You are using an outdated browser. We suggest you update your browser for a better experience. Click here for update.
Close this notification.
Skip to main content Skip to search

COVID-19: Get the latest updates or take a self-assessment.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Find out more about hepatitis B virus screening and management.

Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.

ramucirumab

( RA-mue-SIR-ue-mab )
Funding:
New Drug Funding Program
  • Ramucirumab - Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma
Other Name(s): Cyramza®
Appearance: solution mixed into larger bags of fluids
A - Drug Name

ramucirumab

COMMON TRADE NAME(S):   Cyramza®

 
B - Mechanism of Action and Pharmacokinetics

Ramucirumab is a VEGF2 receptor antagonist that blocks the binding of VEGF-A, VEGF-C and VGEF-D, thereby having an inhibitory effect on tumour angiogenesis.



Metabolism

No information found. Antibodies are generally cleared by catabolism.

Elimination
Half-life

15 days

 
C - Indications and Status
Health Canada Approvals:

  • Gastric cancer 
  • Gastro-esophageal junction adenocarcinoma

Refer to the product monograph for a full list and details of approved indications.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   None

The following adverse effects include those considered related to ramucirumab; incidence in combination with paclitaxel is presented where there appeared to be a clinically relevant increased incidence when compared to single-agent ramucirumab. Adverse effects likely related to paclitaxel are not reported.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism (1.7%) E
Cardiotoxicity (rare) E  D
Hypertension (16%) (8% severe; 15% severe with paclitaxel) E
Venous thromboembolism (2%) E
Dermatological Rash (4%) (11% with paclitaxel) E
Gastrointestinal Abdominal pain (29%) E
Diarrhea (14%) (32% with paclitaxel) E
GI perforation (2%)
Nausea, vomiting (<1%) (35% with paclitaxel) E
General Edema - limbs (<1%) (25% with paclitaxel) E
Fatigue (<1%) (57% with paclitaxel) E
Wound dehiscence (rare) E
Hematological Myelosuppression ± infection, bleeding (4%) (severe; 41% with paclitaxel) E
Hepatobiliary ↑ LFTs (1%) (8% with paclitaxel; may be severe) E
Hypersensitivity Infusion related reaction (rare) E
Metabolic / Endocrine Abnormal electrolyte(s) (6%) (decreased Na) E
Hypothyroidism (1%) E
Other (<1%) (Hypoalbuminemia; 11% with paclitaxel) E
Nervous System Headache (9%) E
Posterior reversible encephalopathy syndrome (PRES) (rare) E
Renal Creatinine increased (<1%) (4% with paclitaxel) E
Proteinuria (3%) (17% with paclitaxel; may be severe) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for ramucirumab include abdominal pain, hypertension, diarrhea, headache, abnormal electrolyte(s), myelosuppression ± infection, bleeding, rash, and proteinuria.

Severe arterial thromboembolic events as well as congestive heart failure have been reported with antiangiogenic drugs, including ramucirumab. Patients with an increased risk of coronary artery disease should be treated with caution.

Hypertension is common and may be severe. In most cases it is manageable with antihypertensive therapy. Posterior reversible encephalopathy syndrome (PRES) has been reported rarely. Ramucirumab should be discontinued if PRES is confirmed.

Severe gastrointestinal hemorrhage and fatal events were reported in patients with gastric cancer treated with combination therapy, and other cancers treated with monotherapy.

Gastrointestinal perforation has been reported and may be fatal; the risk may be increased with prior GI procedures (such as endoscopy) and diseases (such as diverticulitis). Ramucirumab may also increase the risk of fistulas.

There is increased risk of myelosuppression, including severe neutropenia and thrombocytopenia in patients treated with combination therapy compared to paclitaxel alone. Patients should be closely monitored and treated, as indicated.

Ramucirumab can cause new or worsening encephalopathy, ascites or hepatorenal syndrome in patients with Child-Pugh B or C cirrhosis. Treat only if potential benefit outweighs the risk in these patients.

An increased incidence of proteinuria, including nephrotic syndrome has been reported and is more frequent in Asian patients.

Infusion-related reactions generally occur during or following the first or second infusion. Patients should be monitored for signs and symptoms of hypersensitivity and ramucirumab discontinued in case of severe reactions.

Three percent of patients develop anti-ramucirumab antibodies, some of which are neutralizing; the clinical significance is unclear.

 
E - Dosing

Refer to protocol by which patient is being treated.

Hold ramucirumab prior to elective surgery.

Pre-existing hypertension should be controlled before starting treatment.

 

Premedications (prophylaxis for infusion reactions):

  • H1-receptor antagonist IV (e.g. diphenhydramine)

For patients who experienced a grade 1 or 2 infusion reaction:

  • H1-receptor antagonist IV (e.g. diphenhydramine)
  • Dexamethasone IV (or equivalent)
  • Acetaminophen
     

Consult the paclitaxel drug monograph and PACL(W)+RAMU regimen monograph for premedications for the combination.



Adults:

Single agent:

Intravenous: 8 mg/kg every 2 weeks


Combination therapy:

Refer to the related regimen monographs for details.


Dosage with Toxicity:

Dose level Ramucirumab dose (mg/kg)
0 8
-1 6
-2 5

 

Toxicity

Severity

Ramucirumab dose

Hypertension

Grade 3 or 4

Hold until controlled with antihypertensive therapy. Discontinue if cannot be controlled.

Proteinuria

 

 

1st occurrence urine protein ≥ 2 g/24 hours

Hold* and restart at ↓ 1 dose level once urine protein < 2 g/24 hours.  

2nd occurrence urine protein ≥ 2 g/24 hours

Hold* and restart at ↓ 2 dose levels once urine protein < 2 g/24 hours.  

3rd occurrence OR urine protein > 3 g/24 hours OR nephrotic syndrome

Discontinue

Delayed wound healing

n/a

Hold prior to scheduled surgery until the wound is fully healed. Discontinue if wound healing complications arise.

Arterial thromboembolism

Life-threatening VTE

Bleeding

Grade 3 or 4

Discontinue

GI perforation

PRES

Any

Discontinue

*In the clinical trial, doses were held up to 2 weeks. If urine protein does not return to < 2 g/24 hours, discontinue.


Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion.
  • Manage the symptoms.
     

Restart:

  • Slow the rate to 50% of the original rate at which the IR occurred for the remainder of the infusion.
  • Consider re-challenge pre-medications (H1-receptor antagonist, dexamethasone and acetaminophen) and reduce administration rate by 50% at which the IR occurred.
3 or 4
  • Stop the infusion.
  • Aggressively manage symptoms.
  • Discontinue permanently (do not re-challenge).


Dosage with Hepatic Impairment:

New onset or worsening ascites, encephalopathy or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. Treat only if potential benefit outweighs risk in these patients. No studies have been conducted for patients with hepatic impairment.



Dosage with Renal Impairment:

Population pharmacokinetic analysis suggests no dosage adjustment needed for mild to moderate renal impairment. No data available for patients with CrCl < 30 ml/min.



Dosage in the elderly:

No dose adjustment required. No overall differences in safety or effectiveness were observed between patients ≥65 years compared with younger patients.

 



Dosage based on ethnicity:

Higher incidences of proteinuria and nephrotic syndrome were reported in Asian patients living in East Asia compared to Caucasian patients.



Children:

Safety and effectiveness have not been established in pediatric patients.



 
F - Administration Guidelines
  • Administer as IV infusion only. DO NOT administer as IV push or bolus.
  • Withdraw required volume and transfer into an empty IV container.
  • Dilute with normal saline to a total volume of 250 mL. DO NOT use dextrose as a diluent.
  • Gently invert container to mix. DO NOT shake.
  • Give ramucirumab before administering paclitaxel when used in combination.
  • Infuse IV over approximately 60 minutes (maximum rate 25 mg/min) using a separate infusion line, with a protein sparing 0.22 micron filter.
  • Flush the line with normal saline at the end of the infusion.
  • DO NOT dilute or co-administer with other electrolytes or medications.
  • Refrigerate unopened vials in original carton (2-8°C). Protect from light and DO NOT freeze.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 
G - Special Precautions
Contraindications:

  • Hypersensitivity to ramucirumab or any of the components in the formulation

Other Warnings/Precautions:

  • Treat only if potential benefit outweighs risk in patients with Child-Pugh Class B or C cirrhosis as clinical deterioration has been reported.
  • Use with caution in patients with known or increased risk of coronary artery disease and/or those receiving cardiotoxic chemotherapy.
  • Use with caution in patients at risk of bleeding, including those receiving concomitant antiplatelets and/or anticoagulants.
  • Ramucirumab has not been evaluated in patients with serious or non-healing wounds and may impair healing. Withhold prior to surgery until the wound has fully healed.
  • Use with caution in patients with risk factors for GI perforation, including intra-abdominal metastases, inflammatory bowel disease, diverticulitis, ischemic bowel, peptic ulcers, obstruction and injury from endoscopy and surgery.


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Genotoxicity: Unknown
  • Embryotoxicity: Probable

    Ramucirumab should not be used in pregnancy. Adequate contraception should be used by both sexes during treatment and at least for 3 months after the last dose.

  • Excretion into breast milk: Unknown

    IgGs are secreted into breast milk. Breastfeeding is not recommended during treatment and for at least 3 months after the last dose.

  • Fertility effects: Probable

    Female fertility may be compromised based on animal studies.

 
H - Interactions

No pharmacokinetics interactions were observed between ramucirumab and paclitaxel. No other drug-drug interaction studies have been performed.

AGENT EFFECT MECHANISM MANAGEMENT
Bisphosphonates, anti-angiogenic drugs ↑ risk of osteonecrosis of the jaw Additive Caution and monitor
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Blood pressure

Baseline and every 2 weeks, or more frequently as clinically indicated

CBC

Baseline and before each dose

Liver function tests

Baseline and before each dose

Urinalysis (for protein)

Baseline and before each cycle; if urine protein level is 2+ or higher, perform 24-hour urine collection (see dose modifications table under proteinuria)

Thyroid function tests

Baseline and every 2 to 3 cycles. Continue after treatment as indicated (thyroid dysfunction may persist)

Clinical toxicity assessment for infusion-related reactions, bleeding, infection, thromboembolism, cardiotoxicity, GI and neurologic effects, and impaired wound healing

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Ramucirumab - Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma

 
K - References

Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9.

Product monograph Cyramza (ramucirumab). Eli Lilly Canada Inc. January 2017 and June 2022.

Ramucirumab: Drug information. Lexicomp Inc. 2015.

Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. 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 Oct;15(11):1224-35.


December 2022 Modified Indication, Dosing, Administration guidelines and Pregnancy / Lactation sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.