CYRAMZA

Eli Lilly and Company

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use CYRAMZA safely and effectively. See full prescribing information for CYRAMZA.CYRAMZA (ramucirumab) injection, for intravenous infusionInitial U.S. Approval: 2014 BOXED WARNING WARNING: HEMORRHAGE See full prescribing information for complete boxed warning. CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. INDICATIONS AND USAGECYRAMZATM is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist indicated for the treatment of: Gastric Cancer Advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine- or platinum-containing chemotherapy. (1.1) DOSAGE AND ADMINISTRATION Administer 8 mg/kg intravenously every 2 weeks. (2.1, 2.2, 2.5) For intravenous infusion only. Do not administer as an intravenous push or bolus. (2.1, 2.5) DOSAGE FORMS AND STRENGTHS 100 mg/10 mL (10 mg per mL) solution, single-dose vial (3) 500 mg/50 mL (10 mg per mL) solution, single-dose vial (3) CONTRAINDICATIONSNone WARNINGS AND PRECAUTIONS Arterial Thromboembolic Events (ATEs): Serious, sometimes fatal ATEs have been reported in clinical trials. Discontinue CYRAMZA for severe ATEs. (5.2) Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend CYRAMZA for severe hypertension. Discontinue CYRAMZA for hypertension that cannot be medically controlled. (5.3) Infusion Related Reactions: Monitor for signs and symptoms during infusion. (5.4) Gastrointestinal perforation: Discontinue CYRAMZA. (5.5) Impaired Wound Healing: Withhold CYRAMZA prior to surgery. (5.6) Clinical Deterioration in Patients with Cirrhosis: New onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. (5.7) Reversible Posterior Leukoencephalopathy Syndrome: Discontinue CYRAMZA. (5.8) Side EffectsThe most common adverse reactions observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Pregnancy: Based on its mechanism of action, CYRAMZA may cause fetal harm. (8.1) Nursing Mothers: Discontinue nursing or discontinue CYRAMZA. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: HEMORRHAGE
• 1 CYRAMZA INDICATIONS AND USAGE
  • 1.1 Gastric Cancer
• 2 CYRAMZA DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dose and Schedule
  • 2.2 Premedication
  • 2.3 Dose Modifications
  • 2.4 Preparation for Administration
  • 2.5 Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 CYRAMZA CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hemorrhage
  • 5.2 Arterial Thromboembolic Events
  • 5.3 Hypertension
  • 5.4 Infusion Related Reactions
  • 5.5 Gastrointestinal Perforations
  • 5.6 Impaired Wound Healing
  • 5.7 Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis
  • 5.8 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
• 6 CYRAMZA ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Immunogenicity
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
  • 8.8 Females and Males of Reproductive Potential
• 10 OVERDOSAGE
• 11 CYRAMZA DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
  • 14.1 Gastric Cancer
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Gastric Cancer

CYRAMZA^TM as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

• The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Do not administer CYRAMZA as an intravenous push or bolus.

2.2 Premedication

• Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H₁ antagonist (e.g., diphenhydramine hydrochloride).
• For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion [see Dosage and Administration (2.3)].

2.3 Dose Modifications

Infusion Related Reactions (IRR)

• Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs.
• Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].

Hypertension

• Interrupt CYRAMZA for severe hypertension until controlled with medical management.
• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy [see Warnings and Precautions (5.3)].

Proteinuria

• Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.
• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome [see Adverse Reactions (6.1)].

Wound Healing Complications

• Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed [see Warnings and Precautions (5.6)].

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding

• Permanently discontinue CYRAMZA [see Warnings and Precautions (5.1, 5.2, 5.5)].

2.4 Preparation for Administration

Inspect vial contents for particulate matter and discoloration prior to dilution [see Description (11)]. Discard the vial, if particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light.

• Calculate the dose and the required volume of CYRAMZA needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of CYRAMZA.
• 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.
• Gently invert the container to ensure adequate mixing.
• DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications.
• Store diluted infusion 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 [77°F]).
• Discard vial with any unused portion of CYRAMZA.

2.5 Administration

Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution.

Administer diluted CYRAMZA infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.

3 DOSAGE FORMS AND STRENGTHS

• 100 mg/10 mL (10 mg per mL) solution, single-dose vial
• 500 mg/50 mL (10 mg per mL) solution, single-dose vial

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; 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 bleeding [see Dosage and Administration (2.3)].

5.2 Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE [see Dosage and Administration (2.3)].

5.3 Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%).

Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment.

Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.3)].

5.4 Infusion Related Reactions

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (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.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs [see Dosage and Administration (2.3)].

5.5 Gastrointestinal Perforations

CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.3)].

5.6 Impaired Wound Healing

CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing.

Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed [see Dosage and Administration (2.3)].

5.7 Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis

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.

5.8 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and 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.

6 ADVERSE REACTIONS

The following adverse drug reactions are discussed in greater detail in other sections of the label:

• Hemorrhage [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
• Arterial Thromboembolic Events [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
• Hypertension [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].
• Infusion Related Reactions [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].
• Gastrointestinal Perforation [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)].
• Impaired Wound Healing [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)].
• Patients with Child-Pugh B or C Cirrhosis [see Warnings and Precautions (5.7)].
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)].

6.1 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 safety of CYRAMZA as a single agent was evaluated in 570 patients, including patients in Study 1 who received CYRAMZA. Study 1 randomized patients (2:1) to receive CYRAMZA 8 mg/kg intravenously every two weeks (n=236) versus placebo every two weeks (n=115) in a double-blind, placebo-controlled trial in previously treated gastric cancer.

In Study 1, patients with an ECOG performance status of 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 excluded. Patients received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, 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. The most common serious adverse events 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.

Table 1 provides the frequency and severity of adverse reactions in Study 1.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo) [see Dosage and Administration (2.3) and Warnings and Precautions (5.1, 5.2)].

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 infusion related reactions.

In Study 1, 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 Study 1 was 0.8% and the rate of infusion related reactions was 0.4% [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.4, 5.5)].

6.2 Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZA-treated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

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.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data

No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal 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.

8.3 Nursing Mothers

It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA's impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 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, 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.

8.5 Geriatric Use

Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over [see Clinical Studies (14.1)].

8.6 Renal Impairment

No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

8.7 Hepatic Impairment

No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab [see Warnings and Precautions (5.7)].

8.8 Females and Males of Reproductive Potential

Fertility

Advise females of reproductive potential that CYRAMZA may impair fertility [see Nonclinical Toxicology (13.1)].

Contraception

Based on its mechanism of action, CYRAMZA may cause fetal harm [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

10 OVERDOSAGE

There is no data on overdose in humans. CYRAMZA was administered at doses up to 10 mg/kg every two weeks without reaching a maximum tolerated dose.

11 DESCRIPTION

CYRAMZA (ramucirumab) is a recombinant human IgG1 monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2. CYRAMZA has an approximate molecular weight of 147 kDa. CYRAMZA is produced in genetically engineered mammalian NS0 cells.

CYRAMZA is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion following dilution and preparation. CYRAMZA is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-dose vials. CYRAMZA is formulated in glycine (9.98 mg/mL), histidine (0.65 mg/mL), histidine monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 mg/mL), sodium chloride (4.383 mg/mL), and Water for Injection, USP, pH 6.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

12.3 Pharmacokinetics

With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastroesophageal cancer, the geometric means of the minimum ramucirumab concentrations (C_min) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

13.2 Animal Toxicology and/or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred with doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single-agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single-agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

14 CLINICAL STUDIES

14.1 Gastric Cancer

Study 1 was a multinational, randomized, double-blind, multicenter study of CYRAMZA plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received either an intravenous infusion of CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ).

Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the 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 adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy 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 fluoropyrimidine (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.

Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA as compared to patients randomized to receive placebo. Efficacy results are shown in Table 2 and Figure 1.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

CYRAMZA is supplied in single-dose vials as a sterile, preservative-free solution.

• NDC 0002-7669-01
  100 mg/10 mL (10 mg/mL), individually packaged in a carton
• NDC 0002-7678-01
  500 mg/50 mL (10 mg/mL), individually packaged in a carton

16.2 Storage and Handling

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial.

For product diluted in 0.9% sodium chloride, the chemical and physical stability have been demonstrated for up to 24 hours at 2°C to 8°C (36°F to 46°F) or for 4 hours at room temperature (below 25°C [77°F]). DO NOT FREEZE OR SHAKE the diluted product.

17 PATIENT COUNSELING INFORMATION

Advise patients:

• That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness [see Warnings and Precautions (5.1)].
• Of increased risk of an arterial thromboembolic event [see Warnings and Precautions (5.2)].
• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.3)].
• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.5)].
• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions (5.6)].
• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA [see Use in Specific Populations (8.1, 8.8)].
• To discontinue nursing during CYRAMZA treatment [see Use in Specific Populations (8.3)].

Literature issued April 21, 2014

Eli Lilly and Company, Indianapolis, IN 46285, USA

Copyright © 2014, Eli Lilly and Company. All rights reserved.

PA000IPAM00

PACKAGE LABELING

This section contains a representative sample of product package labeling. Product may be manufactured at other manufacturing sites.

PACKAGE CARTON –CYRAMZA 100 mg/10 mL single-use vial.

NDC 0002-7669-01

Cyramza^TM

(ramucirumab)

Injection

100 mg/10 mL

(10 mg/mL)

For Intravenous Infusion Only

Must Dilute Prior to Use

Single-Dose Vial

Discard Unused Portion

Keep Refrigerated

Rx only

www.lilly.com

Lilly