Ramucirumab is a monoclonal antibody medication that is used in the treatment of certain types of cancer. It is specifically designed to target and inhibit the activity of vascular endothelial growth factor receptor 2 (VEGFR-2). VEGFR-2 is a protein that plays a key role in the formation of new blood vessels, a process called angiogenesis. In cancer, angiogenesis is often overactive, leading to the growth and spread of tumors.

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

• Before giving the medicine through an intravenous (IV) drip, you should give the patient another drug to prevent certain side effects.
• This other drug is called an H antagonist, like diphenhydramine.
• It helps reduce the chances of the patient having an allergic reaction when the medicine is given.

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Ramucirumab Dosage in the treatment of metastatic colorectal cancer:

• For treating metastatic colorectal cancer with ramucirumab, the dose is given through an intravenous (IV) drip.
• The dose amount is 8 milligrams (mg) for every kilogram (kg) of the patient's body weight.
• This treatment is done once every 2 weeks.
• It is used alongside another chemotherapy regimen called FOLFIRI, which includes irinotecan, leucovorin, and fluorouracil.
• Continue giving ramucirumab until the cancer gets worse (disease progression) or if the patient experiences severe side effects that make the treatment too risky (unacceptable toxicity).

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Ramucirumab Dosage in the treatment of advanced or metastatic Gastric cancer:  

• Ramucirumab is used to treat advanced or metastatic gastric (stomach) cancer.
• It is administered through an intravenous (IV) drip.
• The dose is 8 milligrams (mg) for every kilogram (kg) of the patient's body weight.
• This treatment is given once every 2 weeks.
• Ramucirumab can be given alone as a single agent or combined with another chemotherapy drug called paclitaxel, which is given weekly.
• Continue giving ramucirumab until the cancer worsens (disease progression) or if the patient experiences severe side effects that make the treatment too risky (unacceptable toxicity).

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

• Ramucirumab is used to treat advanced hepatocellular carcinoma (liver cancer) that has either relapsed (come back) or hasn't responded to previous treatments (refractory).
• It is given through an intravenous (IV) drip.
• The dose is 8 milligrams (mg) for every kilogram (kg) of the patient's body weight.
• This treatment is administered once every 2 weeks.
• Ramucirumab can be given alone as a single agent, without the need for combination with other drugs.
• Continue giving ramucirumab until the cancer gets worse (disease progression) or if the patient experiences severe side effects that make the treatment too risky (unacceptable toxicity). This information is based on a study from 2019 conducted by Zhu.

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

• Ramucirumab is used to treat metastatic Non-small cell lung cancer (NSCLC).
• It is given through an intravenous (IV) drip.
• The dose is 10 milligrams (mg) for every kilogram (kg) of the patient's body weight.
• This treatment is administered on day 1 of every 21-day cycle.
• Ramucirumab is used in combination with another chemotherapy drug called docetaxel.
• Continue giving ramucirumab until the cancer gets worse (disease progression) or if the patient experiences severe side effects that make the treatment too risky (unacceptable toxicity).

Cyramza (Ramucirumab) dose in Childrens

Not recommended for use in children

Ramucirumab (Cyramza) Pregnancy Risk Category: C

• Ramucirumab works by blocking angiogenesis, a process that is crucial for the development of human fetuses (unborn babies).
• Because of how it works, ramucirumab could potentially harm a developing fetus if it is given to a pregnant woman.
• Therefore, it is essential to confirm whether a female of reproductive age is pregnant before starting ramucirumab treatment.
• Females who can become pregnant should use effective birth control methods while receiving ramucirumab and for at least 3 months after their last dose to prevent pregnancy.
• Ramucirumab might also affect the ability of females to have children in the future (impair fertility).

These precautions are important to minimize the risk of harm to a developing fetus and to ensure the safety of female patients who may receive ramucirumab treatment.

Ramucirumab can be used during breastfeeding

• It is uncertain whether ramucirumab is present in breast milk.
• Immunoglobulins, which ramucirumab is a type of, can be found in breast milk, and it is possible that ramucirumab may also be present.
• Because of the potential for serious side effects in a breastfed infant, the manufacturer recommends against breastfeeding while receiving ramucirumab treatment.
• It is advisable for mothers to avoid breastfeeding during the course of ramucirumab treatment and for at least 2 months after their last dose.

This caution is important to protect the health of the infant, as the effects of ramucirumab on breastfed babies are not well understood, and there may be potential risks associated with exposure through breast milk.

Cyramza (Ramucirumab) dose in Renal disease:

• No dosage adjustment required.

Cyramza (Ramucirumab) dose in Liver disease:

• For individuals with mild or moderate impairment in liver function, which is determined by measuring bilirubin and AST levels, no changes in the dosage of ramucirumab are necessary. This means that the standard dosing can be used in these cases.
• For individuals with severe impairment in liver function, characterized by significantly elevated bilirubin levels (greater than 3 times the upper limit of normal, ULN) along with any elevation in AST levels, the manufacturer's labeling does not provide specific dosage adjustments. This is because such patients have not been extensively studied in clinical trials.
• In cases of severe liver impairment, the decision to use ramucirumab should be carefully considered. It should only be used in patients with Child-Pugh class B or C cirrhosis if the potential benefits of the treatment are believed to outweigh the potential risks. Child-Pugh scoring is a system used to assess the severity of cirrhosis, with class B and C indicating more advanced liver disease.

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:

• In the United States, the manufacturer's labeling for ramucirumab does not list any specific contraindications, which are situations or conditions where the use of the medication is strictly prohibited.
• In the Canadian labeling for ramucirumab, it is contraindicated in individuals who have a hypersensitivity (allergic) reaction to ramucirumab itself or to any component of the medication's formulation. This means that if a patient has a known allergy or severe sensitivity to ramucirumab or any of its ingredients, the use of ramucirumab should be avoided in Canada.

Warnings and precautions

Arterial thrombotic episodes:

• Ramucirumab can lead to serious and sometimes fatal arterial thrombotic events, which are blockages in the arteries that carry blood away from the heart.
• These events can include heart attacks (MI), cardiac arrest, strokes (cerebrovascular accidents), and reduced blood flow to the brain (cerebral ischemia).
• Some of these arterial thrombotic events can be severe, classified as grade 3 or higher in terms of severity.
• If a patient receiving ramucirumab experiences any of these arterial thrombotic events, it is crucial to discontinue the medication permanently.
• This means that the treatment with ramucirumab should be stopped immediately in such cases.

Suppression of bone marrow

• When ramucirumab is used in combination with paclitaxel, there is a greater likelihood of experiencing bone marrow suppression, which can affect the production of blood cells.
• Specifically, there is a higher incidence of two types of bone marrow suppression: neutropenia (a decrease in a type of white blood cell called neutrophils) and thrombocytopenia (a decrease in the number of platelets, which help with blood clotting).
• To monitor and manage this potential side effect, healthcare providers should regularly perform a complete blood count (CBC) with differential when ramucirumab is used in combination with paclitaxel.
• Regular monitoring of blood cell counts allows healthcare providers to detect and address any significant decreases in neutrophils or platelets, which can help prevent or manage complications associated with bone marrow suppression.

Perforation of the gastrointestinal tract:

• Ramucirumab carries a risk of causing gastrointestinal perforation, a severe and potentially life-threatening condition where there is a hole or tear in the gastrointestinal tract, such as the stomach or intestines.
• If a patient undergoing ramucirumab treatment experiences a gastrointestinal perforation, it is crucial to discontinue the medication permanently. This means that treatment with ramucirumab should be stopped immediately if this serious event occurs.
• Gastrointestinal perforation can lead to serious complications, including infection and internal bleeding. Therefore, swift action is necessary to ensure the patient's well-being.

Hemorrhage

• Hemorrhage, which is bleeding, is a known risk associated with ramucirumab treatment.
• This risk includes not only general hemorrhage but also specifically gastrointestinal hemorrhage, which involves bleeding in the digestive tract.
• Hemorrhage events can range in severity, with some being grade 3 or 4, which can be severe and even fatal.
• If a patient on ramucirumab treatment experiences serious bleeding (grade 3 or 4), it is essential to discontinue ramucirumab permanently. This means that the treatment with ramucirumab should be stopped immediately in such cases.
• Patients who are taking nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from some clinical trials involving ramucirumab. The risk of gastric hemorrhage (bleeding in the stomach) in patients with gastric tumors who are also taking NSAIDs is not well understood.
• In addition, some specific patient groups, such as those with non-small cell lung cancer who are receiving therapeutic anticoagulation, chronic NSAID use (other than aspirin), or other antiplatelet therapy, or who have certain radiographic evidence of major airway or blood vessel involvement or intratumor cavitation, were excluded from clinical studies involving ramucirumab. Therefore, the risk of pulmonary hemorrhage (bleeding in the lungs) in such patients is not well known.

Hypertension

• Ramucirumab can lead to the development or worsening of high blood pressure (hypertension), and it's important to be aware of this potential side effect.
• In some cases, hypertension can become severe while using ramucirumab.
• Before starting ramucirumab treatment, blood pressure should be well-controlled.
• During ramucirumab treatment, blood pressure should be closely monitored every 2 weeks, and more frequent checks may be necessary if there are indications of blood pressure problems.
• If a patient develops severe hypertension, the administration of ramucirumab should be temporarily stopped until their blood pressure is under control with medical intervention.
• If hypertension becomes medically significant and cannot be adequately controlled with antihypertensive medications, or if a patient experiences a hypertensive crisis or hypertensive encephalopathy (severe complications of high blood pressure), ramucirumab should be permanently discontinued.

Infusion reaction

• Ramucirumab can lead to infusion-related reactions, which can sometimes be severe. These reactions often occur with the first or second dose of the medication.
• Symptoms of infusion reactions can vary but may include chills, flushing (reddening of the skin), low blood pressure (hypotension), bronchospasm (narrowing of the airways), difficulty breathing (dyspnea), low oxygen levels (hypoxia), wheezing, chest pain or tightness, rapid heart rate (supraventricular tachycardia), back pain or muscle spasms, shivering or tremors (rigors/tremors), and tingling or numbness (paresthesia).
• To reduce the risk of infusion reactions, premedications are recommended before starting the infusion.
• Doctor’s should closely monitor patients for any signs or symptoms of infusion reactions during the infusion itself.
• If a patient experiences a grade 1 or 2 infusion reaction (mild to moderate in severity), the infusion rate may be reduced.
• However, if a grade 3 or 4 infusion reaction (severe) occurs, the infusion should be immediately and permanently discontinued.
• The administration of ramucirumab should take place in a healthcare facility equipped to manage infusion reactions, ensuring prompt and appropriate treatment if they occur.

Nephrotic syndrome/proteinuria:

• Ramucirumab use is associated with proteinuria, which is the presence of excess protein in the urine. This can include severe cases of proteinuria and even the development of nephrotic syndrome, a kidney disorder characterized by heavy proteinuria.
• To monitor for the development or worsening of proteinuria during treatment, healthcare providers should regularly assess protein levels in the urine using methods such as urine dipstick testing and/or urinary protein creatinine ratio measurement.
• If urine protein levels reach 2 grams per 24 hours or higher, treatment with ramucirumab should be temporarily withheld. Upon restarting therapy, the dose may need to be reduced.
• If urine protein levels exceed 3 grams per 24 hours or if nephrotic syndrome develops, ramucirumab should be permanently discontinued.

Reversible posterior Leukoencephalopathy Syndrome:

• Ramucirumab has been associated with cases of reversible posterior leukoencephalopathy syndrome (RPLS), a rare but potentially life-threatening neurological condition.
• Symptoms of RPLS can include severe headache, seizures, confusion, lethargy, changes in vision or blindness, and other neurological disturbances.
• To confirm the diagnosis of RPLS, magnetic resonance imaging (MRI) of the brain is typically used.
• If a patient is diagnosed with RPLS while receiving ramucirumab treatment, the medication should be permanently discontinued.
• Some individuals with RPLS may experience a resolution of their symptoms within days after discontinuing ramucirumab, but neurological issues may persist in some cases.
• RPLS is a serious condition that requires immediate medical attention and the discontinuation of ramucirumab treatment.

Thyroid dysfunction

• While using ramucirumab, some individuals may develop hypothyroidism, which is an underactive thyroid gland.
• Hypothyroidism that occurs as a result of ramucirumab treatment is typically mild to moderate in severity, graded as either grade 1 or grade 2.

Inability to heal wounds

• The use of antibodies that inhibit the vascular endothelial growth factor (VEGF) or VEGF receptor pathway, like ramucirumab, can potentially impair the normal process of wound healing.
• To minimize the risk of impaired wound healing, it is recommended to withhold ramucirumab for 28 days before scheduled elective surgery.
• Additionally, after a major surgical procedure, ramucirumab should be withheld for at least 28 days, and treatment should not resume until the wound is fully healed.
• If a patient develops complications related to wound healing that require medical intervention, ramucirumab treatment should be permanently discontinued.
• It's important to note that ramucirumab has not been studied in patients with serious or nonhealing wounds, so the potential risks in such cases are not well understood.

Hepatic impairment

• Patients with hepatic impairment, specifically those with more severe liver disease classified as Child-Pugh class B or C cirrhosis, have experienced clinical deterioration while receiving ramucirumab.
• This deterioration may include the onset or worsening of conditions such as encephalopathy (brain dysfunction), ascites (fluid buildup in the abdomen), or hepatorenal syndrome (kidney dysfunction associated with liver disease).
• Ramucirumab should be used cautiously in patients with Child-Pugh class B or C cirrhosis, and its use in such cases should be determined based on a careful evaluation of the potential benefits versus the potential risks.
• Clinical trial data for the treatment of hepatocellular carcinoma showed that the combined incidence of hepatic encephalopathy and hepatorenal syndrome was higher in patients with Child-Pugh class A liver cirrhosis who received ramucirumab compared to those who received a placebo.

Ramucirumab: Drug Interaction

Risk Factor C (Monitor therapy)
Bisphosphonate Derivatives	Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased.

Monitor:

Liver Function Tests:

• Regularly assess liver function to monitor for any abnormalities.

Urine Protein:

• Check for excess protein in the urine using urine dipstick and/or urinary protein creatinine ratio measurements.

Thyroid Function:

• Monitor thyroid function to ensure it stays within normal levels.

CBC with Differential (in Combination Chemotherapy):

• For patients receiving combination chemotherapy, check complete blood counts, including different types of blood cells.

Pregnancy Status (Females of Reproductive Potential):

• Verify if female patients can become pregnant before starting treatment.

Blood Pressure:

• Monitor blood pressure every 2 weeks during treatment, or more frequently if needed.

Infusion-Related Reactions:

• Watch for signs and symptoms of infusion-related reactions during the infusion process.

Arterial Thromboembolic Events:

• Be vigilant for signs and symptoms of arterial blood clots.

Bleeding/Hemorrhage:

• Be alert to any signs of bleeding or hemorrhage.

Gastrointestinal Perforation:

• Monitor for any symptoms that might indicate a hole or tear in the gastrointestinal tract.

Wound Healing Impairment:

• Pay attention to wound healing, especially around surgical procedures.

Reversible Posterior Leukoencephalopathy Syndrome:

• Watch for symptoms of reversible posterior leukoencephalopathy syndrome, a rare neurological condition.

How to administer Ramucirumab (Cyramza)?

Premedication Before Infusion:

• Before starting the infusion of ramucirumab, premedicate the patient with an IV H antagonist (e.g., diphenhydramine).
• For patients who previously experienced a grade 1 or 2 infusion reaction with a prior infusion of ramucirumab, also premedicate with dexamethasone (or an equivalent steroid) and acetaminophen.

Infusion Process:

• Administer ramucirumab intravenously (IV) over a period of 60 minutes.
• Use a separate infusion line with an infusion pump for this purpose.
• It's recommended to use a 0.22-micron protein sparing filter during the infusion.
• Do not administer ramucirumab as an IV push or bolus.
• After completing the infusion, flush the IV line with normal saline (NS).

Infusion Compatibility:

• Do not infuse ramucirumab in the same IV line with solutions other than normal saline (NS).
• Avoid infusing it with electrolytes or other medications to prevent potential interactions.

Monitoring and Reaction Management:

• Continuously monitor the patient during the infusion for any signs of an infusion reaction.
• In the case of a grade 1 or 2 infusion reaction, reduce the infusion rate by 50%.
• If a grade 3 or 4 infusion reaction occurs, discontinue ramucirumab permanently.

Combination Therapy:

• When administering ramucirumab in combination with other medications like docetaxel, paclitaxel, or FOLFIRI, administer ramucirumab before these other agents.

Mechanism of action of Ramucirumab (Cyramza):

• Ramucirumab is a type of medication made through genetic engineering, known as a recombinant monoclonal antibody.
• It works by targeting and inhibiting a specific protein called vascular endothelial growth factor receptor 2 (VEGFR2).
• Ramucirumab has a strong attraction to VEGFR2, meaning it binds tightly to this protein.
• By binding to VEGFR2, ramucirumab prevents other substances in the body, such as VEGF-A, VEGF-C, and VEGF-D, from attaching to and activating VEGFR2.
• This interference with VEGFR2 activation inhibits the natural processes of cell growth and movement (proliferation and migration) in the lining of blood vessels, called endothelial cells.
• Ultimately, by blocking these processes, ramucirumab reduces the development of new blood vessels within tumors (tumor vascularity) and slows down the growth of tumors.

Half-life elimination:

• The half-life elimination of ramucirumab is approximately 14 days.
• This means that it takes about 14 days for half of the administered dose of ramucirumab to be eliminated from the body.

Distribution:

• The distribution volume (V) of ramucirumab is approximately 5.4 liters.
• This parameter provides information about how the medication is distributed throughout the body.

Excretion:

• The clearance of ramucirumab is approximately 0.015 liters per hour. Clearance is a measure of how quickly the body removes a substance, in this case, ramucirumab, from the bloodstream.

International Brand of Ramucirumab:

• Cyramza

Cyramza (Ramucirumab) Brands in Pakistan:

Not available.