Drug Safety-related Labeling Changes (SrLC)

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VECTIBIX (BLA-125147)

(PANITUMUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/16/2025 (SUPPL-213)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Dermatologic and Soft Tissue Toxicity

Additions and/or revisions underlined:

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.

…

5.2 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

Subsection title revised
Additions and/or revisions underlined:

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)].

5.3 Electrolyte Depletion/Monitoring

Additions and/or revisions underlined:

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.

5.5 Acute Renal Failure

Subsection title revised
Additions and/or revisions underlined:

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.

5.6 Pulmonary Fibrosis/Interstitial Lung Disease (ILD)

Additions and/or revisions underlined:

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.

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.

5.8 Ocular Toxicities

Additions and/or revisions underlined:

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 Vectibix in combination with sotorasib across clinical studies, keratitis occurred in 1.6%, ulcerative keratitis occurred in 0.8%, and vernal keratoconjunctivitis in 0.8% (all were Grade 1-2).

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.

6 Adverse Reactions

Additions and/or revisions underlined:

…

• 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)]

…

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 737 patients who received Vectibix monotherapy for recurrent or refractory mCRC [see Clinical Studies (14.1)], 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (greater than or equal to 65 years of age) treated with Vectibix monotherapy.

Of the 322 patients who received Vectibix plus FOLFOX, for wild-type KRAS-mutated mCRC [see Clinical Studies (14.2)], 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.

In a pooled analysis of 132 patients who received Vectibix in combination with sotorasib 960 mg for KRAS G12C-mutated mCRC, 30% were 65 and over while 9% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (greater than or equal to 65 years of age) compared to younger patients treated with Vectibix in combination with sotorasib.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Additions and/or revisions underlined:

…

Vectibix in Combination with Sotorasib:

Advise patients taking Vectibix in combination with sotorasib:

• to take the first dose of sotorasib prior to the first Vectibix infusion [see Dosage and Administration (2.2)].

• stop taking Vectibix whenever sotorasib is withheld or discontinued [see Dosage and Administration (2.3)].

08/25/2021 (SUPPL-210)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Ocular Toxicities

Additions and/or revisions underlined:

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.

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

• Eye Disorders: Keratitis/ulcerative keratitis, corneal perforation [see Warnings and Precautions (5.8)]

06/29/2017 (SUPPL-207)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Dermatologic and Soft Tissue Toxicity

(addition underlined)

In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

…

5.10 Embryo-fetal Toxicity

(new subsection added)

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.

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

(additions underlined)

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”.

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.

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

5.3 Electrolyte Depletion/Monitoring

(addition underlined)

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

(addition underlined)

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. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions to the text and Tables 1 & 2, please refer to label)

6.2 Immunogenicity

(additions underlined)

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.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to pregnant women. 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 . 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

(PLLR conversion, additions underlined)

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

(PLLR conversion)

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.

8.4 Pediatric Use

(additions underlined)

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

(additions underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Discuss the following with patients prior to treatment with Vectibix:

Skin and eye disorders:

 patients to contact a healthcare professional  if they experience skin or ocular/visual changes.

Electrolyte monitoring:

Inform patients of the need for periodic monitoring of electrolytes.

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.

Infusion reactions:

Advise patients of the risk of infusion reactions.

Respiratory:

Advise patients to contact a healthcare professional if they experience persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling.

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.

Lactation:

Advise women not to breastfeed during treatment with Vectibix and for 2 months after the last dose.

Infertility:

Advise females of reproductive potential of the potential for reduced fertility from Vectibix.

Sun exposure:

 patients to limit sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy.