Vectibix

Panitumumab.

Each mL of concentrate contains 20 mg panitumumab.
Each single-use vial contains 100 mg (5 mL vial) of panitumumab (20 mg/mL).
Excipients/Inactive Ingredients: Sodium chloride, Sodium acetate trihydrate, Glacial acetic acid (for pH adjustment), Water for injection.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates. ATC code: L01FE02.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Panitumumab is a recombinant fully human IgG2 monoclonal antibody that binds with high affinity to the ligand binding domain of human epidermal growth factor receptor (EGFR) and competitively inhibits receptor autophosphorylation induced by all known EGFR ligands. The addition of VECTIBIX to chemotherapy, radiation, or other targeted therapeutic agents in animal studies results in an increase in anti-tumor effects compared to chemotherapy or targeted therapeutic agents alone.
KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. KRAS and NRAS genes encodes a small, GTP-binding protein involved in signal transduction. A variety of stimuli, including that from the EGFR activates KRAS and NRAS, which in turn stimulates other intracellular proteins to promote cell proliferation, cell survival, and angiogenesis.
Activating mutations in the RAS gene occur frequently in a variety of human tumors and have been implicated in both oncogenesis and tumor progression.
Pharmacodynamic effects: In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumor cells expressing EGFR. No anti-tumor effects of panitumumab were observed in human tumor xenografts lacking EGFR expression. The addition of panitumumab to radiation, chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase in anti-tumor effects compared to radiation, chemotherapy or targeted therapeutic agents alone.
Pharmacokinetics: Panitumumab administered as a single agent or in combination with chemotherapy exhibits nonlinear pharmacokinetics.
Following a single-dose administration of panitumumab as a 1-hour infusion, 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 increases 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 micrograms/mL, respectively. The mean (± SD) AUC_0-tau and CL were 1,306 ± 374 micrograms·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), gender, race, hepatic function, renal function, chemotherapeutic agents, and EGFR membrane staining intensity (1+, 2+, 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.
Clinical studies: Clinical efficacy as monotherapy: The efficacy of VECTIBIX as monotherapy in patients with metastatic colorectal cancer (mCRC) who had disease progression during or after prior chemotherapy was studied in a randomized controlled trial (463 patients, Study 20020408) and open-label, single-arm trials (384 patients, Study 20030167/20030250).
A multinational, randomized, controlled trial was conducted in 463 patients (Study 20020408) with EGFR-expressing metastatic carcinoma of the colon or rectum after confirmed failure of oxaliplatin and irinotecan-containing regimens. Patients were randomized 1:1 to receive VECTIBIX at a dose of 6 mg/kg given once every two weeks plus best supportive care (not including chemotherapy) (BSC) or BSC alone. Patients were treated until disease progression or unacceptable toxicity occurred. Upon disease progression BSC alone patients were eligible to crossover to a companion study and receive VECTIBIX at a dose of 6 mg/kg given once every two weeks.
Of 463 patients, 63% were male. The median age was 62 years (range 27 to 83), and 99% were Caucasian. Three hundred and ninety-six (86%) patients had a baseline ECOG Performance Status of 0 or 1. Sixty-seven percent of patients had colon cancer and 33% had rectal cancer.
The primary endpoint was progression-free survival (PFS). In an analysis adjusting for potential bias from unscheduled assessments, the rate of disease progression or death in patients who received VECTIBIX was reduced by 40% relative to patients that received BSC [hazard ratio = 0.60, (95% CI: 0.49, 0.74), stratified log-rank p < 0.0001]. There was no difference seen in median PFS times as more than 50% of patients progressed in both treatment groups before the first scheduled visit.
The study was retrospectively analysed by wild-type KRAS status versus mutant KRAS status. KRAS mutation status was determined by analysis of archived paraffin embedded tumor tissue.
Tumor samples obtained from the primary resection of colorectal cancer were analysed for the presence of the seven most common activating mutations in the codon 12 and 13 (Gly12Asp, Gly12Ala, Gly12Val, Gly12Ser, Gly12Arg, Gly12Cys, and Gly13Asp) of the KRAS gene by using an allele-specific polymerase chain reaction. 427 (92%) patients were evaluable for KRAS status of which 184 had mutations. In an analysis adjusting for potential bias from unscheduled assessments the hazard ratio for PFS was 0.49 (95% CI: 0.37 - 0.65) in favor of panitumumab in the wild-type KRAS group and 1.07 (95% CI: 0.77 - 1.48) in the KRAS mutant group. The difference in median PFS in the wild-type KRAS group was 8 weeks. The progression-free survival rates at the first scheduled visit (week 8) in the wild-type KRAS group were 59.7% on VECTIBIX plus BSC and 21.0% on BSC alone, a difference of 38.7% [95% CI: 27.4, 50.0]. The difference in median PFS in the mutant KRAS group was 0 weeks. The progression-free survival rates at the first scheduled visit (week 8) in the mutant KRAS group were 21.4% on VECTIBIX plus BSC and 28.0% on BSC alone, a difference of -6.6% [95% CI: -19.0, 5.9]. There were no differences in overall survival seen in either group. In the wild-type KRAS group the response rate was 17% for panitumumab and 0% for BSC. In the mutant KRAS group there were no responses in either treatment arm. Stable disease rates in the wild-type KRAS group were 34% for panitumumab and 12% for BSC. The stable disease rates in the mutant KRAS group were 12% for panitumumab and 8% for BSC. Response rate (investigator assessment) in patients that crossed over to panitumumab after progression on BSC alone was 22% (95% CI: 14.0, 31.9) for those with wild-type KRAS tumors and 0% (95% CI: 0.0, 4.3) for those with mutant KRAS tumors (Study 20030194). (See Figures 1 and 2.)

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Clinical efficacy in combination with chemotherapy: Summary of key efficacy results in pivotal studies: VECTIBIX in combination with chemotherapy. (See Table 1.)

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The efficacy of VECTIBIX in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) was evaluated in a randomized, controlled trial of 1,183 patients with mCRC with the primary endpoint of progression-free survival (PFS) (Study 20050203). Other key endpoints included the overall survival (OS), objective response rate (ORR), time to response, time to progression (TTP), and duration of response. The study was prospectively analysed by tumor KRAS status. A summary of results in patients with wild-type KRAS mCRC are presented in Table 1.
Primary analysis: The efficacy results in patients with wild-type KRAS (exon 2) mCRC and mutant KRAS mCRC are presented in the table as follows. (See Table 2.)

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The results of an exploratory covariate analysis according to ECOG status in patients with wild-type KRAS (exon 2) mCRC are shown as follows: See Table 3.

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Final analysis: The efficacy results from the pre-specified final analysis which occurred 2 years after the last patient was enrolled in patients with wild-type KRAS (exon 2) mCRC and mutant KRAS mCRC are presented in the table as follows. (See Table 4.)

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The results of an exploratory covariate analysis according to ECOG status in patients with wild-type KRAS (exon 2) mCRC are shown as follows: See Table 5.

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Exploratory analysis of overall survival (OS): An exploratory analysis of mature overall survival (> 80% OS events) estimated the treatment effect of panitumumab plus FOLFOX compared with FOLFOX alone on OS by KRAS (exon 2) status. Previous analyses in patients with wild-type KRAS (exon 2) tumor status reported OS with an event rate of 54% of patients in the primary analysis and 68% of patients in the final analysis. Of 656 patients, 535 (82%) with wild-type KRAS (exon 2) mCRC had an OS event at the time of this analysis. Results are shown as follows. (See Table 6.)

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Predefined retrospective subset analysis of efficacy and safety by RAS (i.e., KRAS and NRAS) and RAS/BRAF biomarker status: A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) mCRC was performed. The primary objective of this analysis was to examine the treatment effect of panitumumab plus FOLFOX compared with FOLFOX alone in patients who were wild-type for RAS (KRAS and NRAS exons 2, 3, and 4) or wild-type for RAS and BRAF (KRAS and NRAS exons 2, 3, and 4 and BRAF exon 15). In this analysis, patient tumor samples with wild-type KRAS exon 2 (codons 12/13) status were tested using Sanger bidirectional sequencing and Surveyor/WAVE analysis in parallel for additional RAS mutations in KRAS exon 3 (codon 61) and exon 4 (codons 117/146) and NRAS exon 2 (codons 12/13), exon 3 (codon 61), and exon 4 (codons 117/146). In the analysis, the incidence of these additional RAS mutations in the wild-type KRAS (exon 2) population was approximately 16%.
In this analysis, BRAF mutation was not found to be predictive of negative outcome for panitumumab treatment.
Results in patients with wild-type RAS mCRC, mutant RAS mCRC and wild-type KRAS (exon 2) mutant RAS mCRC from the primary analysis are presented in the table as follows. (See Table 7.)

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Subsequent to the predefined analysis, additional mutations in KRAS and NRAS at exon 3 (codon 59) were identified (n = 7). In an exploratory analysis, adding codon 59 also appeared to be predictive of negative outcomes for panitumumab treatment.
The efficacy of VECTIBIX in combination with irinotecan, 5-fluorouracil (5-FU) and leucovorin (FOLFIRI) was evaluated in a randomized, controlled trial of 1,186 patients with mCRC with the primary endpoints of overall survival (OS) and progression-free survival (PFS) (Study 20050181). Other key endpoints included the objective response rate (ORR), time to response, time to progression (TTP), and duration of response. The study was prospectively analysed by tumor KRAS status. A summary of results in patients with wild-type KRAS mCRC are presented in the previous table.
In patients with wild-type KRAS mCRC (n = 597) a statistically significant difference in PFS in favor of panitumumab was demonstrated (p = 0.0036). The estimated median PFS times were 5.9 months (95% CI: 5.5, 6.7) in the panitumumab plus FOLFIRI arm and 3.9 months (95% CI: 3.7, 5.3) in the FOLFIRI alone arm, an absolute difference of 2.0 months. The hazard ratio was 0.732 (95% CI: 0.593, 0.903), favoring the panitumumab plus FOLFIRI arm. Estimated PFS rate (95% CI) at six (6) months was 49% (42%, 55%) in the panitumumab plus FOLFIRI arm and 35% (29%, 41%) in the FOLFIRI alone arm.
The estimated median OS was 14.5 months (95% CI: 13.0, 16.0) in the panitumumab plus FOLFIRI arm and 12.5 months (95% CI: 11.2, 14.2) in the FOLFIRI alone arm, an absolute difference of 2.0 months. The OS difference did not achieve statistical significance (p = 0.1154). The hazard ratio was 0.854 (95% CI: 0.702, 1.039), favoring the panitumumab plus FOLFIRI arm. Estimated OS rate (95% CI) at twelve (12) months was 59% (53%, 64%) in the panitumumab plus FOLFIRI arm and 53% (47%, 59%) in the FOLFIRI alone arm. Estimated OS rate (95% CI) at eighteen (18) months was 40% (35%, 46%) in the panitumumab plus FOLFIRI arm and 33% (27%, 39%) in the FOLFIRI alone arm. Subsequent chemotherapy (irinotecan, oxaliplatin, or fluoropyrimidine) was given to 142 (47%) subjects in the panitumumab plus FOLFIRI arm and 142 (48%) subjects in the FOLFIRI alone arm. Subsequent anti-EGFR therapy was received by 31 (10%) subjects in the panitumumab plus FOLFIRI arm and 90 (31%) subjects in the FOLFIRI alone arm. The median time to subsequent chemotherapy was 9.9 months in the panitumumab plus FOLFIRI arm and 7.6 months in the FOLFIRI alone arm. The median time to anti-EGFR therapy was 11.8 months (panitumumab plus FOLFIRI) and 7.6 months (FOLFIRI alone). The role of subsequent anti-EGFR therapy or chemotherapy on the estimated OS treatment effect is unknown.
The objective response rate was 35% for patients receiving panitumumab plus FOLFIRI and 10% for patients receiving FOLFIRI alone (all partial responses). The odds ratio for objective response was 5.33 (95% CI: 3.21, 8.60), favoring the panitumumab plus FOLFIRI arm. Stable disease was seen in 116 (39%) patients in the panitumumab plus FOLFIRI arm and 156 (55%) patients in the FOLFIRI alone arm.
The estimated mean (SD) for time to response for responding patients was 2.8 (1.6) months (panitumumab plus FOLFIRI) versus 3.3 (1.4) months (FOLFIRI alone). The duration of response was longer in the panitumumab plus FOLFIRI arm (median 7.6 months [95% CI: 6.7, 9.4]) than in the FOLFIRI alone arm (median 6.6 months [95% CI: 5.7, 10.4]). Time to disease progression was also longer in the panitumumab plus FOLFIRI arm (median 7.3 months [95% CI: 5.9, 7.5]) compared with the FOLFIRI alone arm (median 5.3 months [95% CI: 3.9, 5.7]; hazard ratio 0.683), favoring the panitumumab plus FOLFIRI arm.
Eighteen% (18%) (n = 115) of panitumumab patients had been exposed to prior bevacizumab treatment. PFS and Response Rate were similar regardless of prior bevacizumab treatment.
In an exploratory covariate analysis, longer median OS was observed in the panitumumab plus FOLFIRI arm than in the FOLFIRI alone arm regardless of ECOG performance status (ECOG 0 or 1: 14.7 months vs. 12.8 months, hazard ratio 0.839; 95% CI: 0.685, 1.027; p = 0.0885; ECOG 2: 5.7 months vs. 4.8 months, hazard ratio 1.135; 95% CI: 0.512, 2.517; p = 0.7549).
In patients with mutant KRAS mCRC (n = 486), no significant difference in PFS (HR (95% CI): 0.85 (0.68, 1.06)) and OS (HR (95% CI): 0.94 (0.76, 1.15)) was observed between treatment arms. VECTIBIX is indicated only for the treatment of wild-type KRAS mCRC.
In a randomized, open-label, controlled clinical trial, chemotherapy (oxaliplatin or irinotecan) and bevacizumab were given with and without panitumumab in the first-line treatment of patients with metastatic colorectal cancer (n = 1,053 [n = 823 oxaliplatin cohort, n = 230 irinotecan cohort]) (Study 20040249). Panitumumab treatment was discontinued due to a statistically significant reduction in PFS in patients receiving panitumumab observed in an interim analysis.
The major study objective was comparison of PFS in the oxaliplatin cohort. In the final analysis, the hazard ratio for PFS was 1.27 (95% CI: 1.06, 1.52). Median PFS was 10.0 (95% CI: 8.9, 11.0) and 11.4 (95% CI: 10.5, 11.9) months in the panitumumab and the non-panitumumab arm, respectively. There was an increase in mortality in the panitumumab arm. The hazard ratio for overall survival was 1.43 (95% CI: 1.11, 1.83). Median overall survival was 19.4 (95% CI: 18.4, 20.8) and 24.5 (95% CI: 20.4, 24.5) in the panitumumab arm and the non-panitumumab arm.
An additional analysis of efficacy data by KRAS status did not identify a subset of patients who benefited from panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. For the wild-type KRAS subset of the oxaliplatin cohort, the hazard ratio for PFS was 1.36 with 95% CI: 1.04 - 1.77. For the mutant KRAS subset, the hazard ratio for PFS was 1.25 with 95% CI: 0.91 - 1.71. A trend for OS favoring the control arm was observed in the wild-type KRAS subset of the oxaliplatin cohort (hazard ratio = 1.89; 95% CI: 1.30, 2.75). A trend towards worse survival was also observed with panitumumab in the irinotecan cohort regardless of KRAS mutational status. Overall, panitumumab treatment combined with chemotherapy and bevacizumab is associated with an unfavorable benefit-to-risk profile irrespective of tumor KRAS mutational status.
Toxicology: Preclinical safety data/Nonclinical toxicology: Carcinogenesis: The carcinogenic potential of VECTIBIX has not been evaluated.
Mutagenesis: The mutagenic potential of VECTIBIX has not been evaluated in vitro or in vivo.
Impairment of fertility: Formal male fertility studies have not been conducted; however, microscopic evaluation of male reproductive organs from cynomolgus monkeys administered VECTIBIX for 26 weeks at doses ranging up to 5-fold the human dose revealed no differences compared to control male monkeys. Fertility studies conducted in female cynomolgus monkeys showed that VECTIBIX may produce secondary effects that could impact the ability of a woman to become pregnant while receiving VECTIBIX.

VECTIBIX in combination with oxaliplatin-based chemotherapy is indicated for the treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC).
VECTIBIX is indicated for the treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC) in combination with irinotecan-based chemotherapy.
VECTIBIX monotherapy is indicated for the treatment of patients with wild-type RAS mCRC after failure of standard chemotherapy.

Posology: VECTIBIX treatment should be supervised by a physician experienced in the use of anti-cancer therapy.
RAS mutational status should be determined by an experienced laboratory using a validated test method.
Recommended dose: 6 mg/kg bodyweight given once every 2 weeks.
Prior to infusion, VECTIBIX should be diluted in 0.9% sodium chloride to a final concentration not to exceed 10 mg/mL (for preparation instructions see Special instructions for use and handling under Cautions for Usage).
DOSE MODIFICATIONS - INFUSION REACTIONS: See Infusion reactions under Precautions. Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.
Stop infusion if a severe or life-threatening infusion reaction occurs and depending on the severity and/or persistence of the reaction, consider permanently discontinuing VECTIBIX.
DOSE MODIFICATIONS - DERMATOLOGIC TOXICITY: See Table 8.

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MANAGEMENT OF SKIN TOXICITIES: Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), topical steroid cream (not stronger than 1% hydrocortisone) and an oral antibiotic, as prescribed by the physician, may be useful in the management of skin toxicities. Patients may be advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night. Treatment of skin reactions should be based on severity and may include a moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by the physician.
Method of administration: VECTIBIX must be administered as an intravenous (IV) infusion via an infusion pump, using a low protein binding 0.2 or 0.22 micrometer in-line filter, through a peripheral line or indwelling catheter.
The recommended infusion time is approximately 60 minutes. Doses higher than 1,000 mg should be infused over approximately 90 minutes. The infusion line should be flushed with 0.9% sodium chloride solution before and after VECTIBIX administration to avoid mixing with other medicinal products or IV solutions.
Do not administer VECTIBIX as an IV push or bolus.
For instructions on dilution of the medicinal product before administration, see Special instructions for use and handling under Cautions for Usage.

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

VECTIBIX is contraindicated in patients with a history of life-threatening hypersensitivity reactions to panitumumab or any of the excipients.
For patients with mutant RAS mCRC or for whom RAS status is unknown, the combination of VECTIBIX with oxaliplatin-based chemotherapy is contraindicated (see Precautions).

Dermatologic and soft tissue toxicity: Skin and subcutaneous tissue disorders, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, were frequently reported [approximately 93% in patients across the monotherapy mCRC clinical trials (n = 1,052)].
It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving VECTIBIX as sunlight can exacerbate any skin reactions that may occur.
For dose modifications related to dermatological toxicity, see DOSE MODIFICATIONS - DERMATOLOGIC TOXICITY under Dosage & Administration.
Patients who develop dermatologic or soft tissue toxicities while receiving VECTIBIX should be monitored for the development of inflammatory or infectious sequelae.
Life-threatening and fatal infectious complications including events of necrotising fasciitis and/or sepsis have been observed in patients treated with VECTIBIX.
Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with VECTIBIX in the postmarketing setting.
Stop or discontinue VECTIBIX for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications.
Eye toxicity: Serious cases of keratitis, ulcerative keratitis, and corneal perforation have been reported. Patients who develop eye toxicities while receiving VECTIBIX should be monitored for evidence of keratitis, ulcerative keratitis, or corneal perforation.
Infusion reactions: Infusion reactions, including anaphylactic reactions, bronchospasm, and hypotension, have been reported in clinical trials and postmarketing experience. Across the monotherapy mCRC clinical trials (n = 1,052), severe infusion reactions (NCI-CTC grade 3 and grade 4) occurred with the administration of VECTIBIX in 0.5% of patients.
In the (pooled) irinotecan-based chemotherapy with VECTIBIX (n = 951) and the irinotecan-based chemotherapy alone (n = 594) settings, severe infusion reactions (NCI-CTC grade 3 and grade 4) occurred in 0.1% and 0.2% of patients, respectively. In the oxaliplatin-based chemotherapy with VECTIBIX (n = 585) and the oxaliplatin-based chemotherapy alone (n = 584) settings, severe infusion reactions (NCI-CTC grade 3 and grade 4) occurred in 2.4% of patients in both treatment arms.
Stop infusion if a severe or life-threatening infusion reaction occurs. Depending on the severity and/or persistence of the reaction, consider permanently discontinuing VECTIBIX.
Other hypersensitivity reactions: Hypersensitivity reactions have been reported, including a fatal case of angioedema that occurred more than 24 hours after the infusion. Depending on the severity (e.g., presence of bronchospasm, edema, angioedema, hypotension, need for parenteral medication, or anaphylaxis) and/or persistence, of the hypersensitivity reactions; permanently discontinue VECTIBIX (see Contraindications and Adverse Reactions).
Pulmonary toxicity: Fatal and non-fatal cases of interstitial lung disease (ILD) have been observed in patients treated with EGFR inhibitors including VECTIBIX. In the event of acute onset or worsening of pulmonary symptoms, VECTIBIX therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, VECTIBIX should be permanently discontinued and the patient should be treated appropriately.
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.
VECTIBIX in combination with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapy: In a single-arm study (n = 19), patients receiving VECTIBIX in combination with irinotecan, bolus 5-fluorouracil, and leucovorin administered as the IFL regimen experienced a high incidence of severe diarrhea (58%), therefore, administration of VECTIBIX in combination with IFL should be avoided.
VECTIBIX in combination with bevacizumab and oxaliplatin-containing chemotherapeutic regimens or VECTIBIX in combination with bevacizumab and irinotecan-containing chemotherapeutic regimens for first-line treatment of metastatic colorectal cancer: A randomized, open-label, multicenter study of 1,053 patients evaluated the efficacy and safety of bevacizumab and oxaliplatin- or irinotecan-containing chemotherapeutic regimens with and without VECTIBIX in the first-line treatment of metastatic colorectal cancer.
Across both chemotherapy treatment groups, more toxicity was seen in the VECTIBIX group, manifesting as a greater incidence of grade 3 and higher adverse events, a greater incidence of serious adverse events, and more overall deaths relative to the control group. Similar safety trends were seen for the oxaliplatin and irinotecan treatment groups separately.
Serious adverse events were experienced by 59% in the VECTIBIX group versus 37% in the control group, with higher incidences in the VECTIBIX group of dehydration, diarrhea, pulmonary embolism, nausea, and vomiting. Serious infections overall displayed a treatment difference (15% versus 9%); however, no one specific type of infection occurred at a high frequency. Nineteen percent of patients receiving VECTIBIX experienced a serious event that was considered related to VECTIBIX, the most common of which were diarrhea, dehydration, and vomiting.
This study did not demonstrate an improvement in progression-free survival (the primary endpoint) by the addition of VECTIBIX to bevacizumab and oxaliplatin-based chemotherapy. The addition of VECTIBIX to the combination of bevacizumab and chemotherapy in first-line metastatic colorectal cancer is not indicated.
VECTIBIX in combination with oxaliplatin-based chemotherapy in patients with mutant RAS mCRC or for whom RAS status is unknown: VECTIBIX should not be administered in combination with oxaliplatin-containing chemotherapy to patients with mutant RAS mCRC or for whom RAS status is unknown (see Contraindications).
In the primary analysis of a phase 3 study (n = 1,183; 656 patients with wild-type KRAS (exon 2) and 440 patients with mutant KRAS mCRC) evaluating VECTIBIX in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared with FOLFOX alone as first-line therapy for mCRC, a significant shortening of progression-free survival (PFS) was observed in patients with mutant KRAS mCRC who received VECTIBIX and FOLFOX (n = 221) versus FOLFOX alone (n = 219). A trend toward shortened overall survival (OS) time was also observed in the mutant KRAS mCRC population.
A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) mCRC from the phase 3 study identified additional RAS (KRAS [exons 3 and 4] or NRAS [exons 2, 3, 4]) mutations in 17% (n = 108) of patients. A shortening of PFS and OS was observed in patients with mutant RAS mCRC who received VECTIBIX and FOLFOX (n = 51) versus FOLFOX alone (n = 57) (see Laboratory tests as follows).
Acute renal failure: Acute renal failure has been observed in patients who develop severe diarrhea and dehydration.
Patients with ECOG 2 performance status treated with VECTIBIX in combination with chemotherapy: In a phase 3 study (n = 1,183; 656 patients with wild-type KRAS and 440 patients with mutant KRAS mCRC) evaluating VECTIBIX in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy, wild-type KRAS mCRC patients with ECOG 2 (Eastern Cooperative Oncology Group) performance status [n = 37; n = 19 (VECTIBIX plus FOLFOX), n = 18 (FOLFOX alone)] were observed to have increased toxicity and significant shortening of progression-free survival (PFS) and overall survival (OS) relative to ECOG 0 or 1 performance status (n = 611). In patients with wild-type KRAS mCRC, adverse events with > 20% difference between treatment arms within each ECOG group, and a > 5% difference between ECOG groups of the VECTIBIX plus FOLFOX arm were hypomagnesemia, hypokalemia, anemia, and weight decreased. Similar safety findings were observed in patients with wild-type RAS mCRC. For patients with ECOG 2 performance status, assessment of risk-benefit is recommended prior to initiation of VECTIBIX in combination with chemotherapy for treatment of mCRC.
Laboratory tests: Electrolyte disturbances/monitoring: Progressively decreasing serum magnesium levels leading to severe hypomagnesaemia have been observed in some patients. Patients should be monitored for hypomagnesaemia and accompanying hypocalcaemia prior to initiating VECTIBIX treatment, and periodically during VECTIBIX treatment and for up to 8 weeks after the completion of treatment. Magnesium repletion is recommended, as appropriate.
Other electrolyte disturbances, including hypokalaemia, have also been observed. Repletion of these electrolytes is also recommended, as appropriate.
Tumor genetic marker testing: Evidence of wild-type RAS (KRAS and NRAS) status is required before initiating treatment with VECTIBIX. Mutational status should be determined by an experienced laboratory using validated test methods for detection of KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) mutations (see Contraindications).
Effects on ability to drive and use machines: No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving panitumumab. If patients experience treatment-related symptoms affecting their vision and/or ability to concentrate and react, it is recommended that they do not drive or use machines until the side effect subsides.
Use in Children: The safety and effectiveness of VECTIBIX in pediatric patients has not been established.
Use in the Elderly: No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with VECTIBIX monotherapy. However, an increased number of serious adverse events were reported in elderly patients treated with VECTIBIX in combination with irinotecan or oxaliplatin-based chemotherapy compared to chemotherapy alone.

Pregnancy: There are no studies in pregnant women. Women of reproductive potential should be advised to avoid becoming pregnant.
EGFR has been implicated in the control of pre-natal development. VECTIBIX has been shown to be an abortifacient in cynomolgus monkeys when administered during the period of organogenesis.
In women of childbearing potential, effective contraceptive measures must be used during treatment with VECTIBIX, and for 2 months following the last dose of VECTIBIX. If the patient becomes pregnant while receiving VECTIBIX, the patient should be apprised of the potential risk for loss of the pregnancy or potential hazard to the fetus (see PHARMACOLOGY: Toxicology: Preclinical safety data/Nonclinical toxicology under Actions).
Lactation: Because human IgG is secreted into human milk, VECTIBIX might also be secreted. The potential for absorption and harm to the infant after ingestion is unknown.
It is recommended that women discontinue nursing when during treatment with VECTIBIX and for 2 months after the last dose of VECTIBIX.
Fertility: No data are available on the effect of VECTIBIX on human fertility. See PHARMACOLOGY: Toxicology: Preclinical safety data/Nonclinical toxicology under Actions for the effects on fertility in nonclinical study in the monkey.

Summary of safety profile: Based on an analysis of mCRC clinical trial patients receiving VECTIBIX monotherapy and in combination with chemotherapy (n = 2,224), adverse reactions occurring in ≥ 20% of patients were gastrointestinal disorders [diarrhea (46%), nausea (39%), vomiting (26%), abdominal pain (23%) and constipation (23%)]; general disorders [fatigue (35%) and pyrexia (21%)]; infections and infestations [paronychia (20%)]; metabolism and nutrition disorders [decreased appetite (30%)]; and skin and subcutaneous disorders [rash (47%), dermatitis acneiform (39%), pruritus (36%), erythema (33%) and dry skin (21%)].
Tabulated summary of adverse reactions: Adverse reactions are presented in table as follows by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in a dataset of pooled clinical studies (N = 2,224). (See Tables 9a and 9b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Postmarketing Experience: The following serious adverse reactions have been reported in the postmarketing setting: corneal perforation^a; skin necrosis; Stevens-Johnson syndrome; toxic epidermal necrolysis; ulcerative keratitis.
^a Corneal perforation includes keratorhexis and corneal perforation.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. 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) and a Biacore biosensor immunoassay. For patients whose sera tested positive in either screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
As monotherapy: The incidence of binding antibodies (excluding predose and transient positive patients) was < 1% as detected by the acid-dissociation ELISA and 3.3% as detected by the Biacore assay.
The incidence of neutralizing antibodies (excluding predose and transient positive patients) was < 1%.
There was no evidence of altered pharmacokinetic or toxicity profiles in patients who developed antibodies to VECTIBIX.
In combination with irinotecan- or oxaliplatin-based chemotherapy [Optional wild-type KRAS incidences are presented in brackets]: The incidence of binding antibodies (excluding predose positive patients) was 1.0% [(1.2% in patients with wild-type KRAS mCRC)] as detected by the acid-dissociation ELISA and < 1% [(< 1% in patients with wild-type KRAS mCRC)] as detected by the Biacore assay.
The incidence of neutralizing antibodies (excluding predose positive patients) was < 1% [(< 1% in patients with wild-type KRAS mCRC)].
No evidence of an altered safety profile was found in patients who tested positive for antibodies to VECTIBIX.
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 with the subject incidence of antibodies to other products may be misleading.

Data from a drug-drug interaction study involving VECTIBIX and irinotecan in patients with mCRC indicate that the pharmacokinetics of irinotecan and its active metabolite, SN-38, are not altered when the drugs are co-administered.
Results from a cross-study comparison indicated that irinotecan-containing regimens (IFL or FOLFIRI) have no effect on the pharmacokinetics of panitumumab.

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Special instructions for use and handling: Prior to administration, VECTIBIX is diluted in 0.9% sodium chloride to a maximum concentration of ≤ 10 mg/mL: VECTIBIX should be inspected visually prior to administration. The solution should be colorless and may contain visible translucent-to-white, amorphous, proteinaceous particulates (which will be removed by in-line filtration). Do not administer VECTIBIX if its appearance is not as described previously.
Do not use a hypodermic needle with a gauge less than a 21-gauge to withdraw the necessary amount of VECTIBIX for a dose of 6 mg/kg or 2.5 mg/kg as appropriate. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents.
Dilute in 0.9% sodium chloride injection USP/Ph Eur/JP to a maximum concentration of ≤ 10 mg/mL and total volume of 100 mL.
Diluted solution should be mixed by gentle inversion. DO NOT SHAKE.
Discard the vial and any liquid remaining in the vial after the single-use.

Store in a refrigerator (2 - 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from direct light.
Do not shake.
VECTIBIX does not contain any antimicrobial preservative or bacteriostatic agent. The product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should be no longer than 24 hours at 2°C to 8°C.

Targeted Cancer Therapy

L01FE02 - panitumumab ; Belongs to the class of EGFR (Epidermal Growth Factor Receptor) inhibitors. Used in the treatment of cancer.

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