorrhage, GI perforation, wound healing impairment, and posterior reversible encephalopathy syndrome.

Reproductive Considerations

Verify pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during and for 3 months after the last ramucirumab dose.

Pregnancy Considerations

Based on the mechanism of action, ramucirumab may cause fetal harm if administered during pregnancy.

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Increased tears

• Mouth irritation

• Trouble sleeping

• Mouth sores

• Abdominal pain

• Back pain

• Loss of strength and energy

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Bleeding like 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 severe or persistent bleeding

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Low thyroid level like constipation; trouble handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Infusion reaction like chills, tremors, fast heartbeat, back pain, back spasm, flushing, shortness of breath, wheezing, burning or numbness feeling, severe dizziness, or passing out

• Swelling

• Chest pain

• Passing out

• Severe dizziness

• Severe headache

• Severe diarrhea

• Severe nausea

• Vomiting

• Lack of appetite

• Trouble with wound healing

• Redness or irritation of palms or soles of feet

• Vision changes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.