ramucirumab (Rx)

Brand and Other Names:Cyramza
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

IV solution

  • 10mg/mL (10mL and 50mL vials)

Non-Small Cell Lung Cancer

Indicated in combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) 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

Day 1: Ramucirumab 10 mg/kg IV PLUS docetaxel 75 mg/m2 IV

Repeat cycle every 21 days

Continue until disease progression or unacceptable toxicity

Gastric Cancer

As a single agent or in combination with paclitaxel for advanced gastric or gastro-esophageal junction adenocarcinoma in patients with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy

Single agent: Ramucirumab 8 mg/kg IV q2wk

Combination with paclitaxel

  • Days 1 and 15: Ramucirumab 8 mg/kg IV
  • Days 1, 8, and 15: Paclitaxel 80 mg/m2
  • Repeat cycle every 28 days
  • Continue until disease progression or unacceptable toxicity

Colorectal Cancer

Indicated for use in combination with FOLFIRI for patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen

Ramucirumab 8 mg/kg IV q2wk in combination with FOLFIRI

Continue until disease progression or unacceptable toxicity

Hepatocellular Carcinoma

Indicated as a single agent for hepatocellular carcinoma (HCC) in patients with alpha fetoprotein (AFP) of ≥400 ng/mL who have been treated with sorafenib

8 mg/kg IV q2wk

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Arterial thromboembolic events, GI perforation, or grade 3 or 4 hemorrhage: Permanently discontinue

Wound healing (all grades)

  • Withhold drug for 28 days before elective surgery; resume no sooner than 28 days after surgery after wound fully healed
  • Discontinue for would healing complications requiring medical intervention

Infusion-related reactions

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

Hypertension

  • Severe hypertension: Interrupt therapy until controlled with medical management
  • Uncontrolled severe hypertension despite antihypertensive therapy: Permanently discontinue

Proteinuria

  • First occurrence of increased urine protein levels ≥2 g/24 hr: Withhold dose until urine protein levels <2 g/24 hr; resume at reduced dose (eg, reduce 8 mg to 6 mg, 10 mg to 8 mg)
  • Reoccurrence of protein level ≥2 g/24 hr: Withhold dose until urine protein <2 g/24 hr; resume at reduced dose (eg, reduce 6 mg to 5 mg, 8 mg to 6 mg)
  • Urine protein level >3 g/24 hr or nephrotic syndrome: Permanently discontinue

Hepatic impairment

  • Mild-to-moderate (total bilirubin ≤3x ULN and any AST): No dosage adjustment necessary
  • Severe (total bilirubin >3x ULN and any AST): Pharmacokinetics unknown
  • Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single agent ramucirumab

Renal impairment

  • Mild-to-severe (CrCl 15-89 mL/min): No clinically meaningful effect on pharmacokinetics

Dosing Considerations

Blood pressure should be controlled before initiating treatment and monitored every 2 weeks or more frequently if indicated

Safety and efficacy not established

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Adverse Effects

>10%

All grades unless otherwise states

GI cancer (plus paclitaxel)

  • Fatigue/asthenia (57%)
  • Neutropenia (54%)
  • Diarrhea (32%)
  • Epistaxis (31%)
  • Peripheral edema (25%)
  • Stomatitis (20%)
  • Proteinuria (17%)
  • Hypertension (25%)
  • Infusion-related reactions (16%)
  • Hypertension grade 3-4 (15%)
  • Thrombocytopenia (13%)
  • Hypoalbuminemia (11%)

NSCLC (plus docetaxel)

  • Neutropenia (55%)
  • Fatigue/asthenia (55%)
  • Stomatitis/mucosal inflammation (37%)
  • Epistaxis (19%)
  • Febrile neutropenia (16%)
  • Peripheral edema (16%)
  • Thrombocytopenia (13%)
  • Lacrimation increased (13%)
  • Hypertension (11%)

HCC

  • Thrombocytopenia (46%)
  • Fatigue (36%)
  • Hypoalbuminemia (33%)
  • Hyponatremia (32%)
  • Peripheral edema, hypertension, abdominal pain (25%)
  • Neutropenia (24%)
  • Decreased appetite (23%)
  • Proteinuria (20%)
  • Nausea (19%)
  • Ascites (18%)
  • Hypocalcemia (16%)
  • Headache (14%)
  • Epistaxis (14%)
  • Insomnia (11%)

1-10%

GI hemorrhage events, gastric cancer (10%)

<1%

Gastrointestinal perforation (single agent) (0.7%)

Reversible posterior leukoencephalopathy syndrome (<0.1%)

Postmarketing Reports

Thrombotic microangiopathy

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Warnings

Contraindications

None

Cautions

Increased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhagic events; permanently discontinue in patients who experience severe bleeding

Serious, sometimes fatal, arterial thromboembolic events including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia reported during clinical trials

Increased incidence of severe hypertension reported; control hypertension before initiating treatment and monitor blood pressure q2weeks or more frequently as indicated; temporarily suspend therapy for severe hypertension

Infusion-related reactions observed that include rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia; in severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension

Ramucirumab is an antiangiogenic therapy that can increase the risk of GI perforation and affect wound healing; withhold prior to surgery; permanently discontinue ramucirumab in patients who experience a gastrointestinal perforation

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway; VEGFR2 antagonist has the potential to adversely affect wound healing; not studied in patients with serious or non-healing wounds

Clinical deterioration, manifested by new-onset or worsening encephalopathy, ascites, or hepatorenal syndrome, reported in patients with Child-Pugh B or C cirrhosis; use only if the benefits outweigh the risks

Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), reported; confirm diagnosis with magnetic resonance imaging; permanently discontinue in patients who develop PRES; symptoms may resolve or improve within days; some patients can experience ongoing neurologic sequelae or death

Severe proteinuria, including nephrotic syndrome, reported, particularly when administered with FOLFIRI

May cause hypothyroidism; monitor thyroid function during treatment

Based on its mechanism of action, ramucirumab can cause fetal harm when administered to pregnant women

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Pregnancy & Lactation

Pregnancy

Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman

There are no available data on use in pregnant women

Animal data

  • Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development
  • Advise a pregnant woman of the potential risk to a fetus

Pregnancy testing

  • Verify pregnancy status of females of reproductive potential before initiating therapy

Contraception

  • Females: Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose

Infertility

  • Advise females of reproductive potential that based on animal data, fertility may be impaired

Lactation

Unknown if distributed in human breast milk; a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother

Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D

As a result, ramucirumab inhibits ligand-stimulated activation of VEGF2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells

Absorption

Steady-state achieved at ~ 12 weeks

Distribution

Vd (steady-state): 5.4L

Elimination

Clearance: 0.015 L/hr

Half-life: 14 days

Pharmacogenomics

NSCLC: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab

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Administration

IV Compatibilities

0.9% NaCl

IV Incompatibilities

Dextrose-containing solutions

IV Preparation

Visually inspect vials for particulate matter and discoloration

Discard if particulate matter or discolorations identified

Calculate dose and withdraw required volume

Further dilute with only 0.9% NaCl in IV infusion container to final volume of 250 mL

Do not shake; gently invert container to ensure adequate mixing

Do not dilute with other solutions or infuse with other electrolytes or medications; do not freeze

Discard any unused portion

Premedication

Before each infusion, premedicate all patients with an IV histamine-1 receptor antagonist (eg, diphenhydramine)

For patients who have experienced a grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen before each infusion

IV Administration

Visually inspect diluted solution for particulate matter and discoloration before administration

Discard if particulate matter or discolorations are identified; do not administer as an IV push or bolus

Administer diluted solution via infusion pump through a separate infusion line; use a protein sparing 0.22 micron filter

Infuse IV infusion over 60 min; if first infusion is tolerated, all subsequent infusion may be administered over 30 min

When given in combination therapy, administer ramucirumab first 1 hr prior to other therapies (eg, paclitaxel, docetaxel, or FOLFIRI)

Flush line with sterile 0.9% NaCl at the end of infusion

Storage

Unopened vials

  • Refrigerate at 2-8°C (36-46°F)
  • Keep the vial in the outer carton to protect from light

Diluted infusion

  • Administer within 24 hr of dilution
  • Store refrigerated at 2-8°C (36-46°F) or 4 hr at room temperature (ie, below 25°C [77°F])
  • Do not freeze
  • Discard partially used vials
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Formulary

FormularyPatient Discounts

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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.