39/15 PRODUCT DETAILS 

Drug Name-                PORTAZZA

Active Ingredient-        Necitumumab

 Approved date         11/16/2015                                                                                       

FDA approved use-  to  treat patients with advanced (metastatic) squamous non-                                            small cell lung cancer (NSCLC) who have not previously                                                  received   medication for treating their advanced lung cancer

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use PORTRAZZA safely and effectively.

See full prescribing information for PORTRAZZA. PORTRAZZA (necitumumab) injection, for intravenous use

Initial U.S. Approval: 2015

WARNING: CARDIOPULMONARY ARREST and HYPOMAGNESEMIA See full prescription information for complete boxed warning

• Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with PORTRAZZA in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after PORTRAZZA administration.

 • Hypomagnesemia occurred in 83% of patients receiving PORTRAZZA in combination with gemcitabine and cisplatin, and was severe in 20%.

Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of PORTRAZZA during treatment and for at least 8 weeks following completion of PORTRAZZA. Withhold PORTRAZZA for Grade 3 or 4 electrolyte abnormalities. Replete electrolytes as medically appropriate.

INDICATIONS AND USAGE --

 PORTRAZZA™ is an epidermal growth factor receptor (EGFR) antagonist indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

 Limitation of Use: PORTRAZZA is not indicated for treatment of non-squamous non-small cell lung cancer. 

ADVERSE REACTIONS-

 The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of =30% and =2% higher than gemcitabine and cisplatin alone arm were rash and hypomagnesemia. 

CONTRAINDICATIONS -

 None

WARNINGS AND PRECAUTIONS-

 • Cardiopulmonary Arrest: Closely monitor serum electrolytes during and after PORTRAZZA.

 • Hypomagnesemia: Monitor prior to each infusion and for at least 8 weeks following the completion of PORTRAZZA. Withhold PORTRAZZA for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of PORTRAZZA may be administered in these patients once electrolyte abnormalities have improved to Grade =2. Replete electrolytes as necessary.

 • Venous and Arterial Thromboembolic Events (VTE and ATE): Discontinue PORTRAZZA for severe VTE or ATE. 

• Dermatologic Toxicities: Monitor for dermatologic toxicities and withhold or discontinue PORTRAZZA for severe toxicity. Limit sun exposure.

 • Infusion-Related Reactions: Monitor for signs and symptoms during and following infusion. Discontinue PORTRAZZA for severe reactions.

 • Increased Toxicity: Non-Squamous NSCLC -Increased toxicity and increased mortality.

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. -

DOSAGE AND ADMINISTRATION-

 Recommended dose of PORTRAZZA is 800 mg (absolute dose) as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle.

DOSAGE FORMS AND STRENGTHS-

 Injection: 800 mg/50 mL (16 mg/mL) solution in a single-dose vial. 

PATIENT COUNSELING INFORMATION -

 Hypomagnesemia -                                                                                                     Advise patients of risk of decreased blood levels of magnesium, potassium and calcium.

Take medicines to replace the electrolytes exactly as advised by the physician. [see

 Venous and Arterial Thromboembolic Events -                                                            Advise patients of increased risk of venous and arterial thromboembolic events

Skin reactions Advise patients to minimize sun exposure with protective clothing and use of sunscreen while receiving PORTRAZZA 

Infusion-Related Reactions -                                                                                        Advise patients to report signs and symptoms of infusion reactions such as fever, chills, or breathing problems 

Embryo-Fetal Toxicity -                                                                                                     Advise pregnant women of the potential risk to a fetus

Advise females of reproductive potential to use effective contraception during treatment with PORTRAZZA and for three months following final dose

Lactation -                                                                                                                           Advise women not to breastfeed during treatment with PORTRAZZA and for three months following the final dose

Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285 US License No. 1891 Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved. A6.0-POR-0000-USPI-YYYYMMDD

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-

Necitumumab is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands.

3. Pharmacokinetics-

 Based on population pharmacokinetic (popPK) analysis of serum concentration data from patients in clinical studies with PORTRAZZA, necitumumab exhibits dose-dependent kinetics.

Effect of Age, Body Weight, Sex and Race: Based on the popPK analysis with data obtained in 807 patients, age (range 19-84 years), sex (75% males), and race (85% Whites) have no effect on the systemic exposure of necitumumab.

Renal Impairment Patients with Renal Impairment-

PopPK analysis did not identify a correlation between necitumumab exposure and renal function as assessed by estimated creatinine clearance ranging from 11-250 mL/min.

Hepatic Impairment -                                                                                               Patients with Hepatic Impairment

 PopPK analysis did not identify a correlation between the exposure of necitumumab and hepatic function as assessed by alanine aminotransferase (ranging from 2-615 U/L), aspartate transaminase (ranging from 1.2-619 U/L) and total bilirubin (ranging from 0.1-106 µmol/L).

Drug Interactions-                                                                                                         Effect of Necitumumab on Gemcitabine and Cisplatin -                                                       In 12 patients with advanced solid tumors who received gemcitabine and cisplatin in combination with PORTRAZZA, the geometric mean dose-normalized AUC of gemcitabine was increased by 22% and Cmax increased by 63% compared to administration of gemcitabine and cisplatin alone while exposure to cisplatin was unchanged.

Effect of Gemcitabine and Cisplatin on Necitumumab -                                       Concomitant administration of gemcitabine and cisplatin had no effect on the exposure of necitumumab. Immunogenicity In Study 1, the CLtot of necitumumab was 26% higher and Css,ave was 34% lower in patients who tested positive for anti-necitumumab antibodies (ADA) post-treatment than patients who tested negative for ADA post-treatment.

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary Based on animal data and its mechanism of action, PORTRAZZA can cause fetal harm when administered to a pregnant woman [see

Clinical Pharmacology-                                                                                             Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development.

The absence of EGFR signaling has resulted in embryolethality as well as post-natal death in animals (see Data).

Advise pregnant women of the potential risk to a fetus, and the risk to postnatal development.

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. Data

Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses.

Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to be transmitted from the mother to the developing fetus.

8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, PORTRAZZA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PORTRAZZA and for three months following the final dose.

8.4 8.5 Pediatric Use The safety and effectiveness of PORTRAZZA have not been established in pediatric patients. Geriatric Use Of the 545 patients in the PORTRAZZA plus gemcitabine and cisplatin arm in Study 1, 213 (39%) were 65 years and over, while 108 (20%) were 70 years and over. In an exploratory subgroup analysis of Study 1, the hazard ratio for overall survival in patients 70 years or older was 1.03 (95% CI: 0.75, 1.42).

Of the adverse reactions listed in Table 1 [see Adverse Reactions (6.1)], there was a higher incidence (=3%) of venous thromboembolic events including pulmonary embolism in patients age 70 and over compared to those who were younger than age 70. 8.6 Renal Impairment No formal studies have been conducted to evaluate the effect of renal impairment on the exposure to necitumumab.

Renal function has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis of data from clinical trials [see Clinical Pharmacology (12.3)]

. 8.7 Hepatic Impairment No formal studies have been conducted to evaluate the effect of hepatic impairment on the exposure to necitumumab. Mild or moderate hepatic impairment has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis. No patients with severe hepatic impairment were enrolled in the clinical trials with PORTRAZZA [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There has been limited experience with PORTRAZZA overdose in human clinical trials. The highest dose of PORTRAZZA studied clinically in a human dose-escalation Phase 1 study was 1000 mg once a week and once every other week. Two out of 9 patients in the every other week cohort experienced dose-limiting toxicities (e.g., a combination of Grade 3 headache, vomiting, and nausea). There is no known antidote for PORTRAZZA overdose.