Cyramza Drug Information

Premedication Prior to each

CYRAMZA infusion, premedicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion.

Recommended Dosage for Gastric Cancer

The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.

When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel. Refer to the prescribing information for paclitaxel for dosage information.

Recommended Dosage for Non-Small Cell Lung Cancer EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. Refer to the prescribing information for erlotinib for dosage information. Disease Progression On Or After Platinum-based Chemotherapy – CYRAMZA in Combination with Docetaxel The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion.

Refer to the prescribing information for docetaxel for dosage information.

Recommended Dosage for Colorectal Cancer

The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.

Dosage Modifications for Adverse Reactions

Reduce dose, withhold dose, or discontinue CYRAMZA to manage adverse reactions as described in Table 1. Table 1: Posterior Reversible Encephalopathy Syndrome (PRES)

Preparation and Administration Preparation

Visually inspect vials for particulate matter and discoloration. Discard if particulate matter or discolorations are identified. Calculate the dose and the required volume of CYRAMZA needed for the calculated dose.

Withdraw the required volume of CYRAMZA and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use dextrose containing solutions. Do not shake.

Gently invert the container to ensure adequate mixing. Do not dilute with other solutions or co-infuse with other electrolytes or medications. Do not freeze.

Store diluted solution for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C ). Discard any unused portion of CYRAMZA. Administration Visually inspect the diluted solution for particulate matter and discoloration prior to administration.

Do not administer CYRAMZA as an intravenous push or bolus. Administer diluted CYRAMZA solution via infusion pump through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended.

Flush the line with sterile 0.9% Sodium Chloride Injection at the end of the infusion.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section reflect exposure to CYRAMZA in 2137 patients from six studies: REGARD, RAINBOW, RAISE, REVEL, REACH-2, and RELAY. Gastric Cancer The safety of CYRAMZA was evaluated in REGARD and RAINBOW.

Patients in both trials had locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) and had previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Both trials excluded patients with uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin.

REGARD excluded patients with bilirubin ≥1.5 mg/dL and RAINBOW excluded patients with bilirubin >1.5 times the upper limit of normal (ULN). CYRAMZA Administered as a Single Agent (REGARD) Patients received either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. 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 versus 8.7% of patients who received placebo. The most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. Table 2 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in REGARD.

In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 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%.

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%). The most common adverse reactions (all grades) observed in patients who received CYRAMZA with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis.

Table 3 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAINBOW. Patients had previously untreated EGFR exon 19 deletion or exon 21 (L858R) substitution mutation-positive metastatic NSCLC. Patients had ECOG PS 0 or 1.

RELAY excluded patients with bilirubin greater than the ULN, central nervous system (CNS) metastases, clinically active interstitial lung disease (ILD), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months. The study also excluded patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously every two weeks in combination with erlotinib 150 mg taken orally once daily.

The most common serious adverse reactions in patients who received CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo. Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common.

The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%). The most common laboratory abnormalities ≥30% and ≥2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Table 4 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 5 provides the incidence and severity of laboratory abnormalities in RELAY.

Patients had NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease and ECOG PS 0 or 1. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, REVEL was amended and 24 patients (11 patients receiving CYRAMZA with docetaxel, 13 patients receiving placebo with docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m 2 every three weeks. The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%).

The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%). Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%).

The most common adverse reactions (all grades) observed in CYRAMZA with docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Table 6 provides the frequency and severity of adverse reactions (NCI CTCAE, version 4.0) in REVEL. Patients had mCRC with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine and ECOG PS 0 or 1.

RAISE excluded patients with uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding event; or bowel perforation. Patients received either CYRAMZA 8 mg/kg or placebo intravenously in combination with FOLFIRI intravenously every two weeks. The most common serious adverse reactions with CYRAMZA with FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI-treated patients (13%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%). Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony-stimulating factors.

Table 7 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAISE. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Hepatocellular Carcinoma The safety of CYRAMZA was evaluated in REACH-2.

Patients had Barcelona Clinic Liver Cancer (BCLC) stage B HCC who were no longer amenable to locoregional therapy, or BCLC stage C HCC, Child-Pugh score A, and baseline AFP ≥400 ng/mL. Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%). The most common adverse reactions reported in ≥15% of patients and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites.

The most common laboratory abnormalities ≥30% and ≥2% higher than placebo were thrombocytopenia, hypoalbuminemia, and hyponatremia. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system: Thrombotic microangiopathy Neoplasms benign, malignant and unspecified: Hemangioma Respiratory, thoracic, and mediastinal: Dysphonia Vascular: Arterial (including aortic) aneurysms, dissections, and rupture Cardiac: Heart failure

Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA 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.

In mice, loss of the VEGFR2 gene resulted in embryo-fetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. The safety and effectiveness of CYRAMZA were assessed but not established in a single-arm, multicenter, open-label trial that included 23 pediatric patients aged 1 year to <17 years with relapsed or refractory solid tumors who received CYRAMZA as a single agent and two multicenter, randomized, controlled trials that included 16 pediatric patients aged 1 to <17 years with relapsed, recurrent, or progressive desmoplastic small round cell tumors or synovial sarcoma who received CYRAMZA in combination with chemotherapy versus chemotherapy alone. The effect on open tibial growth plates in pediatric patients who received CYRAMZA has not been adequately studied; however, one patient had progressive widening of distal femoral growth plate.

No other new safety signals were observed in pediatric patients. The pharmacokinetic (PK) parameters for these pediatric patients who received CYRAMZA as a single agent or in combination was within the range of the values previously observed in adults given the same dose per body weight. Juvenile Animal Toxicity Data In animal studies, effects on epiphyseal growth plates were identified.

In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.