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)
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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

10 mg/kg IV infused over ~1 hr prior to docetaxel (75 mg/m²) IV infusion on Day 1 of a 21-day cycle

Continue until disease progression or unacceptable toxicity

Gastric Cancer

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

Single agent or in combination with paclitaxel: 8 mg/kg IV q2wk; infuse over 1 hr

Paclitaxel dose (if given in combination): 80 mg/m² once weekly for 3 weeks of every 28-day cycle

When given in combination, administer ramucirumab prior to administration of paclitaxel

Continue until disease progression or unacceptable toxicity

Colorectal Cancer

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

8 mg/kg IV q2wk; administer by IV infusion over 60 minutes prior to FOLFIRI administration

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Wound healing: Interrupt prior to scheduled surgery until wound is fully healed

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

Infusion-related reactions

  • Reduce the infusion rate by 50% for grade 1 or 2; add dexamethasone (or equivalent) and acetaminophen to diphenhydramine premedication regimen before each ramucirumab dose
  • Permanently discontinue for grade 3 or 4

Hypertension

  • Interrupt therapy for severe hypertension until controlled with medical management
  • Permanently discontinue for severe hypertension that cannot be controlled with antihypertensive therapy

Proteinuria

  • Interrupt therapy for urine protein levels ≥2 g/24 hr; reinitiate treatment at reduced dose of 6 mg/kg q2wk (gastric cancer) or 8 mg/kg q3wk (NSCLC) when urine protein level returns to <2 g/24 hr
  • If the protein level ≥2 g/24 hr reoccurs, interrupt therapy and reduce dose to 5 mg/kg q2wk(gastric cancer) or 6 mg/kg q3wk (NSCLC) when urine protein level returns to <2 g/24 hr
  • Permanently discontinue for urine protein level >3 g/24 hr or in the setting of nephrotic syndrome

Dosing Considerations

Premedicate with IV diphenhydramine before each ramucirumab infusion

For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each ramucirumab infusion

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

Available exclusively from Biologics, a specialty pharmacy

Hepatocellular Carcinoma (Orphan)

Orphan designation for treatment of hepatocellular carcinoma

Sponsor

  • Eli Lilly and Company; Lilly Corporate Center; Indianapolis, IN 46285

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%)

1-10%

GI hemorrhage events, gastric cancer (10%)

<1%

Gastrointestinal perforation (single agent) (0.7%)

Reversible posterior leukoencephalopathy syndrome (<0.1%)

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Warnings

Black Box Warnings

Hemorrhage

  • Increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events Permanently discontinue patients who experience severe bleeding

Gastrointestinal perforation

  • Can increase the risk of gastrointestinal perforation, a potentially fatal event
  • Permanently discontinue in patients who experience a gastrointestinal perforation

Impaired wound healing

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

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 (see Black Box Warnings)

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 (see Black Box Warnings)

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway; withhold drug before surgery and discontinue if patient develops wound healing complications (see Black Box Warnings)

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

Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare); discontinue ramucirumab

Severe proteinuria reported, particularly when administered with FOLFIRI (see Dosage Modifications)

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, ramucirumab can cause fetal harm Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development

There are no available data on ramucirumab use in pregnant women to inform any drug–associated risks

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development Advise females of reproductive potential to use effective contraception while receiving ramucirumab and for at least 3 months after the last dose

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

Minimum concentration levels: 50 mcg/mL (range: 6-228 mcg/mL) after 3rd dose; 74 mcg/mL (range: 14-234 mcg/mL) after 6th dose

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

Inspect vial contents for particulate matter and discoloration prior to dilution

Discard the vial if particulate matter or discolorations are identified

Calculate the dose and the required volume needed to prepare the infusion solution

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

Do not dilute with solutions other than 0.9% NaCl or co-infuse with other electrolytes or medications

Gently invert the container to ensure adequate mixing

IV Administration

Premedicate all patients with diphenhydramine IV

If grade 1 or 2 infusion reaction occurs, also premedicate with dexamethasone and acetaminophen

Use protein sparing 0.22-micron filter

Administer diluted solution by IV infusion via infusion pump over 60 minutes through a separate infusion line

Do NOT administer as IV push or bolus

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

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

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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