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]

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 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: 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.

Dosage and Administration

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 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 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 every 2 weeks (as a single agent); continue ramucirumab until disease progression or unacceptable toxicity (Zhu 2019).

Non-small cell lung cancer, metastatic: IV: 10 mg/kg on day 1 every 21 days in combination with docetaxel; continue ramucirumab until disease progression or unacceptable toxicity (Garon 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Infusion-related reaction:

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

Grade 3 or 4: Permanently discontinue ramucirumab.

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.

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.

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

GI perforation (all grades): Discontinue ramucirumab permanently.

Hemorrhage, grade 3 or 4: Discontinue ramucirumab permanently.

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

Wound healing complications (all grades): Withhold ramucirumab treatment for 28 days prior to elective surgery; do not reinitiate for at least 28 days after surgery and until the surgical wound is fully healed. Discontinue ramucirumab for wound healing complications that require medical intervention.

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

Adverse Reactions

As reported with monotherapy.

>10%:

Cardiovascular: Peripheral edema (25%), hypertension (11% to 26%), severe hypertension (6% to 15%)

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

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

Genitourinary: Proteinuria (3% to 20%)

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

Dermatologic: Skin rash (4%)

Endocrine & metabolic: Hypothyroidism (≤3%)

Gastrointestinal: Vomiting (10%), intestinal obstruction (2%)

Hematologic & oncologic: Anemia (4%)

Hepatic: Hepatic encephalopathy (5% to 6%), hepatorenal syndrome (2% to 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)

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cerebral ischemia, cerebrovascular accident

Gastrointestinal: Gastrointestinal hemorrhage, gastrointestinal perforation

Hematologic & oncologic: Major hemorrhage

<1%, postmarketing, and/or case reports: Hemangioma, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome, thrombotic microangiopathy

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 permanently in patients who experience 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: Ramucirumab may increase the risk of GI perforation, a potentially fatal event. Discontinue 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, non-small cell lung cancer 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. 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. 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 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 treatment for urine protein levels ≥2 g/24 hours; reduce dose upon therapy reinitiation. Discontinue 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 antibodies inhibiting the vascular endothelial growth factor (VEGF) or VEGF receptor pathway. Withhold ramucirumab for 28 days prior to elective surgery, and for at least 28 days following a major surgical procedure (and until the wound is fully healed). Discontinue in patients who develop wound healing complications requiring medical intervention. Ramucirumab was not studied in patients with serious or nonhealing wounds.

Disease-related concerns:

• 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. 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, ramucirumab may cause fetal harm if administered during pregnancy. Verify pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during and for at least 3 months after the last ramucirumab dose.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Increased tears
• Mouth irritation
• Trouble sleeping
• Mouth sores
• Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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; difficulty handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Swelling
• Back pain
• Back spasms
• Tremors
• Burning or numbness feeling
• Chest pain
• Passing out
• Fast heartbeat
• Chills
• Flushing
• Severe dizziness
• Severe headache
• Severe diarrhea
• Severe nausea
• Vomiting
• Not able to eat
• Severe abdominal pain
• Shortness of breath
• Trouble with wound healing
• Redness or irritation of palms or soles of feet
• Severe loss of strength and energy
• Vision changes
• Signs of a significant reaction like 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. 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.