Vectibix (Page 2 of 7)

5.2 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS -Mutant mCRC

Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [ see Indications and Usage ( 1.1), Dosage and Administration ( 2.1), Clinical Pharmacology ( 12.1) and Clinical Studies ( 14) ].

Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage ( 1.1), and Clinical Pharmacology ( 12.1)].

Additionally, in Study 20050203, 272 patients with RAS -mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS -mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone [see Indications and Usage ( 1.1)].

5.3 Electrolyte Depletion/Monitoring

Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

5.4 Infusion Reactions

In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration [see Adverse Reactions ( 6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration ( 2.3)].

5.5 Acute Renal Failure in Combination with Chemotherapy

Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.

5.6 Pulmonary Fibrosis/Interstitial Lung Disease (ILD)

Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.

5.7 Photosensitivity

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

5.8 Ocular Toxicities

​ Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred with Vectibix use. Monitor for evidence of keratitis, ulcerative keratitis, or corneal perforation. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis, ulcerative keratitis, or corneal perforation.

5.9 Increased Mortality and Toxicity with Vectibix in Combination with Bevacizumab and Chemotherapy

In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.

5.10 Embryo-fetal Toxicity

Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to a pregnant woman. When given during organogenesis, panitumumab administration resulted in embryolethality in cynomolgus monkeys at exposures approximately 1.25 to 5-times the recommended human dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix [see Use in Specific Populations ( 8.1, 8.3), Clinical Pharmacology ( 12.1)].

6 ADVERSE REACTIONS

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

• Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration ( 2.3), and Warnings and Precautions ( 5.1)]
  
• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS -Mutant mCRC [see Indications and Usage ( 1.1) and Warnings and Precautions ( 5.2)]
  
• Electrolyte Depletion/Monitoring [see Warnings and Precautions ( 5.3)]
  
• Infusion Reactions [see Dosage and Administration ( 2.3), and Warnings and Precautions ( 5.4)]
  
• Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions ( 5.5)]
  
• Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.6)]
  
• Photosensitivity [see Warnings and Precautions ( 5.7)]
  
• Ocular Toxicities [see Warnings and Precautions ( 5.8)]
• Increased Mortality and Toxicity with Vectibix in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions ( 5.9)]