IMPORTANT SAFETY INFORMATION FOR CYRAMZA® (ramucirumab)
Warnings and Precautions
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%.
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 VEGFR2 antagonist, 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.
Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs 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 IRRs occurred between <1-9%. Grade 3-5 IRRs incidence was <1%.
Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Premedicate prior to each CYRAMZA infusion. Reduce the infusion rate by 50% for Grade 1-2 IRRs. Permanently discontinue CYRAMZA for Grade 3-4 IRRs.
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%).
Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA.
Confirm the diagnosis of RPLS with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS 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 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams 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 1-2 hypothyroidism 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 VEGFR2 to 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 2 months after the last dose.
Most Common Adverse Reactions—CYRAMZA Administered as a Single Agent (REACH-2)
The most commonly reported adverse reactions (all Grades; Grade ≥3) occurring in ≥10% of patients receiving CYRAMZA and ≥2% higher than placebo in REACH-2 were fatigue (36% vs 20%; 5% vs 3%), peripheral edema (25% vs 14%; 2% vs 0%), hypertension (25% vs 13%; 13% vs 5%), abdominal pain (25% vs 16%; 2% vs 2%), decreased appetite (23% vs 20%; 2% vs 1%), proteinuria (20% vs 4%; 2% vs 0%), nausea (19% vs 12%; 0% vs 0%), ascites (18% vs 7%; 4% vs 1%), headache (14% vs 5%; 0% vs 1%), epistaxis (14% vs 3%; <1% vs 0%), insomnia (11% vs 6%; 0% vs 1%), pyrexia (10% vs 3%; 0% vs 0%), vomiting (10% vs 7%; 0% vs 0%), and back pain (10% vs 7%; <1% vs 1%). The most common laboratory abnormalities (all Grades; Grade ≥3) occurring in ≥15% of patients receiving CYRAMZA and ≥2% higher than placebo were thrombocytopenia (46% vs 15%; 8% vs 1%), hypoalbuminemia (33% vs 16%; <1% vs 0%), hyponatremia (32% vs 25%; 16% vs 5%), neutropenia (24% vs 12%; 8% vs 3%), and hypocalcemia (16% vs 5%; 2% vs 0%).
The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).
Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%).
Clinically relevant adverse reactions reported in ≥1% and <10% of CYRAMZA-treated patients in REACH-2 were IRRs (9%), hepatic encephalopathy (5%) including 1 fatal event, and hepatorenal syndrome (2%) including 1 fatal event.