INDICATION AND IMPORTANT SAFETY INFORMATION FOR CYRAMZA®
CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
IMPORTANT SAFETY INFORMATION FOR CYRAMZA® (ramucirumab)
Warnings and Precautions Hemorrhage
CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade >3 hemorrhagic events. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage occurred between 13-44%. Grade 3-5 hemorrhage incidence ranged from 2-5%.
Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs)were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.
Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4)bleeding.
CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.
Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing
Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.
Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 28 days following a major surgical procedure and until the wound is fully healed. Discontinue CYRAMZA in patients who develop wound healing complications that require medical intervention.
Arterial Thromboembolic Events
Serious, sometimes fatal, arterial thromboembolic events (ATEs),including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 2-3%. Grade 3-5 ATE incidence was 1-2%.
Permanently discontinue CYRAMZA in patients who experience an ATE.
An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension occurred between 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%.
Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-related reactions (IRR),including severe and life threatening IRR, occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR occurred between <1-9%. Grade 3-5 IRR incidence was <1%.
Premedicate prior to each CYRAMZA infusion Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR.
Worsening of Pre-existing Hepatic Impairment
Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.
Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%)compared to patients who received placebo (0%).
Posterior Reversible Encephalopathy Syndrome
Posterior Reversible Encephalopathy Syndrome (PRES)(also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.
Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome
Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-20%. Grade>3 proteinuria [including 4 patients with nephrotic syndrome]incidence ranged from <1-3%.
Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.
Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA.
Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.
Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2months after the last dose.
Most Common Adverse Reactions—CYRAMZA Administered as a Single Agent (REGARD)
The most commonly reported adverse reactions (all Grades; Grade 3-4)occurring in >5% of patients receiving CYRAMZA and >2% higher than placebo in REGARD were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%),headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
The most common serious adverse reactions with CYRAMZA were anemia (3.8%)and intestinal obstruction (2.1%)Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactionsreported in >1% and <5% of CYRAMZA-treated patients in REGARD were neutropenia (4.7%), epistaxis (4.7%), rash (4.2%),intestinal obstruction (2.1%),and arterial thromboembolic events (1.7%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade >3)reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRR. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRR was 0.4%.
Most Common Adverse Reactions—CYRAMZA Administered in Combination with Paclitaxel (RAINBOW)
The most commonly reported adverse reactions (all Grades; Grade >3)occurring in >5% of patients receiving CYRAMZA with paclitaxel and>2% higher than placebo with paclitaxel in RAINBOW were fatigue/asthenia (57% vs 44%; 12% vs 6%),neutropenia (54% vs 31%; 41% vs 19%),diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%),peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%),thrombocytopenia (13% vs 6%; 2% vs 2%),hypoalbuminemia (11% vs 5%; 1% vs 1%),and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
The most common serious adverse reactions in patients who received CYRAMZA with paclitaxel were neutropenia (3.7%)and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in >2% of patients in RAINBOW were neutropenia (4%)and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in >1% and <5% of patients receiving CYRAMZA with paclitaxel were sepsis (3.1%), including 5 fatal events, and gastrointestinal perforations (1.2%),including 1fatal event.