Included as part of the PRECAUTIONS section.
Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with PORTRAZZA 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 PORTRAZZA 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 PORTRAZZA during treatment and after PORTRAZZA administration for at least 8 weeks after the last dose. 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 medically appropriate [see BOXED WARNING and Hypomagnesemia].
Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with PORTRAZZA 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 PORTRAZZA 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 PORTRAZZA. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion of PORTRAZZA during treatment 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 hypomagnesemia and related electrolyte abnormalities have improved to Grade ≤ 2. Replete electrolytes as medically appropriate [see BOXED WARNING, Cardiopulmonary Arrest, and ADVERSE REACTIONS].
Venous and Arterial Thromboembolic Events
Venous and arterial thromboembolic events (VTE and ATE), some fatal, were observed with PORTRAZZA in combination with gemcitabine and cisplatin. In Study 1, the incidence of VTE was 9% in patients receiving PORTRAZZA 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 PORTRAZZA 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 PORTRAZZA for patients with serious or life threatening VTE or ATE.
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 PORTRAZZA 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 PORTRAZZA [See DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Limit sun exposure [see PATIENT INFORMATION].
Discontinue PORTRAZZA for severe (Grade 4) skin reactions, or for Grade 3 skin induration/fibrosis.
In Study 1, 1.5% of PORTRAZZA treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No patients received premedication for IRR for the first dose of PORTRAZZA in Study 1. Most IRRs occurred after the first or second administration of PORTRAZZA. Monitor patients during and following PORTRAZZA infusion for signs and symptoms of IRR. Discontinue PORTRAZZA for serious or life-threatening IRR [See DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
Non-Squamous NSCLC - Increased Toxicity and Increased Mortality
PORTRAZZA is not indicated for the treatment of patients with non-squamous NSCLC. In a study of PORTRAZZA plus pemetrexed and cisplatin (PC) versus PC alone (Study 2), patients treated with PORTRAZZA 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 [see Clinical Studies].
Based on animal data and its mechanism of action, PORTRAZZA 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 PORTRAZZA and for three months following the final dose [see Use in Specific Populations and CLINICAL PHARMACOLOGY].
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.
Use In Specific Populations
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). No animal reproduction studies have been conducted with necitumumab. There are no available data for PORTRAZZA 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.
No animal studies have been conducted to evaluate the effect of necitumumab on reproduction and fetal development; however, based on its mechanism of action, PORTRAZZA 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.
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 PORTRAZZA, advise a nursing woman not to breastfeed during treatment with PORTRAZZA and for three months following the final dose.
Females and Males of Reproductive Potential
Based on its mechanism of action, PORTRAZZA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with PORTRAZZA and for three months following the final dose.
The safety and effectiveness of PORTRAZZA have not been established in pediatric patients.
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], 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.
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].
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].