Portrazza

SIDE EFFECTS

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

• Cardiopulmonary Arrest [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
• Hypomagnesemia [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
• Venous and Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS].
• Dermatologic Toxicities [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Infusion-Related Reactions [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Non-Squamous NSCLC - Increased Toxicity and Increased Mortality [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Clinical Trials Experience

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 PORTRAZZA was evaluated in two randomized, open-label trials comparing PORTRAZZA plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and PORTRAZZA 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 PORTRAZZA 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 PORTRAZZA until progressive disease or unacceptable toxicity.

Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the PORTRAZZA plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of PORTRAZZA until disease progression or unacceptable toxicity. The median duration of exposure to PORTRAZZA 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 PORTRAZZA-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 PORTRAZZA-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 PORTRAZZA 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 PORTRAZZA in Study 1

Clinically relevant adverse reactions (all grades) reported in ≥ 1% and <5% of patients treated with PORTRAZZA 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 PORTRAZZA arm discontinued study treatment due to an adverse reaction. The most common PORTRAZZA related toxicity leading to PORTRAZZA 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 PORTRAZZA arm and at >2% higher incidence than the control arm.

The median time to onset of hypomagnesemia was 6 weeks (25^th percentile 4 weeks; 75^th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received PORTRAZZA. In Study 1, 32% of the patients in the PORTRAZZA 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 PORTRAZZA in Study 1^a

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 PORTRAZZA. 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 [see CLINICAL PHARMACOLOGY].

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

Read the entire FDA prescribing information for Portrazza (Necitumumab Intravenous Injection)