Ramucirumab

Approved Indications:

• Gastric Cancer or Gastroesophageal Junction Adenocarcinoma (GEJ):
• As monotherapy or in combination with paclitaxel for advanced or metastatic disease after prior fluoropyrimidine- or platinum-containing therapy.
• Non-Small Cell Lung Cancer (NSCLC):
• In combination with docetaxel for metastatic NSCLC with disease progression during or after platinum-based chemotherapy.
• Colorectal Cancer (mCRC):
• In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for patients with mCRC with disease progression on or after bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing therapy.
• Hepatocellular Carcinoma (HCC):
• For patients with alpha-fetoprotein (AFP) ≥400 ng/mL who have been previously treated with sorafenib.

Clinically Accepted Off-Label Uses:

• Investigational use in combination regimens for other VEGF-expressing solid tumors (based on clinical trials and NCCN guidelines).

Adults:

• Gastric/GEJ Cancer (monotherapy):
• 8 mg/kg IV every 2 weeks.
• Gastric/GEJ Cancer (with paclitaxel):
• Ramucirumab 8 mg/kg IV on Days 1 and 15 of a 28-day cycle.
• Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of each 28-day cycle.
• NSCLC (with docetaxel):
• 10 mg/kg IV every 3 weeks, with docetaxel 75 mg/m².
• mCRC (with FOLFIRI):
• 8 mg/kg IV every 2 weeks.
• HCC:
• 8 mg/kg IV every 2 weeks.

Pediatrics:

• Safety and efficacy not established in pediatric patients.

Elderly:

• No specific dose adjustment required, but monitor closely for adverse events.

Hepatic Impairment:

• Mild hepatic impairment: No dose adjustment needed.
• Moderate to severe hepatic impairment: Use with caution; limited safety data available.

Renal Impairment:

• No specific dose adjustment; monitor closely.

Administration:

• Intravenous infusion only.
• Infuse over 60 minutes. Do not administer as IV push or bolus.
• Premedicate with an IV histamine-1 receptor antagonist prior to infusion to minimize infusion-related reactions.

Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically binds to the vascular endothelial growth factor receptor-2 (VEGFR-2), blocking the binding of all VEGF ligands (VEGF-A, VEGF-C, and VEGF-D). By inhibiting receptor activation, it prevents downstream signaling involved in angiogenesis, endothelial cell proliferation, and new blood vessel formation. This results in impaired tumor vasculature development, leading to reduced tumor growth and metastasis.

• Absorption: Not applicable (administered IV).
• Distribution: Volume of distribution: ~5.6 L.
• Metabolism: Proteolytic catabolism into small peptides and amino acids via the reticuloendothelial system.
• Elimination Half-life:
• Approx. 14 days (range: 13–15 days).
• Clearance: Decreases with increasing dose (non-linear PK); steady state achieved by second cycle.
• Excretion: Not excreted renally or hepatically in unchanged form.

• Pregnancy:
• FDA Category: Not assigned under the new PLLR rule.
• Based on mechanism of action and animal data, may cause fetal harm. Avoid use during pregnancy. Women of reproductive potential should use effective contraception during and for at least 3 months after treatment.
• Lactation:
• Unknown if excreted in human milk. Due to potential adverse effects in breastfed infants, avoid breastfeeding during treatment and for at least 3 months following the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Anti-VEGFR-2 Monoclonal Antibody (Antiangiogenic agent)

• Known hypersensitivity to Ramucirumab or any of its excipients.
• Uncontrolled hypertension.
• Recent arterial thromboembolic events.
• History of gastrointestinal perforation or fistula related to prior VEGF inhibitors (use with caution).

• Hemorrhage:
• Increased risk of severe bleeding events. Discontinue in cases of grade 3–4 bleeding.
• Gastrointestinal Perforation:
• Can be fatal. Monitor for signs; discontinue permanently if perforation occurs.
• Wound Healing Impairment:
• Suspend therapy for at least 4 weeks prior to elective surgery and resume only after adequate wound healing.
• Hypertension:
• Monitor blood pressure prior to and during therapy. Treat elevated BP; suspend treatment if severe or uncontrolled.
• Proteinuria:
• Monitor urine protein levels. Discontinue if nephrotic syndrome develops.
• Arterial Thromboembolism:
• Increased risk in older adults; discontinue if such events occur.
• Infusion Reactions:
• Premedicate with antihistamines. Interrupt or discontinue for severe reactions.
• Embryo-Fetal Toxicity:
• Advise patients on risk and need for contraception.

Common (>10%):

• Hypertension
• Diarrhea
• Fatigue
• Neutropenia (especially with combination regimens)
• Proteinuria
• Abdominal pain
• Decreased appetite
• Mucosal inflammation

Serious/Rare:

• Gastrointestinal perforation
• Arterial thromboembolic events (e.g., MI, stroke)
• Hemorrhage (pulmonary, GI, CNS)
• Nephrotic syndrome
• Infusion-related reactions
• Impaired wound healing

Timing & Dose-dependence:

• Most events are dose-dependent and may occur within the first few cycles of treatment. Cumulative toxicities possible with long-term use.

• Cytotoxic Chemotherapy:
• Increased risk of additive myelosuppression and GI toxicity when used in combination.
• Antihypertensives:
• Risk of hypotension if blood pressure rapidly decreases during management of treatment-induced hypertension.
• Live Vaccines:
• Avoid during treatment due to immunosuppressive potential.
• No CYP450-mediated metabolism:
• Not expected to affect or be affected by CYP-based interactions.

• HCC Indication:
• Expanded approval for second-line use in HCC with elevated AFP following sorafenib failure.
• EMA/FDA Guidelines:
• Emphasize use in biomarker-selected populations (e.g., high AFP in HCC) and recommend close monitoring for bleeding and thrombotic events.
• Ongoing Trials:
• Studies underway exploring new combinations with immunotherapy and novel targeted agents in gastric, lung, and colorectal cancers.

• Temperature:
• Store vials at 2°C to 8°C (36°F to 46°F). Do not freeze.
• Humidity & Light:
• Protect from light; store in original carton until use.
• Handling Precautions:
• Do not shake. Inspect for particulate matter and discoloration before use.
• Dilution & Use:
• Once diluted, infusions should be used immediately or stored at 2°C to 8°C for up to 24 hours.