What Is Ramucirumab (Cyramza)? FDA Approval, Licensing in Türkiye, and Reimbursement

• FDA-approved: Yes (first approved in 2014)
• Brand name: Cyramza
• Active ingredient: Ramucirumab
• Route of administration: Intravenous (IV) infusion
• Class: Monoclonal antibody, anti-VEGFR antibody
• Category: Targeted agent, antiangiogenic agent
• Manufacturer: Eli Lilly
• Distribution in Türkiye: None. Obtained from abroad
• Cancers for which it is approved:
  • Advanced metastatic colorectal cancer (combined with FOLFIRI)
  • Metastatic gastric or gastroesophageal junction adenocarcinoma
  • Metastatic non-small cell lung cancer (NSCLC, EGFR mutation-positive)
  • Hepatocellular carcinoma (HCC)

What Is Ramucirumab? How Does It Work?

Ramucirumab is a fully human IgG1 monoclonal antibody that binds to VEGFR-2 (vascular endothelial growth factor receptor 2). By blocking VEGF-A, VEGF-C, and VEGF-D ligands from binding to this receptor, it suppresses tumor angiogenesis (new blood vessel formation). This limits tumor cells’ ability to form blood vessels, suppressing new vessel formation in both primary and metastatic tumors. It also reduces tumor vascular permeability, lowering pressure within the tumor and potentially increasing intratumoral blood flow.

FDA (US Food and Drug Administration) Approval History:

• 21 April 2014: The FDA approved Cyramza for stomach cancer treatment.
• 5 November 2014: The FDA approved Cyramza with paclitaxel for advanced stomach cancer after prior chemotherapy.
• 12 December 2014: The FDA approved Cyramza for treating aggressive non-small cell lung cancer (NSCLC).
• 24 April 2015: The FDA approved Cyramza with FOLFIRI for second-line treatment of metastatic colorectal cancer.
• 13 May 2019: The FDA approved Cyramza for hepatocellular carcinoma (HCC) as the first FDA-approved biomarker-based treatment.
• 29 May 2020: The FDA approved Cyramza as first-line treatment for metastatic EGFR-mutated non-small cell lung cancer.

Licensing in Türkiye:

Cyramza, containing ramucirumab, has been licensed by the Republic of Türkiye Ministry of Health.

When its use is required, an application for off-label approval must be submitted to the Ministry. If approved, the drug may be obtained through the Turkish Pharmacists’ Association (TEB).

Is It Reimbursed?

It is not considered within the Social Security Institution (SGK) reimbursement scheme in Türkiye.

Price: as of August 2025, Cyramza 100 mg 2x10 ml vials cost 28.265.24 TL. 

Resistance Mechanism:

Resistance mechanisms to ramucirumab include:

• Increased activation and/or regulation of proangiogenic factors (e.g., bFGF and HGF).
• Migration of bone marrow-derived cells into the tumor microenvironment, bypassing VEGF signaling and restarting new vessel formation and angiogenesis.

Absorption:

Ramucirumab absorption has not been clearly characterized.

Distribution:

Ramucirumab distribution in the body has not been fully characterized. The time to steady state is approximately 28 days.

Metabolism:

Ramucirumab metabolism has not been comprehensively characterized. Mean drug clearance is similar in patients with stomach cancer, NSCLC, and metastatic colorectal cancer (mCRC), and the mean half-life is approximately 15 days.

Dose Range:

• Metastatic colorectal cancer: recommended dose of 8 mg/kg IV every 2 weeks with FOLFIRI.
• Advanced gastric or gastroesophageal junction adenocarcinoma: recommended dose of 8 mg/kg IV every 2 weeks.
• Non-small cell lung cancer (NSCLC): recommended dose of 10 mg/kg IV every 3 weeks with docetaxel.
• EGFR mutation-positive NSCLC: recommended dose of 10 mg/kg IV every 2 weeks with erlotinib.
• Hepatocellular carcinoma (HCC, liver cancer): recommended dose of 8 mg/kg IV every 2 weeks.

Drug Interactions:

Not yet well characterized.

Situations Requiring Caution:

1. Serious, sometimes fatal arterial thromboembolic events (myocardial infarction, stroke, or cerebral ischemia) may occur. Treatment must be permanently discontinued if these events occur.
2. Ramucirumab increases the risk of hemorrhagic events, including severe bleeding. Particular caution is required in gastric cancer patients treated with NSAIDs. NSAID use was excluded in these patients, so the risk is not fully known.
3. Ramucirumab increases hypertension risk. Blood pressure must be closely monitored and controlled, particularly during treatment.
4. Infusion-related symptoms such as fever, chills, headache, and fatigue may occur frequently. Drugs such as paracetamol or diphenhydramine may be used if these symptoms occur.
5. Gastrointestinal perforation (a hole in the digestive tract) may occur; treatment must be stopped immediately if it does.
6. Inhibition of the VEGF signaling pathway may impair wound healing. Treatment should not be restarted until healing is complete.
7. Clinical deterioration may occur in patients with liver impairment. Caution is required in patients with Child-Pugh class B and C cirrhosis.
8. Use cautiously in patients with kidney disease. Proteinuria and nephrotic syndrome have been reported. Treatment must be stopped if urinary protein exceeds certain levels.
9. Thyroid function should be monitored regularly.
10. No dose adjustment is required for mild or moderate kidney impairment.
11. No dose adjustment is required for mild or moderate liver impairment. However, caution and consideration of increased toxicity are necessary in severe liver impairment.
12. Its pregnancy category is B.

Adverse Effects:

From most to least common, adverse effects include:

1. Hypertension (20-30%); more severe hypertension may occur in 8-15%.
2. Bleeding complications (including nosebleeds, gastrointestinal bleeding, and severe bleeding).
3. Fatigue and headache.
4. Nausea, vomiting, loss of appetite, abdominal pain, and diarrhea.
5. Gastrointestinal perforation and wound-healing complications.
6. Proteinuria with nephrotic syndrome.
7. Infusion-related symptoms (fever, chills, flushing, and headache).
8. Arterial and venous thromboembolic events (myocardial infarction and stroke).
9. Hypothyroidism.
10. RPLS (reversible posterior leukoencephalopathy syndrome): rare (less than 0.1%), presenting with symptoms such as headache, seizures, and altered consciousness.