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Ramucirumab

Class: Antineoplastic Agents
Chemical Name: Disulfide with human monoclonal IMs-1121B κ-chain anti-(human vascular endothelial growth factor receptor type VEGFR-2 extracellular domain) (human monoclonal IMS-1121B γ-chain) immunoglobulin G1, dimer
Molecular Formula: C6376H9886N1702O1996S46
CAS Number: 947687-13-0
Brands: Cyramza

Warning(s)

  • Hemorrhage
  • Increased risk of hemorrhage, including severe and sometimes fatal hemorrhage.1 Permanently discontinue ramucirumab if severe hemorrhage occurs.1 (See Hemorrhage under Cautions.)

Introduction

Antineoplastic agent; a recombinant human IgG1 monoclonal antibody and vascular endothelial growth factor receptor (VEGFR)-2 antagonist.1

Uses for Ramucirumab

Gastric Cancer

Used alone or in combination with paclitaxel for the treatment of advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, that has progressed during or following fluoropyrimidine- or platinum-based chemotherapy1 2 11 (designated an orphan drug by FDA for treatment of this cancer7 ).

Non-small Cell Lung Cancer (NSCLC)

Used in combination with docetaxel for the treatment of metastatic NSCLC that has progressed during or following platinum-based chemotherapy.1 Patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumors also should have documented disease progression during or following an FDA-labeled anti-EGFR or anti-ALK therapy prior to initiating therapy with ramucirumab.1

Ramucirumab Dosage and Administration

General

  • Administer in setting where adequate monitoring can be performed and appropriate medical support for treating infusion-related reactions is available.1

  • To minimize risk of infusion-related reactions, premedication with an antihistamine (e.g., IV diphenhydramine) recommended prior to each infusion.1 If grade 1 or 2 infusion-related reaction occurred during a previous infusion, also administer dexamethasone (or equivalent) and acetaminophen prior to subsequent infusions.1 (See Infusion-related Effects under Cautions.)

  • Obtain ramucirumab through a limited network of specialty pharmacies.10 Contact manufacturer at 800-545-5979 or consult the Cyramza website () for availability and ordering information.10

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Administer drug via an infusion pump and through a low-protein-binding 0.22-mcm inline filter.1

Do not administer with any other drug or electrolytes simultaneously in the same IV line.1

Flush IV line with 0.9% sodium chloride injection at end of infusion.1

Dilution

Must be diluted prior to administration.1

Withdraw appropriate volume of ramucirumab injection concentrate from vial labeled as containing 10 mg/mL and dilute in 0.9% sodium chloride to yield a final volume of 250 mL.1

Mix by gentle inversion; do not shake.1

Do not dilute in dextrose-containing solutions or admix with any other drug or electrolytes.1

Discard any partially used vials.1

Rate of Administration

Administer by IV infusion over 1 hour.1

Dosage

Adults

Gastric Cancer
IV

8 mg/kg every 2 weeks (as a single agent or in combination with paclitaxel).1

When used in combination with paclitaxel, administer ramucirumab before administration of paclitaxel.1 In the RAINBOW study in which ramucirumab was used in combination with paclitaxel, patients received ramucirumab (8 mg/kg by IV infusion over 1 hour) on days 1 and 15 of each 28-day cycle and paclitaxel (80 mg/m2 by IV infusion over 1 hour) on days 1, 8, and 15 of each 28-day cycle.1 8 11

Continue therapy until disease progression or unacceptable toxicity occurs.1 In the REGARD study in which ramucirumab was used as a single agent, patients received a median of 4 doses of ramucirumab.1 In the RAINBOW study in which ramucirumab was used in combination with paclitaxel, patients received a median of 9 doses of ramucirumab.1

NSCLC
IV

10 mg/kg every 3 weeks in combination with docetaxel.1

Administer ramucirumab before administration of docetaxel.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 In the REVEL study, patients received a median of 4.5 doses of ramucirumab.1

Dosage Modification for Toxicity

Permanently discontinue therapy if severe (grade 3 or 4) bleeding, arterial thromboembolic events, clinically important hypertension that is not controlled with antihypertensive therapy, hypertensive crisis, hypertensive encephalopathy, grade 3 or 4 infusion-related effects, GI perforation, nephrotic syndrome, proteinuria >3 g per 24 hours, or reversible posterior leukoencephalopathy syndrome (RPLS) occurs.1 (See Warnings/Precautions under Cautions.)

Temporarily suspend therapy prior to surgery, if wound healing complications develop during therapy, or if recurrent or severe hypertension or proteinuria occurs.1 (See Hypertension and also Proteinuria under Dosage and Administration.)

Infusion-related Effects

If grade 1 or 2 infusion-related reaction occurs, reduce infusion rate by 50%.1 (See Infusion-related Effects under Cautions.)

If grade 3 or 4 infusion-related reaction occurs, permanently discontinue therapy.1

Hypertension

If severe hypertension occurs, interrupt therapy until hypertension is controlled.1 (See Hypertension under Cautions.)

Permanently discontinue therapy in patients with clinically important hypertension that is not controlled with antihypertensive therapy or in patients who develop hypertensive crisis or hypertensive encephalopathy.1

Proteinuria

Interrupt therapy for proteinuria ≥2 g per 24 hours; when proteinuria declines to <2 g per 24 hours, resume therapy at a reduced dosage of 6 mg/kg every 2 weeks (for advanced or metastatic gastric adenocarcinoma) or 8 mg/kg every 3 weeks (for metastatic NSCLC).1

If proteinuria recurs, interrupt therapy again; when proteinuria declines to <2 g per 24 hours, resume therapy at a reduced dosage of 5 mg/kg every 2 weeks (for advanced or metastatic gastric adenocarcinoma) or 6 mg/kg every 3 weeks (for metastatic NSCLC).1 (See Proteinuria under Cautions.)

If nephrotic syndrome or proteinuria >3 g per 24 hours occurs, permanently discontinue therapy.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration within the ULN and AST concentration exceeding the ULN, or total bilirubin concentration >1 to 1.5 times the ULN and any AST concentration): No dosage adjustment required.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Ramucirumab

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Hemorrhage

Increased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhage.1 Severe bleeding reported; red blood cell transfusions required in some patients.1

Risk of gastric hemorrhage associated with ramucirumab is unknown in patients with gastric cancer receiving NSAIAs.1

Risk of pulmonary hemorrhage associated with ramucirumab is unknown in patients with NSCLC receiving therapeutic anticoagulation, long-term therapy with NSAIAs, or antiplatelet therapy other than once-daily aspirin.1 Risk of pulmonary hemorrhage also unknown in patients with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation.1

Permanently discontinue therapy if severe (grade 3 or 4) hemorrhage occurs.1

Other Warnings and Precautions

Arterial Thromboembolic Events

Severe, sometimes fatal, arterial thromboembolic events (including MI, cardiac arrest, cerebrovascular accident, and cerebral ischemia) reported.1 2

Permanently discontinue therapy if severe arterial thromboembolic event occurs.1

Hypertension

Grade 3 or 4 hypertension reported.1 2 12

Control hypertension prior to initiating ramucirumab therapy.1 Monitor BP every 2 weeks or more frequently as clinically indicated during therapy.1

If severe hypertension occurs, interrupt therapy until hypertension is controlled.1 Permanently discontinue ramucirumab in patients with clinically important hypertension that is not controlled with antihypertensive therapy or in patients who develop hypertensive crisis or hypertensive encephalopathy.1

Infusion-related Effects

Infusion-related reactions (e.g., bronchospasm, supraventricular tachycardia, hypotension, rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, paresthesia), sometimes severe, reported.1

Generally occur more frequently during or following the first 2 infusions.1

Premedication recommended prior to each infusion.1 (See General under Dosage and Administration.)

Monitor patients during infusions for manifestations of infusion-related reactions.1

If infusion-related reactions occur, reduce infusion rate or discontinue therapy depending on severity of reaction.1 (See Infusion-related Effects under Dosage and Administration.)

GI Perforation

GI perforation, potentially fatal, reported.1 2

Permanently discontinue ramucirumab if GI perforation occurs.1

Surgery and Wound Healing Complications

Effect of ramucirumab on wound healing not specifically studied;1 however, VEGFR inhibitors may impair wound healing.1 3

Discontinue ramucirumab prior to scheduled surgery.1 Decision to resume therapy postoperatively should be based on clinical assessment of adequacy of wound healing.1

If wound healing complications develop during therapy, discontinue ramucirumab until wound is fully healed.1

Hepatic Effects

New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome reported in patients with preexisting Child-Pugh class B or C cirrhosis receiving single-agent ramucirumab.1 (See Hepatic Impairment under Cautions.)

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported in <0.1% of patients receiving ramucirumab in clinical studies.1

If manifestations of RPLS occur, confirm diagnosis by magnetic resonance imaging (MRI) and discontinue ramucirumab therapy.1 Symptoms of RPLS may resolve or improve within days, but ongoing neurologic sequelae or death can occur in some patients.1

Proteinuria

Proteinuria reported.1

Interrupt ramucirumab therapy for proteinuria ≥2 g per 24 hours and resume therapy at a reduced dosage when proteinuria declines below this level.1 If nephrotic syndrome or proteinuria >3 g per 24 hours occurs, permanently discontinue ramucirumab.1 (See Proteinuria under Dosage and Administration.)

Immunogenicity

Antibodies to ramucirumab, including neutralizing antibodies to the drug, reported.1

Impairment of Fertility

Animal studies suggest that VEGFR inhibitors, such as ramucirumab, may impair female fertility or ability to maintain pregnancy.1

Specific Populations

Pregnancy

Category C.1 (See Advice to Patients.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1 2

Thickening of epiphyseal growth plates and osteochondropathy observed in animals receiving ramucirumab at concentrations 0.2 times that of human clinical exposure.1

Geriatric Use

In the REGARD and RAINBOW studies in patients with gastric cancer, no overall differences in safety and efficacy relative to younger adults observed.1

In an exploratory subgroup analysis of the REVEL study in patients with NSCLC, survival benefit not observed in patients ≥65 years of age receiving ramucirumab in combination with docetaxel.1

Hepatic Impairment

Mild (total bilirubin concentration within the ULN and AST concentration exceeding the ULN, or total bilirubin concentration >1 to 1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration >1.5 to 3 times ULN and any AST concentration) hepatic impairment did not substantially affect average steady-state concentrations of ramucirumab.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with severe (total bilirubin concentration >3 times the ULN and any AST concentration) hepatic impairment.1

New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome reported in patients with preexisting Child-Pugh class B or C cirrhosis receiving ramucirumab as a single agent.1 Use in patients with Child-Pugh class B or C cirrhosis only if potential benefit outweighs risk of clinical deterioration.1

Renal Impairment

Mild (Clcr 60–89 mL/minute), moderate (Clcr 30–59 mL/minute), or severe (Clcr 15–29 mL/minute) renal impairment did not substantially affect average steady-state concentrations of ramucirumab.1

Common Adverse Effects

Monotherapy in patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: Hypertension,1 2 diarrhea,1 bleeding or hemorrhage,2 headache,1 8 proteinuria,1 8 hyponatremia.1

Combination therapy with paclitaxel in patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: Fatigue or asthenia,1 11 neutropenia,1 11 diarrhea,1 11 epistaxis,1 11 peripheral edema,1 11 hypertension,1 11 stomatitis,1 11 proteinuria,1 11 thrombocytopenia,1 11 hypoalbuminemia,1 11 GI hemorrhage.1

Combination therapy with docetaxel in patients with metastatic NSCLC: Neutropenia,1 12 fatigue or asthenia,1 12 stomatitis or mucosal inflammation,1 12 epistaxis,1 12 febrile neutropenia,1 12 peripheral edema,1 12 thrombocytopenia,1 12 increased lacrimation,1 12 hypertension,1 12 diarrhea,12 decreased appetite,12 neuropathy,12 leukopenia,12 pyrexia,12 myalgia,12 arthralgia,12 back pain,12 dysgeusia,12 insomnia.12

Interactions for Ramucirumab

Specific Drugs

Drug

Interaction

Docetaxel

No substantial effect on systemic exposure to either drug1

Paclitaxel

No substantial effect on systemic exposure to either drug1

Ramucirumab Pharmacokinetics

Absorption

Special Populations

Hepatic impairment: No clinically meaningful differences in average steady-state ramucirumab concentrations observed between patients with mild (total bilirubin concentration >1 to 1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration >1.5 to 3 times the ULN and any AST concentration) hepatic impairment and those with normal hepatic function.1 No formal pharmacokinetic studies in patients with severe (total bilirubin concentration >3 times the ULN and any AST concentration) hepatic impairment.1

Renal impairment: No clinically meaningful differences in average steady-state ramucirumab concentrations observed between patients with mild (Clcr 60–89 mL/minute), moderate (Clcr 30–59 mL/minute), or severe (Clcr 15–29 mL/minute) renal impairment and those with normal renal function.1

Elimination

Half-life

15 days in patients with advanced or metastatic gastric adenocarcinoma receiving 8 mg/kg every 2 weeks.1

23 days in patients with metastatic NSCLC receiving 10 mg/kg every 3 weeks.1

Special Populations

Age, gender, and race do not substantially affect pharmacokinetics of ramucirumab.1 9

Stability

Storage

Parenteral

Injection

2–8°C in original carton to protect from light.1 Do not freeze or shake.1

Diluted solution: Room temperature (<25°C) for up to 4 hours or 2–8°C for up to 24 hours after dilution.1 Do not freeze or shake.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Incompatible

Dextrose 5% in water

Actions

  • Binds specifically to VEGFR-2 and blocks the interaction of VEGFR-2 with its ligands (VEGFR-A, VEGFR-C, and VEGFR-D), resulting in inhibition of VEGFR-stimulated activation of both VEGFR-2 and downstream signaling pathways.1 8 9

  • The VEGFR signaling pathway plays an important role in tumor angiogenesis, tumor growth, and metastatic spread.4 5 6 9

  • Binding of ramucirumab to VEGFR-2 blocks ligand-induced phosphorylation and activation of the receptor in vitro.1 4

  • Inhibits VEGFR-mediated endothelial cell proliferation and migration in vitro.4

  • Inhibits angiogenesis in vivo.1

Advice to Patients

  • Risk of severe bleeding.1 Importance of informing clinician of any episodes or symptoms of bleeding (e.g., lightheadedness).1

  • Risk of arterial thromboembolic events.1

  • Risk of hypertension.1 Importance of receiving routine monitoring of BP and informing clinician if BP is elevated or if manifestations of hypertension (e.g., severe headache, lightheadedness, neurologic symptoms) occur.1

  • Importance of informing clinician if severe diarrhea, vomiting, or severe abdominal pain occurs.1

  • Risk of wound healing complications.1 Importance of informing clinician of any scheduled surgery.1

  • Risk of fetal or neonatal toxicity and miscarriage.1 Necessity of advising women receiving ramucirumab to use an effective method of contraception during and for ≥3 months after the last dose of ramucirumab.1 Importance of immediately informing clinician if the patient becomes pregnant during therapy.1 If pregnancy occurs, apprise patient of potential hazard to the fetus.1

  • Importance of discontinuing nursing while receiving ramucirumab therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., NSAIAs), as well as any concomitant illnesses (e.g., hypertension, hepatic disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ramucirumab (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate for injection, for IV infusion only

10 mg/mL (100 and 500 mg)

Cyramza

Eli Lilly

AHFS DI Essentials. © Copyright 2016, Selected Revisions April 6, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Eli Lilly. Cyramza (ramucirumab) injection for intravenous infusion prescribing information. Indianapolis, IN; 2014 Dec.

2. Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383:31-9. [PubMed 24094768]

3. GlaxoSmithKline. Votrient (pazopanib hydrochloride) tablets prescribing information. Research Triangle Park, NC: 2014 Jun.

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Pharmacology review(s). From FDA website.

5. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D. 2011; 11:113-26. [PubMed 21679004]

6. Hu-Lowe DD, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008; 14:7272-83. [PubMed 19010843]

7. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Jun 23.

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Summary review. From FDA website.

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125477Orig1s000: Medical review(s). From FDA website.

10. Eli Lilly. How to order Cyramza (ramucirumab). Indianapolis, IN. Accessed 2014 Jun 18.

11. Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15:1224-35. [PubMed 25240821]

12. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014; 384:665-73. [PubMed 24933332]

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