Vectibix

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 )] Most common adverse reactions (≥ 20%) of Vectibix as monotherapy are skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. ( 6.1 ) Most common adverse reactions (≥ 20%) in clinical trials of Vectibix in combination with FOLFOX chemotherapy are diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix: Study 20020408, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 20050203, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 20050203 are limited to 656 patients with wild-type KRAS mCRC. The safety profile of Vectibix in patients with wild-type RAS mCRC is similar with that seen in patients with wild-type KRAS mCRC. Vectibix Monotherapy In Study 20020408, the most common adverse reactions (≥ 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 20020408, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 20020408) Study 20020408 Vectibix Plus Best Supportive Care (N = 229) Best Supportive Care (N = 234) System Organ Class Preferred Term Any Grade n (%) Grade 3-4 n (%) Any Grade n (%) Grade 3-4 n (%) E ye D isorders Growth of eyelashes 13 (6) G astrointestinal D isorders Nausea 52 (23) 2 (< 1) 37 (16) 1 (< 1) Diarrhea 49 (21) 4 (2) 26 (11) Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1) Stomatitis 15 (7) 2 (< 1) G eneral D isorders and A dministration S ite C onditions Fatigue 60 (26) 10 (4) 34 (15) 7 (3) Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1) I nfections and I nfestations Paronychia 57 (25) 4 (2) R espiratory , T horacic , and M ediastinal D isorders Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7) S kin and S ubcutaneous T issue D isorders Erythema 150 (66) 13 (6) 2 (< 1) Pruritus 132 (58) 6 (3) 4 (2) Acneiform dermatitis 131 (57) 17 (7) 2 (< 1) Rash 51 (22) 3 (1) 2 (< 1) Skin fissures 45 (20) 3 (1) 1 (< 1) Exfoliative rash 41 (18) 4 (2) Acne 31 (14) 3 (1) Dry skin 23 (10) Nail disorder 22 (10) Skin exfoliation 21 (9) 2 (< 1) Skin ulcer 13 (6) 1 (< 1) Adverse reactions in Study 20020408 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 20020408, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions ( 5.1 )]. In Study 20020408 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration ( 2.3 )] . Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix in Combination w ith FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 20050203 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix. Table 2 : Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild - t ype KRAS Tumors Treated with Vectibix and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone ( Study 20050203 ) Vectibix Plus FOLFOX (n = 322) FOLFOX Alone (n = 327) S ystem O rgan C lass Preferred Term Any Grade n (%) Grade 3-4 n (%) Any Grade n (%) Grade 3-4 n (%) E ye D isorders Conjunctivitis 58 (18) 5 (2) 10 (3) G astrointestinal D isorders Diarrhea 201 (62) 59 (18) 169 (52) 29 (9) Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1) G eneral D isorders and A dministration S ite C onditions Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1) Asthenia 79 (25) 16 (5) 62 (19) 11 (3) I nfections and I nfestations Paronychia 68 (21) 11 (3) I nvestigations Weight decreased 58 (18) 3 (< 1) 22 (7) M etabolism and N utrition D isorders Anorexia 116 (36) 14 (4) 85 (26) 6 (2) Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1) Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5) Dehydration 26 (8) 8 (2) 10 (3) 5 (2) R espiratory , T horacic , and M ediastinal D isorders Epistaxis 46 (14) 30 (9) S kin and S ubcutaneous T issue D isorders Rash 179 (56) 55 (17) 24 (7) 1 (< 1) Acneiform dermatitis 104 (32) 33 (10) Pruritus 75 (23) 3 (< 1) 14 (4) Dry skin 68 (21) 5 (2) 13 (4) Erythema 50 (16) 7 (2) 14 (4) Skin fissures 50 (16) 1 (< 1) 1 (< 1) Alopecia 47 (15) 30 (9) Acne 44 (14) 10 (3) 1 (< 1) Nail disorder 32 (10) 4 (1) 4 (1) Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1) Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were flushing (3% vs < 1%), abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [ see Dosage and Administration ( 2.2 , 2.3 ) ] . 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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 the incidence of antibodies to panitumumab in the studies described below with the incidence of antibodies to other products may be misleading. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy : The incidence of treatment-emergent binding anti-panitumumab antibodies was 0.5% (7/1295) as detected by ELISA and 5.3% (68/1295) as detected by the Biacore ® assay. The incidence of neutralizing anti-panitumumab antibodies was 0.8% (11/1295). There was no evidence of altered pharmacokinetics or safety profiles in patients who developed antibodies to panitumumab. In combination with chemotherapy : The incidence of treatment-emergent binding anti-panitumumab antibodies was 0.9% (12/1297) as detected by the ELISA and 0.7% (9/1296) as detected by the Biacore ® assay. The incidence of neutralizing anti-panitumumab antibodies was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to panitumumab. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning , Dosage and Administration ( 2.3 ), and Warnings and Precautions ( 5.1 )] Immune system disorders: Infusion reaction [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.4 )] Eye disorders: Keratitis/ulcerative keratitis, corneal perforation [see Warnings and Precautions ( 5.8 )]

4 CONTRAINDICATIONS None. None

11 DESCRIPTION Panitumumab is an epidermal growth factor receptor (EGFR) antagonist for intravenous use. Panitumumab is a human IgG2 kappa monoclonal antibody with an approximate molecular weight of 147 kDa that is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Vectibix (panitumumab) Injection for intravenous use is a sterile, colorless solution with a pH range of 5.6 to 6.0, which may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Each single-dose 5 mL vial contains 100 mg of panitumumab, 34 mg sodium acetate, 29 mg sodium chloride, and Water for Injection, USP. Each single-dose 20 mL vial contains 400 mg of panitumumab, 136 mg sodium acetate, 117 mg sodium chloride, and Water for Injection, USP.

2 DOSAGE AND ADMINISTRATION Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg). ( 2 ) Infusion Reactions: Reduce infusion rate by 50% for mild reactions; terminate the infusion for severe infusion reactions. ( 2.3 , 5.4 ) Dermatologic Toxicity: Withhold or discontinue for severe or intolerable toxicity; reduce dose for recurrent, grade 3 toxicity. ( 2.3 , 5.1 ) 2.1 Patient Selection Prior to initiation of treatment with Vectibix, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both KRAS and NRAS . Information on FDA-approved tests for the detection of RAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dose The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration ( 2.4 )]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions [see Warnings and Precautions ( 5.4 )] . 2.3 Dose Modifications Dose Modifications for Infusion Reactions [ see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 , 6.3 ) ] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modi fi cations for Dermatologic Toxicity [ see Boxed Warning , Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 , 6.3 ) ] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix. Permanently discontinue Vectibix following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. 2.4 Preparation and Administration For intravenous infusion only. Do not administer Vectibix as an intravenous push or bolus. Preparation Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Vectibix solution is colorless and may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Do not use if the solution is discolored or cloudy, or if foreign matter is present. Prepare the solution for infusion, using aseptic technique, as follows: • Do not shake the vial. • Use a 21-gauge or larger gauge (smaller bore) hypodermic needle to withdraw the necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents. • Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. • Discard any unused portion of the vial. Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. • Vectibix must be administered via infusion pump. ○ Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. ○ Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes. • Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE.

1 INDICATIONS AND USAGE Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use ) metastatic colorectal cancer (mCRC): In combination with FOLFOX for first-line treatment. ( 1.1 , 14.2 ) As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. ( 1.1 , 14.1 ) Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC or for whom RAS mutation status is unknown. ( 1.1 , 2.1 , 5.2 , 12.1 ) 1.1 Metastatic Colorectal Cancer Vectibix is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC) [see Dos age and Administration ( 2.1 )] : • As first-line therapy in combination with FOLFOX [ see Clinical Studies ( 14.2 )] . • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies ( 14.1 )] . Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration ( 2.1 ) , Warnings and Precautions ( 5.2 ) , and Clinical Pharmacology ( 12.1 ) ].

10 OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (e.g., EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. Signal transduction through the EGFR can result in activation of the wild-type KRAS and NRAS proteins; however, in cells with activating RAS somatic mutations, the RAS-mutant proteins are continuously active and appear independent of EGFR regulation. Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR. 12.3 Pharmacokinetics Panitumumab administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner. Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC 0-tau and CL were 1306 ± 374 mcg•day/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days). A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88 years), gender, race (15% nonwhite), mild-to-moderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab. No formal pharmacokinetic studies of panitumumab have been conducted in patients with renal or hepatic impairment.

12.1 Mechanism of Action The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (e.g., EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. Signal transduction through the EGFR can result in activation of the wild-type KRAS and NRAS proteins; however, in cells with activating RAS somatic mutations, the RAS-mutant proteins are continuously active and appear independent of EGFR regulation. Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR.

12.3 Pharmacokinetics Panitumumab administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner. Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC 0-tau and CL were 1306 ± 374 mcg•day/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days). A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88 years), gender, race (15% nonwhite), mild-to-moderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab. No formal pharmacokinetic studies of panitumumab have been conducted in patients with renal or hepatic impairment.

20210825

157

3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/5 mL (20 mg/mL) colorless solution in single-dose vial. Injection: 400 mg/20 mL (20 mg/mL) colorless solution in single-dose vial. Injection: 100 mg/5 mL (20 mg/mL) and 400 mg/20 mL (20 mg/mL) in single-dose vials. ( 3 )

Vectibix panitumumab PANITUMUMAB PANITUMUMAB SODIUM ACETATE SODIUM CHLORIDE WATER Vectibix panitumumab PANITUMUMAB PANITUMUMAB SODIUM ACETATE SODIUM CHLORIDE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied; however, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied; however, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

BLA125147

Vectibix

panitumumab

55513-956

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL Single-Dose Vial NDC 55513-954-01 AMGEN ® Vectibix ® (panitumumab) Injection 100 mg Each 5 mL single-dose vial of Vectibix ® contains 100 mg panitumumab in a sterile, preservative-free solution (pH 5.8) containing 29 mg sodium chloride and 34 mg sodium acetate in Water for Injection, USP. Store at 2° to 8°C. Do not freeze or shake. Protect from direct sunlight. Rx Only PRINCIPAL DISPLAY PANEL Single-Dose Vial NDC 55513-954-01 AMGEN® Vectibix® (panitumumab) Injection 100 mg Each 5 mL single-dose vial of Vectibix® contains 100 mg panitumumab in a sterile, preservative-free solution (pH 5.8) containing 29 mg sodium chloride and 34 mg sodium acetate in Water for Injection, USP. Store at 2° to 8°C. Do not freeze or shake. Protect from direct sunlight. Rx Only

Warnings and Precautions – Ocular Toxicities ( 5.8 ) 8/2021

17 PATIENT COUNSELING INFORMATION Discuss the following with patients prior to treatment with Vectibix: Skin and eye disorders: Advise patients to contact a healthcare professional if they experience skin or ocular/visual changes [see Boxed Warning , Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.8 ) , and Adverse Reactions ( 6.1 , 6.3 ) ] . Electrolyte monitoring: Inform patients of the need for periodic monitoring of electrolytes [see Warnings and Precautions ( 5.3 )] . Dehydration: Advise patients of the increased risk of diarrhea and dehydration which may lead to acute renal failure and electrolyte depletion when Vectibix is administered in combination with chemotherapy [see Warnings and Precautions ( 5.5 )] . Infusion reactions: Advise patients of the risk of infusion reactions [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.4 ) , and Adverse Reactions ( 6.1 , 6.3 ) ] . Respiratory: Advise patients to contact a healthcare professional if they experience persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.1 ) ] . Embryo - fetal Toxicity Advise pregnant women and females of reproductive potential that Vectibix can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Vectibix, and for at least 2 months after the last dose and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 , 8.3 ) ] . Lactation : Advise women not to breastfeed during treatment with Vectibix and for 2 months after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility: Advise females of reproductive potential of the potential for reduced fertility from Vectibix [see Use in Specific Populations ( 8.3 )]. Sun exposure: Advise patients to limit sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy [see Warnings and Precautions ( 5.7 )] . Vectibix ® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA U.S. License No. 1080 Patent: http://pat.amgen.com/vectibix/ © 2006-2021 Amgen Inc. All rights reserved. 1xxxxxx – v25

14 CLINICAL STUDIES Figure 1: Kaplan Meier Plot of Overall Survival in Patients with Wild type KRAS mCRC (Study 20080763) Figure 2: Kaplan Meier Plot of Overall Survival in Patients with Wild type RAS mCRC (Study 20100007) Figure 3: Kaplan Meier Plot of Overall Survival in Patients with Wild type KRAS mCRC (Study 20050203) Figure 4: Kaplan Meier Plot of Overall Survival in Patients with Wild Type RAS mCRC (Study 20050203) 14.1 Recurrent or Refractory mCRC The safety and efficacy of Vectibix was demonstrated in Study 20020408, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, in Study 20080763, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type KRAS mCRC, and in Study 20100007, an open-label, multicenter, multinational, randomized trial of 377 patients with wild-type KRAS mCRC. Study 20020408 (NCT00113763) Patients in Study 20020408 were required to have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan; progression was confirmed by an independent review committee (IRC) masked to treatment assignment for 76% of the patients. Patients were randomized (1:1) to receive panitumumab at a dose of 6 mg/kg given once every 2 weeks plus BSC (N = 231) or BSC alone (N = 232) until investigator-determined disease progression. Randomization was stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 and 1 vs 2) and geographic region (Western Europe, Eastern/Central Europe, or other). Upon investigator-determined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC. Based upon IRC determination of disease progression, a statistically significant prolongation in PFS was observed in patients receiving panitumumab compared to those receiving BSC alone. The mean PFS was 96 days in the panitumumab arm and 60 days in the BSC-alone arm. The study results were analyzed in the wild-type KRAS subgroup where KRAS status was retrospectively determined using archived paraffin-embedded tumor tissue. KRAS mutation status was determined in 427 patients (92%); of these, 243 (57%) had no detectable KRAS mutations in either codons 12 or 13. The hazard ratio for PFS in patients with wild-type KRAS mCRC was 0.45 (95% CI: 0.34-0.59) favoring the panitumumab arm. The response rate was 17% for the panitumumab arm and 0% for BSC. There were no differences in OS; 77% of patients in the BSC arm received panitumumab at the time of disease progression. Study 20080763 ( NCT01001377 ) Study 20080763 was an open-label, multicenter, multinational, randomized (1:1) clinical trial, stratified by region (North America, Western Europe, and Australia versus rest of the world) and ECOG PS (0 and 1 vs 2) in patients with wild-type KRAS mCRC. A total of 1010 patients who received prior treatment with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor were randomized to receive Vectibix 6 mg/kg intravenously over 60 minutes every 14 days or cetuximab 400 mg/m 2 intravenously over 120 minutes on day 1 followed by 250 mg/m 2 intravenously over 60 minutes every 7 days. The trial excluded patients with clinically significant cardiac disease and interstitial lung disease. The major efficacy analysis tested whether the OS of Vectibix was noninferior to cetuximab. Data for investigator-assessed PFS and objective response rate (ORR) were also collected. The criteria for noninferiority was for Vectibix to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC CTG CO.17 study relative to BSC. In Study 20080763, 37% of patients were women, 52% were white, 45% were Asian, and 1.3% were Hispanic or Latino. Thirty-one percent of patients were enrolled at sites in North America, Western Europe, or Australia. ECOG performance was 0 in 32% of patients, 1 in 60% of patients, and 2 in 8% of patients. Median age was 61 years. More patients (62%) had colon cancer than rectal cancer (38%). Most patients (74%) had not received prior bevacizumab. The key efficacy analysis for Study 20080763 demonstrated that Vectibix was statistically significantly noninferior to cetuximab for OS. The efficacy results for Study 20080763 are presented in Table 3 and Figure 1. Table 3 : Results in Previously Treated Wild - type KRAS mCRC ( Study 20080763 ) Wild - type KRAS Population Vectibix (n = 499) a Cetuximab (n = 500) a OS Number of OS events (%) 383 (76.8) 392 (78.4) Median (months) (95% CI) 10.4 (9.4, 11.6) 10.0 (9.3, 11.0) Hazard ratio (95% CI) 0.97 (0.84, 1.11) PFS Median (months) (95% CI) 4.1 (3.2, 4.8) 4.4 (3.2, 4.8) Hazard ratio (95% CI) 1.00 (0.88, 1.14) ORR % (95% CI) 22% (18%, 26%) 19% (16%, 23%) a Modified intent-to-treat population that included all patients who received at least one dose of therapy Figure 1 : Kaplan - Meier Plot of Overall Survival in Patients with Wild - type KRAS mCRC ( Study 20080763 ) Study 20100007 ( NCT01412957 ) Study 20100007 was an open-label, multicenter, randomized (1:1) clinical study stratified by ECOG performance status (0 or 1 vs 2) and region (sites in Europe versus Asia versus rest of world) in patients with wild-type KRAS mCRC. Eligible patients were required to have received prior therapy with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor, and have wild-type KRAS exon 2 mCRC as determined by a clinical trial assay. An assessment for RAS status (defined as KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) using Sanger sequencing was conducted in patients for whom tumor tissue was available. Patients were randomized to receive Vectibix (6 mg/kg intravenously every 14 days) plus BSC or BSC alone. Patients received Vectibix and BSC or BSC until disease progression, withdrawal of consent, unacceptable toxicity, or death. Patients randomized to BSC were not offered Vectibix at the time of disease progression. The major efficacy outcome measure was OS in patients with wild-type KRAS mCRC. Secondary efficacy outcome measures included OS in the subgroup of patients with wild-type RAS mCRC; PFS and ORR in patients with wild-type KRAS ; and PFS and ORR in the subgroup of patients with wild-type RAS mCRC. A total of 377 patients were randomized, 189 to the Vectibix plus BSC arm and 188 to the BSC alone arm. Baseline demographics and disease characteristics were: median age of 61 years (range 19, 82); 57% male; 55% White, 43% Asian; 36% ECOG PS-0, 55% ECOG PS-1; 57% had a primary colon tumor and 43% had a primary rectal tumor; and 32% had prior bevacizumab exposure. KRAS tumor mutation status was available for all patients and RAS tumor mutation status was available for 86% of the 377 patients. Among the 377 patients, 270 (72%) patients had wild-type RAS tumors, 54 (14%) had mutant RAS tumors, and 54 (14%) had unknown RAS tumor status. The results of the study demonstrated a statistically significant improvement in overall survival. The efficacy results for Study 20100007 are presented in Table 4 and Figure 2. Table 4 : Results in Previously Treated Wild - type KRAS and Wild - type RAS mCRC ( Study 20100007 ) Wild-type KRAS Population (n = 377) Wild-type RAS Population (n = 270) Vectibix Plus BSC (n = 189) BSC (n = 188) Vectibix Plus BSC (n = 142) BSC (n = 128) OS Number of deaths (%) 136 (72) 135 (72) 104 (73) 95 (74) Median (months) (95% CI) 10.0 (8.7, 11.4) 7.4 (5.8, 9.3) 10.0 (8.7, 11.6) 6.9 (5.2, 7.9) HR (95% CI) 0.73 (0.57, 0.93) 0.70 (0.53, 0.93) p-value 0.0096 0.0135 PFS Number of events (%) 182 (96) 162 (86) 137 (97) 113 (88) Median (months) (95% CI) 3.6 (3.4, 5.3) 1.7 (1.6, 1.9) 5.2 (3.5, 5.3) 1.7 (1.6, 2.2) HR (95% CI) 0.51 (0.41, 0.64) 0.46 (0.35. 0.59) p-value < 0.0001 < 0.0001 ORR % (95% CI ) 27 (20.8, 33.9) 1.6 (0.3, 4.6) 31 (23.5, 39.3) 2.3 (0.5, 6.7) Figure 2 : Kaplan - Meier Plot of Overall Survival in Patients with Wild - type RAS mCRC ( Study 20100007 ) 14.2 First-line in Combination with FOLFOX Chemotherapy Study 20050203 ( NCT00364013 ) Study 20050203 was a multicenter, open-label trial that randomized (1:1) patients with mCRC who were previously untreated in the metastatic setting and who had received no prior oxaliplatin to receive Vectibix every 14 days in combination with FOLFOX or to FOLFOX alone every 14 days. Vectibix was administered at 6 mg/kg over 60 minutes prior to administration of chemotherapy. The FOLFOX regimen consisted of oxaliplatin 85 mg per m 2 IV infusion over 120 minutes and leucovorin (dl-racemic) 200 mg per m 2 intravenous infusion over 120 minutes at the same time on day 1 using a Y-line, followed on day 1 by 5-FU 400 mg per m 2 intravenous bolus. The 5-FU bolus was followed by a continuous infusion of 5-FU 600 mg per m 2 over 22 hours. On day 2, patients received leucovorin 200 mg per m 2 followed by the bolus dose (400 mg per m 2 ) and continuous infusion of 5-FU (600 mg per m 2 ) over 22 hours. Study 20050203 excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified major efficacy measure was PFS in the subgroup of patients with wild-type KRAS mCRC as assessed by a blinded independent central review of imaging. Other key efficacy measures included OS and ORR. In Study 20050203, in the wild-type K RAS subgroup (n = 656), 64% of patients were men, 92% White, 2% Black, and 4% Hispanic or Latino. Sixty-six percent of patients had colon cancer and 34% had rectal cancer. ECOG performance was 0 in 56% of patients, 1 in 38% of patients, and 2 in 6% of patients. Median age was 61.5 years. The efficacy results in Study 20050203 in patients with wild-type K RAS mCRC are presented in Table 5 below. Table 5 : Results in Patient s with Wild - type K RAS mCRC ( Study 20050203 ) Primary Analysis Wild-type KRAS population Vectibix plus FOLFOX (n = 325) FOLFOX Alone (n = 331) PFS Median (months) (95% CI) 9.6 (9.2, 11.1) 8.0 (7.5, 9.3) Hazard ratio (95% CI) p-value 0.80 (0.66, 0.97) p = 0.02 ORR % (95% CI) 54% (48%, 59%) 47% (41%, 52%) E xploratory A nalysis of OS An exploratory analysis of OS with updated information based on events in 82% of patients with wild-type K RAS mCRC estimated the treatment effect of Vectibix plus FOLFOX compared with FOLFOX alone on OS (Figure 3). Median OS among 325 patients with wild-type K RAS mCRC who received Vectibix plus FOLFOX was 23.8 months (95% CI: 20.0, 27.7) vs 19.4 months (95% CI: 17.4, 22.6) among 331 patients who received FOLFOX alone (HR = 0.83, 95% CI: 0.70, 0.98). Figure 3 : Kaplan - Meier Plot of Overall Survival in Patients with Wild - type K RAS mCRC ( Study 20050203 ) Retrospective e xploratory analys e s in the RAS wild - type sub group Among the 656 patients with wild-type KRAS exon 2 mCRC, RAS mutation status was assessed for 620 patients using Sanger bidirectional sequencing and Surveyor ® /WAVE ® analysis. Of these 620 patients, approximately 17% of patients (n = 104) tumors harbored mutations in KRAS exons 3 or 4 or in NRAS exons 2, 3, and 4. Retrospective subset analyses were then conducted among the subset of patients without RAS mutations (n = 512) as described above. In the wild-type RAS subgroup, 65% of patients were men and 91% were White, 2% Black, and 5% Hispanic or Latino. Sixty-five percent of patients had colon cancer and 35% had rectal cancer. ECOG performance was 0 in 57% of patients, 1 in 37% of patients, and 2 in 6% of patients. Median age was 61 years. Table 6: Results in Patients with Wild - Type RAS mCRC ( Study 20050203 ) Primary Analysis Wild-type RA S population Vectibix plus FOLFOX (n = 259) FOLFOX Alone (n = 253) PFS Median (months) (95% CI) 10.1 (9.3, 12.0) 7.9 (7.2, 9.3) Hazard ratio (95% CI) 0.72 (0.58, 0.90) OS* Median (months) (95% CI) 25.8 (21.7; 29.7) 20.2 (17.5; 23.6) Hazard ratio (95% CI) 0.77 (0.64; 0.94) ORR % (95% CI) 58% (51%, 64%) 45% (39%, 51%) *OS with updated information based on events in 82% of patients Figure 4: Kaplan Meier Plot of Overall Survival in Patients with Wild - Type RAS - mCRC ( Study 20050203 ) 14.3 RAS -Mutant mCRC Vectibix is not effective for the treatment of patients with RAS -mutant mCRC, defined as a RAS mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), or exon 4 (codons 117 and 146) of KRAS and NRAS . In Study 20050203, among patients with RAS -mutant tumors, the median PFS was 7.3 months (95% CI: 6.3, 7.9) among 272 patients receiving Vectibix plus FOLFOX and 8.7 months (95% CI: 7.6, 9.4) among patients who received FOLFOX alone (HR = 1.31, 95% CI: 1.07, 1.60). The median OS was 15.6 months (95% CI: 13.4, 17.9) among patients receiving Vectibix plus FOLFOX and 19.2 months (95% CI: 16.7, 21.8) among patients who received FOLFOX alone (HR = 1.25, 95% CI: 1.02, 1.55). In Study 20100007, among patients with RAS -mutant tumors, no differences in OS or PFS were observed between the treatment arms [n = 54; OS HR = 0.99 (95% CI: 0.49, 2.00); PFS HR = 1.03 (95% CI: 0.56, 1.90)].

8.5 Geriatric Use Of the 737 patients who received Vectibix monotherapy in Study 20020408 and 20080763, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix monotherapy. Of the 322 patients in Study 20050203 who received Vectibix plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.

8.4 Pediatric Use The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetics of panitumumab at doses ranging from 2.5 mg/kg intravenous weekly, 6 mg/kg intravenous every 2 weeks, or 9 mg/kg intravenous every 3 weeks were evaluated in 28 pediatric patients. Panitumumab exposures were comparable in adult and adolescent patients of 12 to 17 years of age. Limited data suggested that pediatric patients of 2 to < 12 years of age had lower panitumumab exposure and higher clearance than that in adolescent patients following 6 mg/kg intravenous administration of Vectibix. There was no evidence of an anti-tumor treatment effect in these patients.

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to pregnant women [see Clinical Pharmacology ( 12.1 )] . Limited available data on the use of Vectibix in pregnant women are not sufficient to inform a risk of adverse pregnancy-related outcomes. Vectibix is a human IgG monoclonal antibody and may be transferred across the placenta during pregnancy. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [ see Data]. Advise pregnant women of the potential risk to the fetus. 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. ( 8.2 ) _______________________________________________________________________________________________________________________________________ 8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to pregnant women [see Clinical Pharmacology ( 12.1 )] . Limited available data on the use of Vectibix in pregnant women are not sufficient to inform a risk of adverse pregnancy-related outcomes. Vectibix is a human IgG monoclonal antibody and may be transferred across the placenta during pregnancy. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [ see Data]. Advise pregnant women of the potential risk to the fetus. 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight). 8.2 Lactation Risk Summary There are no data on the presence of panitumumab in human milk or the effects of panitumumab on the breastfed infant or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants from Vectibix, advise women not to breastfeed during treatment with Vectibix and for 2 months after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Vectibix can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Vectibix and for 2 months after the last dose of Vectibix. Infertility Females Based on results from animal fertility studies conducted in female cynomolgus monkeys, Vectibix may reduce fertility in females of reproductive potential. The effects in animal studies were reversible [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetics of panitumumab at doses ranging from 2.5 mg/kg intravenous weekly, 6 mg/kg intravenous every 2 weeks, or 9 mg/kg intravenous every 3 weeks were evaluated in 28 pediatric patients. Panitumumab exposures were comparable in adult and adolescent patients of 12 to 17 years of age. Limited data suggested that pediatric patients of 2 to < 12 years of age had lower panitumumab exposure and higher clearance than that in adolescent patients following 6 mg/kg intravenous administration of Vectibix. There was no evidence of an anti-tumor treatment effect in these patients. 8.5 Geriatric Use Of the 737 patients who received Vectibix monotherapy in Study 20020408 and 20080763, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix monotherapy. Of the 322 patients in Study 20050203 who received Vectibix plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Vectibix is supplied as a sterile, colorless, preservative-free solution containing 20 mg/mL panitumumab in a single-dose vial. Vectibix is provided as one vial per carton. Each 5 mL single-dose vial contains 100 mg of panitumumab in 5 mL (20 mg/mL) (NDC 55513-954-01). Each 20 mL single-dose vial contains 400 mg of panitumumab in 20 mL (20 mg/mL) (NDC 55513-956-01). Store vials in the original carton under refrigeration at 2° to 8°C (36° to 46°F) until time of use. Protect from direct sunlight. DO NOT FREEZE. Discard any unused portion remaining in the vial.

WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 )]. WARNING: DERMATOLOGIC TOXICITY See full prescribing information for complete boxed warning. Dermatologic toxicities were reported in 90 % of patients and were severe in 15 % of patients receiving monotherapy. ( 2.3 , 5.1 , 6.1 )