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Necitumumab

Class: Antineoplastic Agents
ATC Class: L01XC22
VA Class: AN900
Chemical Name: Disulfide with human monoclonal IMC-11F8 κ-chain anti-(human epidermal growth factor receptor) (human monoclonal IMC-11F8 γ1-chain) immunoglobulin G1 dimer
Molecular Formula: C6436H9958N1702O2020S42
CAS Number: 906805-06-9
Brands: Portrazza

Warning(s)

  • Cardiopulmonary Arrest
  • Cardiopulmonary arrest and/or sudden death reported in 3% of patients receiving necitumumab in combination with gemcitabine and cisplatin.1

  • Closely monitor serum electrolytes (including magnesium, potassium, and calcium) prior to each infusion and for ≥8 weeks following the last dose.1

  • Correct electrolyte abnormalities aggressively, as clinically appropriate.1 (See Cardiopulmonary Arrest under Cautions.)

  • Hypomagnesemia
  • Hypomagnesemia reported in 83% of patients receiving necitumumab in combination with gemcitabine and cisplatin and was severe in 20% of patients.1

  • Monitor for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion and for ≥8 weeks following completion of therapy.1

  • Correct electrolyte abnormalities as clinically appropriate.1 Withhold therapy for grade 3 or 4 electrolyte abnormalities.1 (See Hypomagnesemia under Cautions.)

Introduction

Antineoplastic agent; a recombinant, fully human IgG1 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR).1 2 4 5 6

Uses for Necitumumab

Non-small Cell Lung Cancer (NSCLC)

Used in combination with gemcitabine and cisplatin for first-line treatment of metastatic squamous NSCLC;1 2 4 designated an orphan drug by FDA for this cancer.9

In combination with gemcitabine and cisplatin, substantially prolonged median overall survival (11.5 versus 9.9 months) and progression-free survival (5.7 versus 5.5 months) compared with gemcitabine and cisplatin alone in patients with chemotherapy-naive metastatic squamous NSCLC.1 2

No difference in overall survival, progression-free survival, or overall response rate observed in patients with nonsquamous NSCLC treated with necitumumab in combination with pemetrexed and cisplatin compared with pemetrexed and cisplatin alone.1 3

Manufacturer states not indicated for treatment of nonsquamous NSCLC.1 (See Increased Toxicity and Mortality in Nonsquamous NSCLC under Cautions.)

Necitumumab Dosage and Administration

General

Premedication for Infusion-related Reactions

  • In patients who previously experienced a grade 1 or 2 infusion-related reaction to necitumumab, premedicate with an antihistamine (e.g., diphenhydramine or equivalent) prior to each subsequent infusion.1

  • Following a second occurrence of a grade 1 or 2 infusion-related reaction, premedicate with an antihistamine (e.g., diphenhydramine or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each subsequent infusion.1 (See Infusion-related Reactions under Dosage and Administration and also under Cautions.)

Serum Electrolyte Monitoring

  • Closely monitor serum electrolyte concentrations, including magnesium, potassium, and calcium, and aggressively correct electrolyte abnormalities as clinically appropriate prior to each necitumumab infusion and for ≥8 weeks following the last dose.1 (See Electrolyte Abnormalities under Dosage and Administration.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion via an infusion pump.1

Necitumumab injection concentrate must be diluted prior to administration.1 Use within 4 hours following dilution if stored at room temperature or within 24 hours if stored at 2–8°C.1 (See Storage under Stability.)

Do not administer with any other drug or electrolytes simultaneously in the same IV line.1

Flush IV line with 0.9% sodium chloride injection at end of infusion.1

Dilution

Withdraw appropriate volume of necitumumab injection concentrate from vial labeled as containing 800 mg in 50 mL and add to infusion container containing the appropriate volume of 0.9% sodium chloride injection to yield a final volume of 250 mL.1 Mix by gentle inversion; do not shake.1

Do not dilute in dextrose-containing or other solutions or admix with any other drug or electrolytes.1

Discard any partially used vials.1

Rate of Administration

Administer over 60 minutes.1

Dosage

Adults

NSCLC
IV

800 mg on days 1 and 8 of each 3-week cycle; use in combination with gemcitabine and cisplatin.1

Administer necitumumab prior to IV infusion of gemcitabine and cisplatin.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification
Infusion-related Reactions

If grade 1 infusion-related reaction occurs, reduce infusion rate by 50%.1

If grade 2 infusion-related reaction occurs, interrupt infusion until resolution to grade 1 or less; resume at 50% reduced rate for subsequent infusions.1

If grade 3 or 4 infusion-related reaction occurs, permanently discontinue therapy.1 (See Infusion-related Reactions under Cautions.)

Dermatologic Toxicity

If grade 3 rash or acneiform rash develops, interrupt therapy.1 If toxicity improves to grade 2 or less, resume necitumumab at reduced dosage of 400 mg for at least 1 cycle.1 May increase dosage to 600 mg, then to 800 mg in subsequent cycles if symptoms do not worsen.1 If dermatologic toxicity worsens or becomes intolerable at a dosage of 400 mg, permanently discontinue therapy.1 If grade 3 rash or acneiform rash does not improve to grade 2 or less within 6 weeks, permanently discontinue therapy.1

If grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity occurs, permanently discontinue therapy.1 (See Dermatologic Toxicity under Cautions.)

Electrolyte Abnormalities

If grade 3 or 4 electrolyte abnormalities occur, interrupt therapy.1 Resume therapy at previous dosage upon improvement of hypomagnesemia and related electrolyte abnormalities to grade 2 or less.1 (See Cardiopulmonary Arrest and also see Hypomagnesemia under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Body Weight, Race, and Gender

No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Cautions for Necitumumab

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 3% of patients receiving necitumumab in combination with gemcitabine and cisplatin for treatment of metastatic squamous NSCLC in the principal efficacy study.1 Majority of patients died within 30 days of the last dose of necitumumab and had comorbid conditions (e.g., CAD, hypomagnesemia, COPD, hypertension).1 Incremental risk of cardiopulmonary arrest or sudden death with necitumumab therapy in patients with a history of CAD, CHF, or arrhythmias compared with those without these cardiovascular conditions not known.1

Closely monitor serum electrolytes, including magnesium, potassium, and calcium, prior to each necitumumab infusion and for ≥8 weeks after the last dose.1 Withhold therapy for grade 3 or 4 electrolyte abnormalities.1 Aggressively correct electrolyte abnormalities as clinically appropriate.1

Hypomagnesemia

Hypomagnesemia occurred in 83% of patients and was severe (grade 3 or 4) in 20% of patients receiving necitumumab in combination with gemcitabine and cisplatin in the primary efficacy study.1 Median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks following initiation of therapy.1

Monitor serum electrolytes, including magnesium, potassium, and calcium, prior to each necitumumab infusion and for ≥8 weeks after completion of therapy.1 Correct electrolyte abnormalities as clinically appropriate.1 Withhold necitumumab therapy for grade 3 or 4 electrolyte abnormalities.1

Other Warnings and Precautions

Thromboembolic Events

Increased risk of thromboembolic events.1 Venous and arterial thromboembolic events (e.g., PE, DVT, stroke/cerebral ischemia, MI), including fatal cases, reported.1 Relative risk approximately threefold higher in patients with a history of thromboembolic events than in patients without such history.1

If a serious or life-threatening venous or arterial thromboembolic event occurs, permanently discontinue therapy.1

Dermatologic Toxicity

Dermatologic toxicity, including rash, acneiform dermatitis, acne, dry skin, pruritus, generalized rash, skin fissures, maculopapular rash, and erythema, reported in 79% of necitumumab-treated patients in the principal efficacy study and was severe in 8% of patients.1 Dermatologic toxicity usually developed within first 2 weeks of therapy and resolved ≤17 weeks after onset.1

Limit sun exposure.1 (See Advice to Patients.)

If dermatologic toxicity occurs, dosage reduction or discontinuance of therapy may be necessary.1 (See Dermatologic Toxicity under Dosage and Administration.)

Infusion-related Reactions

Infusion-related reactions occurred in 1.5% and grade 3 infusion-related reactions occurred in 0.4% of necitumumab-treated patients in the primary efficacy study.1 Most infusion-related reactions occurred after the first or second infusion of the drug.1 None of the patients received premedication for infusion-related reactions for the first dose of necitumumab in this study.1

Monitor patients for manifestations of infusion-related reaction during and following necitumumab infusions.1 If infusion-related reactions occur, administer premedication before all subsequent infusions.1 (See Premedication for Infusion-related Reactions under Dosage and Administration.) Reduction in infusion rate or discontinuance of therapy may be necessary depending on severity of the reaction.1 (See Infusion-related Reactions under Dosage and Administration.)

Increased Toxicity and Mortality in Nonsquamous NSCLC

Increased incidence of serious toxicity and mortality reported in patients with nonsquamous NSCLC.1 3 Serious toxicity, fatal toxicity, and cardiopulmonary arrest and/or sudden death reported in more patients with nonsquamous NSCLC receiving necitumumab in combination with pemetrexed and cisplatin compared with those receiving pemetrexed and cisplatin alone.1

Necitumumab is not indicated for the treatment of nonsquamous NSCLC.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; developmental toxicity, embryolethality, and postnatal deaths demonstrated in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective contraception during therapy and for 3 months after drug discontinuance.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether necitumumab is distributed into milk.1 Women should not breast-feed during therapy and for 3 months after the last dose.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

In the principal efficacy study in NSCLC, 39% of patients were ≥65 years of age and 20% were ≥70 years of age.1 In a subgroup analysis, overall survival benefit not observed in patients ≥70 years of age receiving necitumumab in combination with gemcitabine and cisplatin.1 2 Although overall safety of necitumumab was generally similar for subgroups of patients <70 years of age and those ≥70 years of age, a higher incidence of venous thromboembolic events, including PE, observed in patients ≥70 years of age.1 2 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Formal studies evaluating the effect of hepatic impairment on the pharmacokinetics of necitumumab not conducted to date.1 In a population pharmacokinetic analysis, systemic exposure not affected by mild or moderate hepatic impairment.1 No patients with severe hepatic impairment were enrolled in clinical trials.1

Renal Impairment

Not formally studied, but systemic exposure does not appear to be affected by renal function.1 10 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Hypomagnesemia,1 2 hypocalcemia,1 rash,1 2 hypophosphatemia,1 vomiting,1 hypokalemia,1 diarrhea,1 acneiform dermatitis.1

Interactions for Necitumumab

Specific Drugs

Drug

Interaction

Gemcitabine and cisplatin

Gemcitabine peak plasma concentration and AUC increased by 63 and 22%, respectively1

No substantial effect on cisplatin or necitumumab exposure1

Necitumumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations predicted to be reached approximately 100 days following IV infusion of necitumumab 800 mg on days 1 and 8 of each 21-day cycle.1

Special Populations

Systemic exposure not affected by renal function in a population pharmacokinetic analysis.1

Systemic exposure not affected by mild or moderate hepatic impairment in a population pharmacokinetic analysis.1 Patients with severe hepatic impairment not enrolled in clinical trials.1

Gender, age (range: 19–84 years), and race do not substantially affect systemic exposure.1

Effect of body weight on necitumumab exposure not clinically important.1 (See Special Populations under Dosage and Administration.)

Distribution

Extent

Not known whether necitumumab distributes into milk.1

Elimination

Half-life

Approximately 14 days.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Keep vial in outer carton until time of use to protect from light; do not freeze or shake vial.1

Diluted infusion solution: Room temperature (≤25°C) for ≤4 hours or 2–8°C for ≤24 hours after dilution.1 Do not freeze or shake infusion solution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Dilute in 0.9% sodium chloride.1

Do not dilute with dextrose-containing or other solutions or admix with other drugs or electrolytes.1

Parenteral

Solution Compatibility

Compatible1

Sodium chloride 0.9%

Incompatible1

Dextrose 5% in sodium chloride 0.225 or 0.9%

Dextrose 5% in water

Actions

  • A recombinant, fully human IgG1 kappa monoclonal antibody that binds with high affinity and specificity to human EGFR.1 2 4 5 6 7 10

  • Necitumumab's mechanism of EGFR inhibition appears similar to that of cetuximab.5 6 8

  • Necitumumab competitively blocks the interaction of EGFR with its ligands, resulting in inhibition of ligand-induced phosphorylation and downstream signaling pathways, which play an important role in cell proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis.1 4 5 7 10

  • Binding of necitumumab induces EGFR internalization and degradation in vitro; in vitro binding also leads to antibody-dependent cell-mediated cytotoxicity (ADCC) in EGFR-expressing cells.1 4 5 10

  • In mice bearing xenografts of human cancer, including NSCLC, necitumumab in combination with gemcitabine and cisplatin resulted in increased antitumor activity compared with gemcitabine and cisplatin alone.1 4 5 10

Advice to Patients

  • Risk of electrolyte abnormalities, including hypomagnesemia, hypokalemia, and hypocalcemia.1 Importance of advising patients to take electrolyte replacement therapy exactly as advised by their clinician.1

  • Risk of venous and arterial thromboembolic events.1

  • Risk of skin reactions.1 Importance of minimizing sun exposure with protective clothing and use of sunscreen during therapy.1

  • Risk of infusion-related reactions.1 Importance of informing patients to report signs and symptoms of infusion reactions (e.g., fever, chills, breathing problems) to a healthcare professional.1

  • Risk of fetal harm.1 Advise women of childbearing potential to use effective methods of contraception while receiving necitumumab and for 3 months after the last dose.1 If pregnancy occurs, apprise patient of potential fetal hazard.1

  • Importance of advising women to avoid breast-feeding during therapy and for 3 months following the last dose.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Necitumumab (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV infusion only

16 mg/mL (800 mg)

Portrazza

Lilly

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: October 03, 2016
Last reviewed: October 03, 2016
Date modified: October 12, 2016

References

1. Eli Lilly and Company. Portrazza (necitumumab) injection for intravenous use prescribing information. Indianapolis, IN; 2015 Nov.

2. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015; 16:763-74. [PubMed 26045340]

3. Paz-Ares L, Mezger J, Ciuleanu TE et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015; 16:328-37. [PubMed 25701171]

4. Garnock-Jones KP. Necitumumab: First Global Approval. Drugs. 2016; 76:283-9. [PubMed 26729188]

5. Sacco PC, Maione P, Rossi A et al. Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer. Expert Rev Respir Med. 2015; 9:245-54. [PubMed 25797462]

6. Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure. 2008; 16:216-27. [PubMed 18275813]

7. Zugazagoitia J, Ponce S, Paz-Ares L. Necitumumab for first-line treatment of advanced, squamous, non-small-cell lung cancer: a relevant step forward?. Transl Lung Cancer Res. 2016; 5:95-7. [PubMed 26958500]

8. AHFS drug information. McEvoy GK, ed. Cetuximab. Bethesda, MD: American Society of Health-System Pharmacists; Updated 11 Mar 2016. From AHFS DI website.

9. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Silver Spring, MD. Accessed 2016 Apr 7.

10. Lilly S.A. Portrazza (necitumumab) concentrate for solution for infusion summary of product characteristics. Madrid, Spain. (undated)

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