DRUG INTERACTIONS

No pharmacokinetic (PK) interactions were observed between ramucirumab and paclitaxel or between ramucirumab and docetaxel

HIGHLIGHTS OF PRESCRIBING INFORMATION

These 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 use

Initial U.S. Approval: 2014

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 

RECENT MAJOR CHANGES

Indications and Usage                                               

Gastric Cancer  11/2014                                                                                                  Non-Small Cell Lung Cancer  12/2014

Dosage and Administration: 

Recommended Dose and Schedule 12/2014                                                               Dose Modifications  12/2014

Warnings and Precautions:

Hemorrhage 12/2014                                                                                                Hypertension  12/2014                                                                                             Gastrointestinal Perforations 12/2014

INDICATIONS AND USAGE

­ CYRAMZA® is a human vascular endothelial growth factor receptor 2 antagonist indicated                                                                                                                               • as a single agent or in combination with paclitaxel, for treatment of advanced                gastric or gastro-esophageal junction adenocarcinoma, with disease progression          on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

• in combination with docetaxel, for treatment of metastatic nonsmall cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. 

DOSAGE AND ADMINISTRATION 

-­ For intravenous infusion only. Do not administer as an intravenous push or bolus.  Gastric Cancer

• The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks. 

 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  

• Of increased risk of an arterial thromboembolic event .

• 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 

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• 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 

. • 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 

• To discontinue nursing during CYRAMZA treatment 

Revised: December 2014

Eli Lilly and Company, Indianapolis, IN 46285, USA US License No. 1891 Copyright © 2014, Eli Lilly and Company. All rights reserved.

 CLINICAL PHARMACOLOGY

1.Mechanism of Action

Ramucirumab is a vascular endothelial growth factor receptor 2 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 ligandstimulated 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.

2. Pharmacokinetics

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

Similar Cmin values of ramucirumab were observed when ramucirumab was administered with paclitaxel. Based on a population PK analysis, the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%).

3.Specific Populations Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis.

Renal Impairment:                                                                                                         The effect of renal impairment on the average concentration of ramucirumab at steady state (Css) was evaluated in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n=368), moderate (CLcr 30-59 mL/min, n=160) or severe (CLcr 15 -29 mL/min, n=4) renal impairment compared to patients with normal renal function (CLcr =90 mL/min, n=360) in a population PK analysis.

No clinically meaningful differences in the average Css of ramucirumab were observed between patients with renal impairment and patients with normal renal function.

Hepatic Impairment:                                                                                                      The effect of hepatic impairment on the average Css of ramucirumab was evaluated in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN or total bilirubin >1.0-1.5 times ULN and any AST, n=143) compared to patients with normal hepatic function (total bilirubin and AST =ULN, n=735) in a population PK analysis.

No clinically meaningful differences in the average Css of ramucirumab were found between patients with mild hepatic impairment and patients with normal hepatic function.

Drug Interaction Studies                                                                                                No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when CYRAMZA 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors.

No clinically meaningful changes in docetaxel exposure were observed when CYRAMZA 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors.

Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumor

 USE IN SPECIFIC POPULATIONS

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 (VEGFR2) 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.

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.

4.Pediatric Use

The safety and effectiveness of CYRAMZA in pediatric patients have not been established

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.

5.Geriatric Use

Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 

6.Renal Impairment

No dose adjustment is recommended for patients with renal impairment based on population PK analysis [see Clinical Pharmacology (12.3)].

7.Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST) based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA 

8.Females and Males of Reproductive Potential Fertility

Advise females of reproductive potential that CYRAMZA may impair fertility

 Contraception -Based on its mechanism of action, CYRAMZA may cause fetal harm  Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

 OVERDOSAGE

There are 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.