Ramucirumab

Ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist indicated:

• As a single agent or in combination with paclitaxel, for treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
• In combination with erlotinib, for first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.
• In combination with docetaxel, for treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Ramucirumab.
• In combination with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
• As a single agent, for the treatment of hepatocellular carcinoma in patients who have an alpha-fetoprotein of ≥400 ng/mL and have been treated with sorafenib.

Ramucirumab is a VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

For intravenous infusion only. Do not administer as an intravenous push or bolus. Premedicate before each infusion.

• Gastric Cancer: Administer Ramucirumab 8 mg/kg every 2 weeks as a single agent or in combination with weekly paclitaxel.
• Non-Small Cell Lung Cancer: Administer Ramucirumab 10 mg/kg every 2 weeks with daily erlotinib. Administer Ramucirumab 10 mg/kg on Day 1 of a 21-day cycle prior to docetaxel.
• Colorectal Cancer: Administer Ramucirumab 8 mg/kg every 2 weeks prior to FOLFIRI.
• Hepatocellular Carcinoma: Administer Ramucirumab 8 mg/kg every 2 weeks.

The most common adverse reactions observed in single agent Ramucirumab-treated gastric cancer patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea.

The most common adverse reactions observed in patients treated with Ramucirumab with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis.

The most common adverse reactions observed in patients treated with Ramucirumab with erlotinib at a rate of ≥30% and ≥2% higher than placebo with erlotinib were, infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities at a rate of ≥30% and ≥2% higher difference in incidence between arms were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia.

The most common adverse reactions observed in patients treated with Ramucirumab with docetaxel at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

The most common adverse reactions observed in patients treated with Ramucirumab with FOLFIRI at a rate of ≥30% and ≥2% higher than placebo with FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis.

The most common adverse reactions observed in single agent Ramucirumab-treated HCC patients at a rate of ≥15% and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities at a rate of ≥30% and a ≥2% higher difference in incidence between arms were thrombocytopenia, hypoalbuminemia, and hyponatremia.

Based on its mechanism of action, Ramucirumab can cause fetal harm when administered to a pregnant woman. There are no available data on Ramucirumab use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with Ramucirumab and for 2 months after the last dose.

Hemorrhage: Ramucirumab increases the risk of hemorrhage and gastrointestinal hemorrhage, including severe and fatal events. Permanently discontinue Ramucirumab in patients who experience severe bleeding.

Gastrointestinal Perforations: Ramucirumab increases the risk of gastrointestinal perforation, which can be fatal. Permanently discontinue Ramucirumab in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Withhold Ramucirumab for 28 days prior to elective surgery. Do not administer Ramucirumab for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of Ramucirumab after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events (ATEs): Serious and sometimes fatal ATEs can occur with Ramucirumab. Permanently discontinue Ramucirumab in patients who experience an ATE.

Hypertension: Monitor blood pressure and treat hypertension. Withhold Ramucirumab for severe hypertension. Permanently discontinue Ramucirumab for hypertension that cannot be controlled with antihypertensive therapy and for hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRR): Monitor for signs and symptoms during infusion. Reduce the infusion rate for Grade 1 or 2 IRR and permanently discontinue for Grade 3 or 4 IRR.

Worsening of Pre-existing Hepatic Impairment: New onset or worsening encephalopathy, ascites or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis.

Posterior Reversible Encephalopathy Syndrome: Permanently discontinue Ramucirumab.

Proteinuria Including Nephrotic Syndrome: Monitor for proteinuria. Withhold Ramucirumab for urine protein levels greater than or equal to 2 g per 24 hours. Permanently discontinue Ramucirumab for urine protein levels greater than 3 g per 24 hours or nephrotic syndrome.

Thyroid Dysfunction: Monitor thyroid function during treatment.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Cytotoxic Chemotherapy

Store vials in a refrigerator at 2°C to 8°C in the original carton to protect from light until time of use. Do not freeze or shake the vial.