雷莫芦单抗注射液CYRAMZATM

【Function and indications】
CYRAMZATM, a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist, is indicated for the treatment of gastric cancer.
⑴ Advanced gastric cancer or gastroesophageal junction adenocarcinoma, as a single agent after previous fluoropyrimidine- or platinum-containing chemotherapy.

【Model and specifications】
⑴ 100mg/10mL (10mg per mL) solution, single-dose vial.
⑵ 500mg/50mL (10mg per mL) solution, single-dose vial.

【Usage and Dosage】
Intravenous injection, 8mg/Kg dose every 2 weeks. Do not push or bolus intravenously.

【Clinical studies】
Pre-treatment is recommended in CYRAMZA clinical trials, and 6/37 patients (16%) experienced infusion-related reactions (IRRs), including two serious events. Most of the IRRs occurred during or after the first or second CYRAMZA infusion during the trial. Symptoms of IRRs include chills/tremors, back pain/cramps, chest pain and/or tightness, chills, flushing, dyspnea, stridor, hypoxia, and paresthesias. In severe cases, symptoms include bronchospasm, supraventricular tachycardia, and hypotension.
Monitor patients for signs and symptoms of IRRs during infusions with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs
Because clinical trials are conducted in widely varying settings, adverse reaction rates observed in clinical trials cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
The safety of CYRAMZA as a single agent was evaluated in 570 patients, including patients who received CYRAMZA in Study 1. Study 1 In a double-blind, placebo-controlled trial in previously treated gastric cancer, patients were randomized (2:1) to receive CYRAMZA 8 mg/kg intravenously every two weeks (n=236) versus placebo every two weeks (n=115).
In Study 1, patients with ECOG performance status 2 or greater, bilirubin greater than or equal to 1.5 mg/dL, uncontrolled hypertension, major surgery within 28 days, or receiving chronic anti-platelet therapy other than once-daily aspirin were discharged. Patients received a median of 4 doses of CYRAMZA; median exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least 6 months.
In Study 1, the most common adverse reactions (all categories) observed in CYRAMZA-treated patients at an incidence ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and ileus (2.1%). Red blood cell transfusions were given in 11% of CYRAMZA-treated patients compared to 8.7% of patients receiving placebo.
A multinational, randomized, double-blind, multicenter study of 355 patients with locally advanced or metastatic gastric cancer (including gastroesophageal junction [GEJ] adenocarcinoma) who had previously received platinum- or fluoropyrimidine-containing chemotherapy were randomized (2:1) to CYRAMZA plus best supportive care (BSC) versus placebo plus BSC. The primary efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have received disease progression within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or 6 months after the last dose of adjuvant therapy for metastatic disease. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received either CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) intravenously every 2 weeks. Randomization was stratified by prior 3-month weight loss (≥10% vs. <10%), geographic region, and location of primary tumor (gastric vs. GEJ).
Demographics and baseline characteristics were similar between treatment arms. The median age was 60 years; 70% of patients were male; 77% were white and 16% were Asian; ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had gastroesophageal junction [GEJ] adenomas. The majority of patients (85%) experienced disease progression during or after first-line treatment for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidines (4%). In Study 1, patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.

【Precautions】
⑴ Arterial thrombotic events (ATEs): Severe, sometimes fatal ATEs have been reported in clinical trials. Discontinue CYRAMZA for severe ATEs.
⑵ Hypertension: Monitor blood pressure and treat hypertension. Withhold CYRAMZA for severe hypertension. Discontinue CYRAMZA for hypertension that cannot be controlled by medication.
⑶ Infusion-related reactions: Monitor for signs and symptoms during infusion.
⑷ Gastrointestinal perforation: Discontinue CYRAMZA.
⑸ Impairment of wound healing: Do not administer CYRAMZA prior to surgery.
⑹ Clinical deterioration in patients with cirrhosis: Patients with Child-Pugh B or C cirrhosis may develop encephalopathy, ascites, or new onset or worsening of hepatorenal syndrome.
⑺ Reversible posterior leukoencephalopathy syndrome: Discontinue CYRAMZA.

【Adverse Reactions and Contraindications】
The most common adverse reactions observed in CYRAMZA-treated patients at an incidence of ≥10% and ≥2% higher than placebo were hypertension and diarrhea.

【Contraindications】
None.

【Use in pregnant women】
⑴ Pregnancy: Based on its mechanism of action, CYRAMZA may cause fetal harm.
⑵ Breastfeeding mothers: Discontinue breastfeeding or discontinue CYRAMZA.

【Pediatric Use】
The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomic pathology revealed adverse effects on epiphyseal growth plates (thickening and osteochondrosis) at all doses tested (5-50 mg/kg). Ramucirumab exposure in cynomolgus monkeys at the lowest weekly dose tested was 0.2 times the exposure at the recommended human dose of ramucirumab as a single agent.

【Drug Interactions】
No formal drug interaction studies have been conducted.

【Storage】
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) before use. Keep vials in carton to protect from light. Do not freeze or shake vials. .
Chemical and physical stability has been demonstrated for product diluted in 0.9% sodium chloride at 2°C to 8°C (36°F to 6°F) for up to 24 hours or at room temperature (below 25°C [77°F]) for 4 hours. Do not freeze or shake the diluted product.

[Manufacturer]
Eli Lilly Pharmaceuticals, Inc.