Necitumumab

Necitumumab
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING: CARDIOPULMONARY ARREST AND HYPOMAGNESEMIA See full prescribing information for complete Boxed Warning. - Cardiopulmonary arrest and/or sudden death occurred in 3.0% of patients treated with Necitumumab in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after Necitumumab administration. - Hypomagnesemia occurred in 83% of patients receiving Necitumumab in combination with gemcitabine and cisplatin, and was severe in 20% of patients. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of Necitumumab during treatment and for at least 8 weeks following completion of Necitumumab. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities. Replete electrolytes as medically appropriate.

Overview

Necitumumab is an epidermal growth factor receptor (EGFR) antagonist that is FDA approved for the treatment of patients with metastatic squamous non-small cell lung cancer (first-line treatment in combination with gemcitabine and cisplatin). There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash and hypomagnesemia (≥30%).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Squamous Non-Small Cell Lung Cancer (NSCLC) Necitumumab is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

• Limitation of Use

Necitumumab is not indicated for treatment of non-squamous non-small cell lung cancer.

Dosage

Recommended Dose and Schedule The recommended dose of Necitumumab is 800 mg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion. Continue Necitumumab until disease progression or unacceptable toxicity.

Premedication For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent Necitumumab infusions. For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each Necitumumab infusion.

Dose Modifications

• Infusion-Related Reactions (IRR)

• Reduce the infusion rate of Necitumumab by 50% for Grade 1 IRR.
• Stop the infusion for Grade 2 IRR until signs and symptoms have resolved to Grade 0 or 1; resume Necitumumab at 50% reduced rate for all subsequent infusions.
• Permanently discontinue Necitumumab for Grade 3 or 4 IRR.

• Dermatologic Toxicity

• Withhold Necitumumab for Grade 3 rash or acneiform rash until symptoms resolve to Grade ≤2, then resume Necitumumab at reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles.
• Permanently discontinue Necitumumab if:

-Grade 3 rash or acneiform rash do not resolve to Grade ≤2 within 6 weeks,

-Reactions worsen or become intolerable at a dose of 400 mg

-Patient experiences Grade 3 skin induration/fibrosis or

-Grade 4 dermatologic toxicity

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in pediatric patients.

Contraindications

None

Warnings

WARNING: CARDIOPULMONARY ARREST AND HYPOMAGNESEMIA See full prescribing information for complete Boxed Warning. - Cardiopulmonary arrest and/or sudden death occurred in 3.0% of patients treated with Necitumumab in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after Necitumumab administration. - Hypomagnesemia occurred in 83% of patients receiving Necitumumab in combination with gemcitabine and cisplatin, and was severe in 20% of patients. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of Necitumumab during treatment and for at least 8 weeks following completion of Necitumumab. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities. Replete electrolytes as medically appropriate.

Cardiopulmonary Arrest

Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Necitumumab plus gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in Study 1. Twelve of the fifteen patients died within 30 days of the last dose of Necitumumab and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in Study 1. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known.

Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium prior to each infusion of Necitumumab during treatment and after Necitumumab administration for at least 8 weeks after the last dose. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.

Hypomagnesemia

Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with Necitumumab as compared to 70% of 457/541 patients with available laboratory results treated with gemcitabine and cisplatin alone in Study 1. Hypomagnesemia was severe (Grade 3 or 4) in 20% of the patients treated with Necitumumab compared to 7% of the patients treated with gemcitabine and cisplatin alone. The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks) after initiation of Necitumumab. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion of Necitumumab during treatment and for at least 8 weeks following the completion of Necitumumab. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once hypomagnesemia and related electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.

Venous and Arterial Thromboembolic Events

Venous and arterial thromboembolic events (VTE and ATE), some fatal, were observed with Necitumumab in combination with gemcitabine and cisplatin. In Study 1, the incidence of VTE was 9% in patients receiving Necitumumab plus gemcitabine and cisplatin versus 5% in patients receiving gemcitabine and cisplatin alone and the incidence of Grade 3 or higher VTE was 5% versus 3%, respectively. The incidence of fatal VTEs was similar between arms (0.2% versus 0.2%). The most common VTEs were pulmonary embolism (5%) and deep-vein thrombosis (2%).

The incidence of ATEs of any grade was 5% versus 4% and the incidence of Grade 3 or higher ATE was 4% versus 2% in the Necitumumab containing and gemcitabine and cisplatin arms, respectively, in Study 1. The most common ATEs were cerebral stroke and ischemia (2%) and myocardial infarction (1%).

In an exploratory analysis of Study 1, the relative risk of VTE or ATE was approximately 3-fold higher in patients with a reported history of VTE or ATE than in patients with no reported history of VTE or ATE.

Discontinue Necitumumab for patients with serious or life threatening VTE or ATE.

Dermatologic Toxicities

Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculo-papular rash and erythema, occurred in 79% of patients receiving Necitumumab in Study 1. Skin toxicity was severe in 8% of patients. Skin toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset. For Grade 3 skin reactions, modify the dose of Necitumumab. Limit sun exposure.

Discontinue Necitumumab for severe (Grade 4) skin reactions, or for Grade 3 skin induration/fibrosis.

Infusion-Related Reactions

In Study 1, 1.5% of Necitumumab treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No patients received premedication for IRR for the first dose of Necitumumab in Study 1. Most IRRs occurred after the first or second administration of Necitumumab. Monitor patients during and following Necitumumab infusion for signs and symptoms of IRR. Discontinue Necitumumab for serious or life-threatening IRR.

Non-Squamous NSCLC - Increased Toxicity and Increased Mortality

Necitumumab is not indicated for the treatment of patients with non-squamous NSCLC. In a study of Necitumumab plus pemetrexed and cisplatin (PC) versus PC alone (Study 2), patients treated with Necitumumab and PC experienced more serious (51% versus 41%) and fatal toxicities (16% versus 10%) and cardiopulmonary arrest/sudden death within 30 days of the last study drug (3.3% versus 1.3%) compared to patients who received PC alone.

Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryofetal 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.

Adverse Reactions

Clinical Trials Experience

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

• Cardiopulmonary Arrest
• Hypomagnesemia
• Venous and Arterial Thromboembolic Events
• Dermatologic Toxicities
• Infusion-Related Reactions
• Non-Squamous NSCLC - Increased Toxicity and Increased Mortality

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 Necitumumab was evaluated in two randomized, open-label trials comparing Necitumumab plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and Necitumumab plus pemetrexed and cisplatin to pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2). Since the data in Study 2 demonstrated similar incidence of adverse reactions over control as observed in Study 1, the safety data from Study 1 alone is described below.

For patients who received at least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to 84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had metastatic disease in 2 or more sites. Patients received Necitumumab 800 mg intravenously on days 1 and 8 of each 21 day cycle in combination with up to six cycles of gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1). Patients received Necitumumab until progressive disease or unacceptable toxicity.

Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the Necitumumab plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of Necitumumab until disease progression or unacceptable toxicity. The median duration of exposure to Necitumumab in 538 patients who received at least 1 dose of treatment in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182 patients exposed for at least 6 months and 41 patients exposed for greater than 1 year. Patients were monitored for safety until 30 days after treatment discontinuation and resolution of treatment-emergent adverse events.

The most common adverse reactions (all grades) observed in Necitumumab-treated patients at a rate of ≥15% and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting (29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe (Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in Necitumumab-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%).

TABLE 1 contains selected adverse drug reactions observed in Study 1 at an incidence of ≥5% in the Necitumumab arm and at ≥2% higher incidence than the control arm.

• Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% All Grades or a ≥2% Grade 3-4 Difference Between Arms in Patients Receiving Necitumumab in Study 1

This image is provided by the National Library of Medicine.

PORTRAZZA: Necitumumab's Brand name

Clinically relevant adverse reactions (all grades) reported in ≥1% and <5% of patients treated with Necitumumab were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRR (1.5%).

In Study 1, 12% of the patients on the Necitumumab arm discontinued study treatment due to an adverse reaction. The most common Necitumumab related toxicity leading to Necitumumab discontinuation was skin rash (1%).

TABLE 2 contains selected electrolyte abnormalities observed in Study 1 according to laboratory assessment at an incidence of >10% in the Necitumumab arm and at >2% higher incidence than the control arm.

The median time to onset of hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received Necitumumab. In Study 1, 32% of the patients in the Necitumumab arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement.

• Table 2: Electrolyte Abnormalities according to Laboratory Assessment at Incidence Rate >10% and a >2% Difference between Arms in Patients Receiving Necitumumab in Study 1(a)

This image is provided by the National Library of Medicine.

PORTRAZZA: Necitumumab's Brand name

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to Necitumumab. No relationship was found between the presence of ADA and incidence of infusion-related reactions. The impact of ADA on efficacy (overall survival) could not be assessed due to the limited number of patients with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower in patients with ADA post-treatment than in patients without detectable ADA.

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 Necitumumab with the incidences of antibodies to other products may be misleading.

Postmarketing Experience

There is limited information regarding Necitumumab Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Necitumumab Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): N

• Risk Summary

• Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. 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. No animal reproduction studies have been conducted with necitumumab. There are no available data for Necitumumab exposure in pregnant women. 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

• Animal Data

• No animal studies have been conducted to evaluate the effect of necitumumab on reproduction and fetal development; however, based on its mechanism of action, Necitumumab can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. 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.

• In monkeys, administration of a chimeric anti-EGFR antibody that binds to an epitope overlapping that of necitumumab during the period of organogenesis resulted in detectable exposure of the antibody in the amniotic fluid and in the serum of embryos from treated dams. While no fetal malformations or other clear teratogenic effects occurred in offspring, there was an increased incidence of embryolethality and abortions.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Necitumumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Necitumumab during labor and delivery.

Nursing Mothers

There is no information regarding the presence of necitumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Necitumumab, advise a nursing woman not to breastfeed during treatment with Necitumumab and for three months following the final dose.

Pediatric Use

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

Geriatic Use

Of the 545 patients in the Necitumumab 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, 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.

Gender

There is no FDA guidance on the use of Necitumumab with respect to specific gender populations.

Race

There is no FDA guidance on the use of Necitumumab with respect to specific racial populations.

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.

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 Necitumumab.

Females of Reproductive Potential and Males

• Contraception

• Females: Based on its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.

Immunocompromised Patients

There is no FDA guidance one the use of Necitumumab in patients who are immunocompromised.

Administration and Monitoring

Administration

• Preparation

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

• Dilute the required volume of Necitumumab with 0.9% Sodium Chloride Injection, USP in an intravenous infusion container to a final volume of 250 mL. Do not use solutions containing dextrose.
• 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 medication.
• Store diluted infusion solution for no more than 24 hours at 2° to 8°C (36° to 46°F), or no more than 4 hours at room temperature (up to 25°C [77°F]).
• Discard vial with any unused portion of Necitumumab.

• Administration

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

Administer diluted Necitumumab infusion via infusion pump over 60 minutes through a separate infusion line. Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion.

Monitoring

There is limited information regarding Necitumumab Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Necitumumab and IV administrations.

Overdosage

There has been limited experience with Necitumumab overdose in human clinical trials.

The highest dose of Necitumumab 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 Necitumumab overdose.

Pharmacology

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. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR internalization and degradation in vitro. In vitro, binding of necitumumab also led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing cells.

In in vivo studies using xenograft models of human cancer, including non-small cell lung carcinoma, administration of necitumumab to implanted mice resulted in increased antitumor activity in combination with gemcitabine and cisplatin as compared to mice receiving gemcitabine and cisplatin alone.

Structure

Necitumumab is an anti-EGFR recombinant human monoclonal antibody of the IgG1 kappa isotype that specifically binds to the ligand binding site of the human EGFR. Necitumumab has an approximate molecular weight of 144.8 kDa. Necitumumab is produced in genetically engineered mammalian NS0 cells.

Necitumumab is a sterile, preservative free, clear to slightly opalescent and colorless to slightly yellow solution. Necitumumab is available in single-dose vials for intravenous infusion following dilution. Each vial contains 800 mg Necitumumab in 50 mL (16 mg/mL).

Each mL contains necitumumab (16 mg), citric acid anhydrous (0.256 mg), glycine (9.984 mg), mannitol (9.109 mg), polysorbate 80 (0.1 mg), sodium chloride (2.338 mg), sodium citrate dihydrate (2.55 mg), and water for injection, pH 6.0.

Pharmacodynamics

There is limited information regarding Necitumumab Pharmacodynamics in the drug label.

Pharmacokinetics

Based on population pharmacokinetic (popPK) analysis of serum concentration data from patients in clinical studies with Necitumumab, necitumumab exhibits dose-dependent kinetics. Following the administration of Necitumumab 800 mg on Days 1 and 8 of each 21 day cycle, the estimated mean total systemic clearance (CLtot) at steady state is 14.1 mL/h (CV=39%), the steady state volume of distribution (Vss) is 7.0 L (CV=31%) and the elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days.

Specific Populations

• 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.

• Body weight is identified as a covariate in the popPK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is necessary.

• 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 Necitumumab, 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of necitumumab for carcinogenicity or genotoxicity.

Fertility studies have not been performed with necitumumab.

Clinical Studies

Squamous Non-Small Cell Lung Cancer

Study 1 was a randomized, multi-center open-label, controlled trial conducted in 1093 patients receiving gemcitabine and cisplatin first-line chemotherapy for metastatic squamous NSCLC. Patients were randomized (1:1) to receive Necitumumab plus gemcitabine and cisplatin or gemcitabine and cisplatin alone. Stratification factors were ECOG performance status (0, 1 versus 2) and geographic region (North America, Europe, and Australia versus South America, South Africa, and India versus Eastern Asia). Gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin (75 mg/m2, Day 1) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Necitumumab (800 mg by intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered prior to gemcitabine and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus gemcitabine and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy or if chemotherapy was discontinued for toxicity.

Of the 1093 randomized patients, the median age was 62 years (range 32 to 86), 83% were male; 84% were Caucasian; and 91% were smokers. The majority of the patients (87%) were enrolled in North America, Europe and Australia, 36 patients (3%) were enrolled at clinical sites in the U.S., 6% of the patients were enrolled in South America, South Africa and India and 8% enrolled at clinical sites in Eastern Asia. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 91% had metastatic disease in 2 or more sites. In the Necitumumab plus gemcitabine and cisplatin arm, 51% of patients continued Necitumumab after completion or discontinuation of chemotherapy. Use of post-study systemic therapy was 47% in the Necitumumab plus gemcitabine and cisplatin arm, and 45% in the gemcitabine and cisplatin arm.

The main outcome measure was overall survival (OS). Investigator-assessed progression-free survival (PFS) and overall response rate (ORR) were also assessed. Overall survival and PFS were statistically significantly improved in patients randomized to receive Necitumumab plus gemcitabine and cisplatin compared to gemcitabine and cisplatin alone. There was no difference in ORR between arms, with an ORR of 31% (95% CI 27, 35) for Necitumumab plus gemcitabine and cisplatin arm and an ORR of 29% (95% CI 25, 33) for gemcitabine and cisplatin arm, p-value 0.40.

Efficacy results are shown in TABLE 3 and FIGURE 1.

• Table 3: Efficacy Results for Metastatic Squamous Non-Small Cell Lung Cancer

This image is provided by the National Library of Medicine.

PORTRAZZA: Necitumumab's Brand name

• Figure 1: Kaplan-Meier Curves of Overall Survival in Patients with Metastatic Squamous Non-Small Cell Lung Cancer

This image is provided by the National Library of Medicine.

PORTRAZZA: Necitumumab's Brand name

Non-Squamous NSCLC - Lack of Efficacy

Lack of efficacy of Necitumumab in combination with pemetrexed and cisplatin for the treatment of patients with metastatic non-squamous non-small cell lung cancer was determined in one randomized, open-label, multicenter trial (Study 2). The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the Necitumumab arm. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive Necitumumab plus pemetrexed and cisplatin or pemetrexed and cisplatin alone. Stratification factors were smoking status (non-smokers versus light smokers versus smokers), ECOG performance status (0 - 1 versus 2), histology (adenocarcinoma/large cell versus others), and geographic region. Necitumumab (800 mg, Days 1 and 8 of each 3-week cycle) was administered prior to pemetrexed and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus pemetrexed and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy.

Of the 633 patients, 315 were randomized to Necitumumab plus pemetrexed and cisplatin arm and 318 in the pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93% were Caucasian and 94% had ECOG PS 0 or 1. More than 75% were smokers and 89% had adenocarcinoma histology.

The main efficacy outcome was OS. Progression-free survival and ORR were also assessed. Addition of Necitumumab to pemetrexed and cisplatin did not improve OS [HR=1.01; 95%CI (0.84, 1.21); p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the Necitumumab plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm).

How Supplied

Necitumumab is supplied in single-dose vials as a sterile, preservative-free solution:

• 800 mg/50 mL (16 mg/mL) NDC 0002-7716-01

Storage

Store vials in a refrigerator at 2° to 8°C (36° 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.

Images

Drug Images

{{#ask: Page Name::Necitumumab |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

This image is provided by the National Library of Medicine.

{{#ask: Label Page::Necitumumab |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

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.

• 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 Necitumumab.

• 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 Necitumumab and for three months following final dose.

• Lactation

• Advise women not to breastfeed during treatment with Necitumumab and for three months following the final dose.

Precautions with Alcohol

Alcohol-Necitumumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

PORTRAZZA™

Look-Alike Drug Names

There is limited information regarding Necitumumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.