Ramucirumab – Uses, Dosage, Side Effects, Interaction

Ramucirumab is a human monoclonal antibody (IgG1) against vascular endothelial growth factor receptor 2 (VEGFR2), a type II trans-membrane tyrosine kinase receptor expressed on endothelial cells. By binding to VEGFR2, ramucirumab prevents the binding of its ligands (VEGF-A, VEGF-C, and VEGF-D), thereby preventing VEGF-stimulated receptor phosphorylation and downstream ligand-induced proliferation, permeability, and migration of human endothelial cells. VEGFR stimulation also mediates downstream signaling required for angiogenesis and is postulated to be heavily involved in cancer progression?, making it a highly likely drug target. In contrast to other agents directed against VEGFR-2, ramucirumab binds a specific epitope on the extracellular domain of VEGFR-2, thereby blocking all VEGF ligands from binding to it. Ramucirumab is indicated for use in advanced gastric or gastro-esophageal junction adenocarcinoma as a single agent or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing chemotherapy?.

Ramucirumab is a human monoclonal antibody to the vascular endothelial growth factor (VEGF) receptor 2 and is an antiangiogenesis agent used in the therapy of advanced colorectal, gastric, and lung cancers. Ramucirumab has not been linked to serum enzyme elevations during therapy or to instances of idiosyncratic acute? liver? injury but has been reported to worsen liver failure in patients with decompensated cirrhosis? (Child Class B or C).

Mechanism of action

Ramucirumab is a human monoclonal antibody (IgG1) against vascular endothelial growth factor receptor 2 (VEGFR2), a type II trans-membrane tyrosine kinase receptor expressed on endothelial cells. By binding to VEGFR2, ramucirumab prevents the binding of its ligands (VEGF-A, VEGF-C, and VEGF-D), thereby preventing VEGF-stimulated receptor phosphorylation and downstream ligand-induced proliferation, permeability, and migration of human endothelial cells.

Ramucirumab is a direct VEGFR2 antagonist, that binds with high affinity to the extracellular domain of VEGFR2 and block the binding of natural VEGFR ligands (VEGF-A, VEGF-C and VEGF-D). These ligands are secreted by solid tumors to promote angiogenesis (formation of new blood vessels from pre-existing ones) and enhance tumor blood supply. The binding of ramucirumab to VEGFR2 leads to inhibition of VEGF-mediated tumor angiogenesis

Indications

• Ramucirumab is indicated for the treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma as a single agent or in combination with paclitaxel for patients who progress after prior fluoropyrimidine- or platinum-containing chemotherapy. It is indicated, in combination with erlotinib, for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor exon 19 deletions or exon 21 (L858R) point mutations. It is also indicated in combination with docetaxel for the treatment of metastatic non-small cell lung cancer in patients who have progressed following prior platinum-based chemotherapy. Patients who have EGFR or ALK genomic aberrations should also have disease progression? following FDA-approved therapy for these aberrations. Ramucirumab, in combination with FOLFIRI (folinic acid, fluorouracil, and irinotecan), is indicated for the treatment of metastatic colorectal cancer in patients who have progressed following therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Lastly, ramucirumab is indicated for the treatment of hepatocellular carcinoma? in patients with an alpha-fetoprotein level ≥400 ng/mL and have previously been treated with sorafenib.^[rx]
• Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
• Hepatocellular Carcinoma
• Metastatic Colorectal Cancer (CRC)
• Metastatic Non-Small Cell Lung Cancer
• Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
• As a single agent, or in combination with paclitaxel, for the treatment of advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
• In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine

Use in Cancer

Ramucirumab is approved to be used alone or with other drugs to treat:

• Colorectal cancer that has metastasized. It is used with FOLFIRI in patients whose disease has gotten worse during or after treatment with bevacizumab, oxaliplatin, and fluoropyrimidine.
• Hepatocellular carcinoma (a type of liver cancer). It is used alone in patients who have a high level of alpha-fetoprotein in the blood and have been treated with sorafenib tosylate.
• Non-small cell lung cancer that has metastasized. It is used:
  • Erlotinib hydrochloride is the first-line therapy in patients whose disease has certain mutations in the EGFR gene.
  • With docetaxel in patients whose disease has gotten worse during or after treatment with platinum chemotherapy. For patients whose disease has a mutation in the EGFR gene or ALK gene, ramucirumab is used if their disease has gotten worse after treatment with FDA-approved therapy for these mutations.
• Stomach adenocarcinoma or gastroesophageal junction adenocarcinoma (a rare type of esophageal cancer) that is advanced or has metastasized (spread to other parts of the body). It is used in patients whose disease has gotten worse after treatment with fluoropyrimidine or platinum chemotherapy. It is used alone or with paclitaxel.

Ramucirumab is also being studied in the treatment of other types of cancer.

Contraindications

• a condition with low thyroid? hormone levels
• high blood pressure
• a heart attack?
• a transient ischemic attack?, a type of stroke? that lasts only a few minutes
• an occurrence of a blood clot in an artery?
• bleeding
• hardening of the liver
• bleeding of the stomach or intestines
• recent operation
• elevation of proteins in the urine
• impaired wound healing
• pregnancy
• a patient who is producing milk and breastfeeding
• a rupture in the wall of the stomach or intestine
• a type of brain disorder called posterior reversible encephalopathy syndrome?
• acute thromboembolic stroke
• Child-Pugh class A liver impairment
• Child-Pugh class B liver impairment
• Child-Pugh class C liver impairment

Dosage?

Strengths: 10 mg/mL

Gastric Cancer

AS A SINGLE AGENT OR IN COMBINATION WITH WEEKLY PACLITAXEL:

• 8 mg/kg IV 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.
• When given in combination, this drug should be administered prior to paclitaxel.
• Refer to the prescribing information for paclitaxel for dosage information.
• Premedicate patients with an IV a H1 antagonist (e.g., diphenhydramine).
• Patients who have developed a Grade 1 or 2 infusion reaction should be premedicated with histamine-1 receptor antagonist or dexamethasone (or equivalent) and acetaminophen prior to each infusion.

Non-Small Cell Lung Cancer

EGFR EXON 19 DELETIONS OR EXON 21 (L858R) SUBSTITUTION MUTATIONS IN COMBINATION WITH ERLOTINIB:

• 10 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity
  NOTE: If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes.

DISEASE PROGRESSION ON OR AFTER PLATINUM-BASED CHEMOTHERAPY IN COMBINATION WITH DOCETAXEL:

• 10 mg/kg IV over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion until disease progression or unacceptable toxicity
  NOTE: If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes.
• Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving this drug.
• Refer to the prescribing information for erlotinib or docetaxel for dosage information.
• Premedicate patients with an IV a H1 antagonist (e.g., diphenhydramine).
• Patients who have developed a Grade 1 or 2 infusion reaction should be premedicated with histamine-1 receptor antagonist or dexamethasone (or equivalent) and acetaminophen prior to each infusion.
• In combination with erlotinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations
• In combination with docetaxel, for the treatment metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma? kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving this drug)

Colorectal Cancer

• 8 mg/kg IV 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.
• Administer this drug prior to administration of FOLFIRI.
• Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.
• Premedicate patients with an IV a H1 antagonist (e.g., diphenhydramine).
• Patients who have developed a Grade 1 or 2 infusion reaction should be premedicated with histamine-1 receptor antagonist or dexamethasone (or equivalent) and acetaminophen prior to each infusion.

Hepatocellular Carcinoma

• 8 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity
  NOTE: If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes.
• Premedicate patients with an IV H1 antagonist (e.g., diphenhydramine).
• Patients who have developed a Grade 1 or 2 infusion reaction should be premedicated with histamine-1 receptor antagonist or dexamethasone (or equivalent) and acetaminophen prior to each infusion.
• As a single agent for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of 400 ng/mL or greater and have been treated with sorafenib

Liver Dose Adjustments

• Mild? (total bilirubin? within ULN and aspartate aminotransferase [AST] greater than ULN or total bilirubin greater than 1 to 1.5 times ULN and any AST) or moderate? (total bilirubin greater than 1.5 to 3 x ULN and any AST) hepatic impairment: No adjustment recommended.
• Severe? renal? impairment: Data not available
• Clinical? deterioration? was reported in patients with Child-Pugh B or C cirrhosis who received this drug as a single agent.

Dose Adjustments

MANUFACTURER-RECOMMENDED DOSE MODIFICATIONS:
HEMORRHAGE:

• Grade 3 or 4: Permanently discontinue therapy.

GI PERFORATION:

• All Grades: Permanently discontinue therapy.

WOUND HEALING COMPLICATIONS:

• All Grades: Withhold therapy for 28 days prior to elective surgery?; resume therapy no sooner than 28 days after surgery and the wound is fully healed; discontinue therapy for wound healing complications that require medical intervention.

ARTERIAL THROMBOEMBOLIC EVENTS:

• All Grades: Permanently discontinue therapy.

HYPERTENSION?:

• Severe hypertension: Withhold therapy until controlled.
• Severe hypertension not controlled with antihypertensives: Permanently discontinue therapy.

INFUSION-RELATED REACTIONS (IRRs):

• Grade 1 or 2 IRRs: Reduce the infusion rate by 50%.
• Grade 3 or 4 IRRs: Permanently discontinue therapy.

PROTEINURIA?:

• The first occurrence of increased urine protein levels greater than or equal to 2 g per 24 hours: Withhold therapy until urine protein level is less than 2 g per 24 hours; resume therapy at a reduced dose: Reduce 8 mg dose to 6 mg; reduce 10 mg dose to 8 mg.
• Reoccurrence of urine protein level greater than 2 g per 24 hours following initial dose reduction: Withhold therapy until urine protein level is less than 2 g per 24 hours; resume therapy at a reduced dose: Reduce 6 mg dose to 5 mg; reduce 8 mg dose to 6 mg.
• Urine protein level greater than 3 g per 24 hours or in the setting of nephrotic syndrome?: Permanently discontinue therapy.

Administration advice:

• Therapy should be initiated and supervised by physicians experienced in oncology.
• Do not administer this drug as an IV push or bolus.
• Gently invert the container for adequate mixing.
• Do not dilute with other solutions or co-infuse with other electrolytes or drugs.
• Administer the drug via infusion pump over 60 minutes through a separate infusion line.
• Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.
• Therapy should be temporarily discontinued if severe hypertension develops.
• Continue use until disease progresses or unacceptable toxicity.

Side Effects

The Most Common

• diarrhea?
• sores in the mouth or throat
• rash
• sudden weakness of an arm or leg
• drooping of one side of the face
• difficulty speaking or understanding
• crushing chest or shoulder pain
• slow or difficult speech
• chest pain
• shortness of breath
• headache
• dizziness or faintness
• seizures
• confusion
• change in vision or loss of vision
• extreme tiredness
• swelling of the face, eyes, stomach, hands, feet, ankles, or lower legs
• unexplained weight gain
• foamy urine
• sore throat, fever, chills, ongoing cough and congestion, or other signs of infection
• coughing up or vomiting blood or material that looks like coffee grounds, unusual bleeding or bruising, pink, red, or dark brown urine, red or tarry black bowel movements, or lightheadedness
• diarrhea, vomiting, abdominal pain, fever, or chills

More common

• Back pain or spasms
• blurred vision
• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
• chest pain
• chills
• cloudy urine
• confusion
• cough
• coughing up blood
• decreased urine output
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, slow, pounding, or irregular heartbeat or pulse
• feeling of warmth
• feeling unusually cold
• fever
• headache
• increased thirst
• lower back or side pain
• muscle pain or cramps
• nausea
• nervousness
• nosebleeds
• painful or difficult urination
• pounding in the ears
• redness of the face, neck, arms, and occasionally, upper chest
• seizures
• shakiness in the legs, arms, hands, or feet
• shivering
• sweating
• swelling of the face, hands, ankles, feet, or lower legs
• trembling or shaking of the hands or feet
• trouble breathing
• unusual tiredness or weakness
• vomiting
• signs of stomach bleeding–severe stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds
• any wound that will not heal;
• headache, confusion, change in mental status, vision loss, seizure (convulsions);
• severe or ongoing nausea, vomiting, or diarrhea;
• rapid weight gain, especially in your face and midsection;
• low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing;
• kidney problems–puffy eyes, swelling in your ankles or feet, weight gain, urine that looks foamy;
• symptoms of a blood clot–sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance; or heart attack symptoms–chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating.
• sores or white patches in or around your mouth, red or swollen gums, trouble swallowing or talking, dry mouth, bad breath, altered sense of taste;

Rare

• Bleeding gums
• difficulty swallowing
• dizziness
• inability to speak
• increased menstrual flow or vaginal bleeding
• loss of consciousness
• low blood pressure or pulse
• pain in the chest, groin, or legs, especially calves of the legs
• pain or discomfort in the arms, jaw, back, or neck
• pale skin
• paralysis
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• severe constipation
• severe headaches of sudden onset
• severe numbness, especially on one side of the face or body
• slurred speech
• sore throat
• stomach pain, cramping, or burning
• sudden loss of coordination
• sudden onset of slurred speech
• sudden vision changes
• sweating
• temporary blindness
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• vomiting of material that looks like coffee grounds, severe and continuing

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action, this drug may cause fetal harm. If a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus. Female patients should be advised to avoid getting pregnant while receiving this drug and for at least 3 months after the last dose. Females of reproductive potential should be advised that this drug may impair fertility.

Lactation

No information is available on the clinical use of this drug during breastfeeding. Because it is a large protein molecule, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant GI tract.

References