Ramucirumab (Cyramza) is a recombinant monoclonal antibody that also inhibits vascular endothelial growth factor receptor 2 (VEGFR2). It is used in the treatment of the following conditions:

• Colorectal cancer, metastatic:

  • It is used in treatment (in combination with FOLFIRI [irinotecan, leucovorin, and fluorouracil]) of metastatic colorectal cancer in patients showing disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

• Gastric cancer, advanced or metastatic:

  • It is used in treatment (single agent or in combination with paclitaxel) of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients showing disease progression on or following fluoropyrimidine- or platinum-containing chemotherapy.

• Hepatocellular carcinoma, advanced or relapsed/refractory:

  • It is used in treatment (as a single agent) of hepatocellular carcinoma in patients who have an alpha-fetoprotein of ≥400 ng/mL and have been previously treated with sorafenib.

• Non-small cell metastatic lung cancer:

  • It is used in treatment (in combination with docetaxel) of metastatic non-small cell lung cancer in patients showing disease progression on or after platinum-based chemotherapy.

  • Disease progression on approved therapy in patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations.

Cyramza (Ramucirumab) dose in Adults

• Premedication is done prior to infusion with an intravenous H-1 antagonist (eg, diphenhydramine);
• Grade 1 or 2 infusion reaction with a prior infusion
• Also, pre-medicate with dexamethasone (or equivalent) and acetaminophen.

Dosage in the treatment of metastatic colorectal cancer:

• 8 mg/kg intravenous is given every 2 weeks in combination with FOLFIRI (irinotecan, leucovorin, and fluorouracil)
• It is continued until toxicity or disease progression.

Dosage in the treatment of advanced or metastatic Gastric cancer:

• 8 mg/kg intravenous is given every 2 weeks as a single agent or in combination with weekly paclitaxel
• continue ramucirumab till disease progression or unacceptable toxicity.

Dosage in the treatment of Hepatocellular carcinoma (advanced, relapsed/refractory):

• 8 mg/kg  intravenous is given every 2 weeks (as a single agent)
• continue ramucirumab till disease progression or unacceptable toxicity.

Dosage in the treatment of metastatic Non-small cell lung cancer:

• 10 mg/kg intravenous is given on day 1 every 21 days in combination with docetaxel;
• continue ramucirumab till disease progression or unacceptable toxicity.

Cyramza (Ramucirumab) dose in Childrens

Not recommended for use in children

Ramucirumab (Cyramza) Pregnancy Risk Category: C

• Ramucirumab is known to inhibit angiogenesis, which is crucial for human fetal development.
• Ramucirumab can cause fetal harm when administered during pregnancy based on its mechanism of action.
• Before initiating treatment for females with reproductive potential, verify your pregnancy status.
• Effective contraception should be used by females with reproductive potential for at least three months following the last dose of ramucirumab. 
• Female fertility may be affected by ramucirumab.

Ramucirumab can be used during breastfeeding

• It is unknown if ramucirumab can be found in breast milk.
• Breast milk contains immunoglobulins, which are excreted in breastmilk. Ramucirumab is also thought to be present in breast milk.
• The manufacturer does not recommend breastfeeding during treatment or for at least 2 months after the last ramucirumab dose.

Cyramza (Ramucirumab) dose in Renal disease:

• No dosage adjustment required.

Cyramza (Ramucirumab) dose in Liver disease:

• Mild (normal bilirubin with AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment:

  • No dosage adjustment required.

• Severe impairment (total bilirubin >3 times ULN and any AST):

  • There are no dosage adjustments given in the manufacturer's labeling (has not been studied).
  • Use in patients with Child-Pugh class B or C cirrhosis if the potential benefits outweigh the potential risks.

Common Side Effects of Ramucirumab (Cyramza) Include:

• Cardiovascular:

  • Peripheral Edema
  • Hypertension

• Central Nervous System:

  • Fatigue
  • Headache
  • Insomnia

• Endocrine & Metabolic:

  • Hypoalbuminemia
  • Hyponatremia
  • Hypocalcemia

• Gastrointestinal:

  • Abdominal Pain
  • Decreased Appetite
  • Nausea
  • Diarrhea

• Genitourinary:

  • Proteinuria

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Neutropenia

• Hepatic:

  • Ascites

• Respiratory:

  • Epistaxis

• Miscellaneous:

  • Infusion Related Reaction

Less Common Side Effects of Ramucirumab (Cyramza) Include:

• Cardiovascular:

  • Arterial Thromboembolism

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Vomiting
  • Intestinal Obstruction

• Hematologic & Oncologic:

  • Anemia

• Hepatic:

  • Hepatic Encephalopathy
  • Hepatorenal Syndrome

• Immunologic:

  • Antibody Development

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Pneumonia

• Miscellaneous:

  • Fever

Rare side effects of Cyramza:

• Cardiovascular:

  • Acute Myocardial Infarction
  • Cerebral Ischemia
  • Cerebrovascular Accident
  • Severe Hypertension

• Endocrine & Metabolic:

  • Hypothyroidism

• Gastrointestinal:

  • Gastrointestinal Hemorrhage
  • Gastrointestinal Perforation

• Hematologic & Oncologic:

  • Major Hemorrhage

Contraindication to Ramucirumab Include:

• The US labeling of the manufacturer does not contain any contraindications.
• Hypersensitivity to ramucirumab and any part of the formula

Warnings and precautions

• Arterial thrombotic episodes:

  • Ramucirumab has been used to treat serious arterial thrombotic events such as myocardial injury, cardiac arrest, cerebrovascular accident and cerebral ischemia.
  • Patients who have suffered arterial thrombotic events should be treated immediately.

• Suppression of bone marrow

  • There may be thrombocytopenia or neutropenia. 
  • Patients who are exposed to combination therapies, especially if they also use paclitaxel, have a higher risk of developing thrombocytopenia.
  • Monitor CBC with differential when used with paclitaxel.

• Perforation of the gastrointestinal tract:

  • Ramucirumab can increase the risk of gastrointestinal bleeding, which could be fatal.
  • Patients who have a gastrointestinal perforation should be treated immediately.

• Hemorrhage

  • Ramucirumab has a higher chance of hemorhage and gastrointestinal bleeding, including events >= grade 3, which can sometimes be fatal or severe.
  • Patients who have suffered severe (grade 3-4) bleeding should be stopped immediately.
  • Some clinical trials excluded patients who were taking nonsteroidal anti-inflammatory drug (NSAIDs).
  • It is unknown if patients with gastric cancers who are taking NSAIDs may experience gastric hemorhage.

• Hypertension

  • It can lead to or worsen hypertension. Ramucirumab may increase the likelihood of severe hypertension.
  • Before treatment can be initiated, it is important to control your BP.
  • During treatment, monitor BP every 14-days (or more frequently if necessary).
  • Stop temporarily if severe hypertension develops.
  • If medically significant hypertension is not controlled by antihypertensive therapy, or in patients suffering from hypertensive crisis and hypertensiveencephalopathy, you should stop permanently.

• Infusion reaction

  • Ramucirumab may cause infusion-related reactions, which can be severe. These reactions usually occur with the second or third dose.
  • Infusion reactions can cause symptoms such as chills, flushing and hypoxia, hypoxia, wheezing and hypotension.
  • Before infusion, it is recommended to take medication(s).
  • When the infusion is administered, monitor for symptoms of an infusion reaction.
  • For grade 1 and 2, reduce the infusion rate; for grade 3 and 4, stop immediately and permanently
  • Infusion reactions can be managed in a facility.

• Nephrotic syndrome/proteinuria:

  • Ramucirumab can also be associated with proteinuria, including >= grade 3 proteinuria or cases of nephrotic Syndrome.
  • For the assessment of proteinuria, use urine dipstick or urinary protein creatinine to determine if it is occurring.
  • Stop treating urine protein levels greater than 2 g/24 hours. Reduce the dose immediately after therapy re-initiation.
  • Permanently stop if your urine protein is greater than 3 g/24 hour or if you have nephrotic syndrome.

• Reversible posterior Leukoencephalopathy Syndrome:

  • Reversible posterior Leukoencephalopathy Syndrome (RPLS) has been reported in some cases.
  • RPLS symptoms include headaches, seizures, confusion, blindness, and/or other visual disturbances.
  • Confirm RPLS diagnosis by MRI. Permanently stop ramucirumab after RPLS diagnosis.
  • Most patients will experience a resolution of symptoms within a few days. However, some patients may have neurologic sequelae.

• Thyroid dysfunction

  • It has been reported that hypothyroidism (grades 1 and 2) has been detected.
  • During treatment, monitor thyroid function.

• Inability to heal wounds

  • An antibody that inhibits the vascular endothelial factor (VEGF), or VEGF receptor pathway can cause impaired wound healing.
  • For 4 weeks before elective surgery, and at least 28 days following major surgery (or until the wound has fully healed), you should withhold ramucirumab.
  • If patients develop complications that cause wound healing, they should be referred to a physician immediately.

• Hepatic impairment

  • Patients with Child-Pugh class C or B cirrhosis have been known to experience worsening encephalopathy, ascites or hepatorenal symptoms.
  • Use in patients with Child-Pugh Class B or C cirrhosis only when the potential benefits outweigh any potential risks.
  • Clinical data regarding the treatment of hepatocellular cancer showed that patients with Child-Pugh class B liver cirrhosis who were given ramucirumab had a higher incidence of hepatic and hepatorenal symptoms than patients who were given a placebo.

Ramucirumab: Drug Interaction

Monitor:

• Liver function tests
• urine protein (by urine dipstick and/or urinary protein creatinine ratio)
• thyroid function tests
• Blood CBC with differential counts (especially when used as a part of combination chemotherapy)
• verify pregnancy status before treatment (in females of reproductive potential).
• Monitor blood pressure (every 2 weeks or more frequently if indicated)
• signs/symptoms of infusion-related reactions (during infusion);
• signs/symptoms of arterial thromboembolic events,
• bleeding/hemorrhage,
• gastrointestinal perforation
• wound healing impairment
• reversible posterior leukoencephalopathy syndrome

How to administer Ramucirumab (Cyramza)?

• Premedicate before infusion with an intravenous H-1 antagonist (eg, diphenhydramine)
• for patients who had a grade 1 or 2 infusion reaction with a prior infusion
• Premedicate with dexamethasone (or equivalent) and acetaminophen.
• Give intravenously over 1 hour through a separate infusion line using an infusion pump
• A 0.22-micron protein-sparing filter should be used.
• an IV push or bolus should be avoided.
• Flush the line with NS after the infusion is complete.
• Do not give in the same IV line with solutions other than NS, or with electrolytes or other medications.
• Monitor for infusion reaction
• reduce infusion rate (by 50%) for grade 1 or 2 infusion reaction
• Stop permanently for grade 3 or 4 infusion reactions.
• Give ramucirumab prior to docetaxel, paclitaxel, or FOLFIRI if administering in combination.

Mechanism of action of Ramucirumab (Cyramza):

•  
• Ramucirumab, a monoclonal recombinant antibody that also inhibits vascular growth factor receptor 2 (VEGFR2), is also available.
• Ramucirumab is highly sensitive to VEGFR2 (Spratlin 2010,). It binds to VEGFR ligands and blocks binding of VEGF ligands, VEGF -A, VEGF -C and VEGF -D to prevent activation of VEGFR2.
• It prevents the ligand-induced migration and proliferation of endothelial cell populations.
• VEGFR2 inhibition can also reduce tumor growth and vascularity.

Half-life elimination: 14 days

Distribution: V : 5.4 L Excretion: Clearance: 0.015 L/hour  

International Brands of Ramucirumab:

• Cyramza

Cyramza (Ramucirumab) Brands in Pakistan:

Cyramza (Ramucirumab) is not available in Pakistan.