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Indications
Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of: Adult patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*: In combination with FOLFOX for first-line treatment. ( 1 , 14.2 ) As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.
( 1 , 14.1 ) KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC)* In combination with sotorasib, for the treatment of adult patients with KRAS G12C- mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. ( 1 ) *Limitations of Use: Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC unless used in combination with sotorasib in KRAS G12C-mutated mCRC.
Vectibix is not indicated for the treatment of patients with mCRC for whom RAS mutation status is unknown ( 1 , 2.1 , 5.2 , 12.1 , 14.3 ). Metastatic Colorectal Cancer (mCRC) RAS Wild-Type mCRC Vectibix is indicated for the treatment of adult patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test) metastatic colorectal cancer (mCRC) [see Dosage 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) ] . KRAS G12C -mutated mCRC Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with KRAS G12C- mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy [see Dosage and Administration (2.1) and Clinical Studies (14.4) ] .
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Limitations of Use : Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC unless used in combination with sotorasib in KRAS G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom RAS mutation status is unknown [see Dosage and Administration (2.1) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ] .
Contraindications
None. None
Warnings and precautions
Dermatologic and Soft Tissue Toxicity: Monitor for dermatologic and soft tissue toxicities. Reduce dose for recurrent Grade 3 toxicity and withhold or discontinue Vectibix for severe or life-threatening complications. Limit sun exposure. ( 2.3 , 5.1 , 5.7 ) Increased tumor progression, increased mortality, or lack of benefit in patients with RAS -mutant mCRC, receiving Vectibix monotherapy or in combination with oxaliplatin-based chemotherapy.
( 2.1 , 5.2 ) Electrolyte Depletion/Monitoring: Monitor electrolytes and institute appropriate treatment. ( 5.3 ) Infusion Reactions: Reduce infusion rate by 50% for mild to moderate reactions; terminate the infusion for severe infusion reactions. ( 2.3 , 5.4 ) Pulmonary Fibrosis/Interstitial Lung Disease (ILD): Permanently discontinue Vectibix in patients developing ILD. ( 5.6 ) Ocular Toxicities: Monitor for keratitis, ulcerative keratitis, or corneal perforation.
Interrupt or discontinue Vectibix for acute or worsening keratitis, ulcerative keratitis, or corneal perforation. ( 5.8 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with Vectibix and for 2 months after the last dose. ( 5.10 , 8.1 , 8.3 )
5.1Dermatologic and Soft Tissue Toxicity
Vectibix can cause dermatologic toxicity, which may be severe. Clinical manifestations included, but were not limited to, acneiform dermatitis, pruritis, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Among 229 patients who received Vectibix as monotherapy, dermatologic toxicity occurred in 90% including Grade 3 (15%). Among 585 patients who received Vectibix in combination with FOLFOX, dermatologic toxicity occurred in 96% including Grade 4 (1%) and Grade 3 (32%).
In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, dermatologic toxicities occurred in 94%, including Grade 3 (16%) of patients. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix.
Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1 , 6.2) ] .
Dose modifications for Vectibix concerning dermatologic toxicity are provided [see Dosage and Administration (2.3) ] .
5.2Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS-
Mutant mCRC Receiving Vectibix Monotherapy or in Combination with Oxaliplatin-based Chemotherapy Vectibix monotherapy or in combination with oxaliplatin-based chemotherapy 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) , Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ] .
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) 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 , overall survival (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) ] .
5.3Electrolyte Depletion/Monitoring
Vectibix can cause progressively decreasing serum magnesium levels leading to severe (Grade 3 or 4) hypomagnesemia. Among 229 patients who received Vectibix as monotherapy, decreased magnesium occurred in 38% including Grade 4 (1.3%) and Grade 3 (2.6%). Among 585 patients who received Vectibix in combination with FOLFOX, decreased magnesium occurred in 51% including Grade 4 (5%) and Grade 3 (6%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, decreased magnesium occurred in 69%, including Grade 4 (2.4%) and Grade 3 (14%).
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.
5.4Infusion 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 , 6.2) ] . Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3) ] .
5.5Acute Renal Failure
Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix. Among 229 patients who received Vectibix as monotherapy, acute renal failure occurred in 2% including Grade 3 or 4 (2%). Among 585 patients who received Vectibix in combination with FOLFOX, acute renal failure occurred in 2% including Grade 3 or 4 (2%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, acute renal failure occurred in 3.2% including Grade 3 (0.8%).
Monitor patients for diarrhea and dehydration, provide supportive care (including anti-emetic or anti-diarrheal therapy) as needed, and withhold Vectibix if necessary.
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. Grade 1 ILD/pneumonitis occurred in 0.8% (1/126) of patients enrolled in clinical studies of Vectibix in combination with sotorasib. 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.
5.7Photosensitivity Exposure
to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
5.8Ocular Toxicities
Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred with Vectibix use. Among 585 patients who received Vectibix in combination with FOLFOX, keratitis occurred in 0.3%. In 126 patients receiving Vectib
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Pregnancy and breastfeeding
8.1Pregnancy 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. 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).
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 Patients with RAS -Mutant mCRC Receiving Vectibix Monotherapy or in Combination with Oxaliplatin-based Chemotherapy [see Indications and Usage (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 [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 ) Most common adverse reactions (≥ 20%) in clinical trials of Vectibix in combination with sotorasib are rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain.
The most common Grade 3 or 4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium. ( 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 .
6.1Clinical 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 data described in WARNINGS AND PRECAUTIONS reflect exposure to Vectibix in four 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; Study 20050203, a randomized, controlled trial (N = 1183) in patients with wild-type KRAS mCRC that evaluated Vectibix in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone; CodeBreaK 300, a randomized controlled trial (N = 160) evaluating Vectibix in combination with sotorasib versus the investigator's choice of standard of care (trifluridine/tipiracil or regorafenib) in patients with KRAS G12C -mutated mCRC; and CodeBreak 101, an open-label, non-randomized trial evaluating sotorasib as a monotherapy and in combination with other drugs in patients with KRAS G12C-mutated advanced solid tumors, including patients with KRAS G12C-mutated mCRC who received Vectibix in combination with sotorasib (N = 79).
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. Safety data for CodeBreaK 300 are limited to 47 patients who received Vectibix in combination with sotorasib 960 mg. 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 monotherapy 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 System Organ Class Preferred Term Vectibix Plus Best Supportive Care (N = 229) Best Supportive Care (N = 234) Any Grade n (%) Grade 3-4 n (%) Any Grade n (%) Grade 3-4 n (%) Eye Disorders Growth of eyelashes 13 (6) Gastrointestinal Disorders 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) General Disorders and Administration Site Conditions Fatigue 60 (26) 10 (4) 34 (15) 7 (3) Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1) Infections and Infestations Paronychia 57 (25) 4 (2) Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7) Skin and Subcutaneous Tissue Disorders 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 with 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
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Composition
Active ingredients
PANITUMUMAB 10ML/200MG
Strengths and forms
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