Vectibix

Vectibix

panitumumab

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Panitumumab.
Description
Each mL of concentrate contains 20 mg panitumumab.
Each vial contains either: 100 mg (5 mL vial) of panitumumab (20 mg/mL).
Excipients/Inactive Ingredients: Sodium chloride, sodium acetate trihydrate, acetic acid, glacial (for pH adjustment), water for injection.
Action
Pharmacotherapeutic Group: Antineoplastic agents, monoclonal antibodies.
ATC code:
L01XC08.
Pharmacology: Pharmacodynamics:
In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumour cells expressing EGFR. No anti-tumour effects of panitumumab were observed in human tumour 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-tumour effects compared to radiation, chemotherapy or targeted therapeutic agents alone.
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 neutralising antibodies.
As monotherapy: The incidence of binding antibodies (excluding predose and transient positive patients) was <1% as detected by the acid-dissociation ELISA and 3.8% as detected by the Biacore assay.
The incidence of neutralising 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: 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 neutralising 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 neutralising 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.
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 antitumour 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 tumours and have been implicated in both oncogenesis and tumour progression.
Pharmacokinetics: VECTIBIX 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) AUC0-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 tumour cells had no apparent impact on the pharmacokinetics of panitumumab.
No clinical studies have been conducted to examine the pharmacokinetics of panitumumab 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 randomised controlled trial (463 patients, Study 20020408) and open-label, single-arm trials (384 patients, Study 20030167/20030250).
A multinational, randomised, 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 randomised 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 tumour tissue.
Tumour 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 favour 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 tumours and 0% (95% CI: 0.0, 4.3) for those with mutant KRAS tumours (Study 20030194).

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Clinical efficacy in combination with chemotherapy: Summary of key efficacy results in pivotal studies: VECTIBIX in combination with chemotherapy.

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The efficacy of VECTIBIX in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) was evaluated in a randomised, controlled trial of 1,183 patients with 17 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 tumour KRAS status. A summary of results in patients with wild-type KRAS mCRC are presented in the table above.
Primary analysis: The efficacy results in patients with wild-type KRAS (exon 2) mCRC and mutant KRAS mCRC are presented in Table 2. (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 in Table 3: (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 Table 4. (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 in Table 5. (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) tumour 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 in Table 6. (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 20 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 tumour 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 Table 7. (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 randomised, 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 tumour 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 favour 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), favouring 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), favouring 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), favouring 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), favouring 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 randomised, 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 favouring 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 unfavourable benefit-to-risk profile irrespective of tumour KRAS mutational status.
Toxicology: Preclinical safety data: Carcinogenicity: The carcinogenic potential of panitumumab has not been evaluated.
Mutagenicity: The mutagenic potential of panitumumab has not been evaluated in vitro or in vivo.
Reproductive toxicology: 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.
Pregnancy: Animal studies are insufficient with respect to embryo-foetal development since foetal panitumumab exposure levels were not examined. Panitumumab has been shown to cause foetal abortions and/or foetal deaths in cynomolgus monkeys when administered during the period of organogenesis at doses approximately equivalent to the recommended human dose. No pre- and post-natal development animal studies have been conducted with panitumumab. All patients should be advised regarding the potential risk of panitumumab on pre- and post-natal development prior to initiation of VECTIBIX therapy.
Indications/Uses
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.
Dosage/Direction for Use
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 Cautions for Usage).
DOSE MODIFICATIONS – INFUSION REACTIONS: 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. (See Table 8.)

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Management of skin toxicities: Proactive skin treatment including skin moisturiser, 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 moisturiser 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 moisturiser, 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 micrometre 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 Cautions for Usage.
Populations: Children: There is no experience in children and VECTIBIX should not be used in those patients less than 18 years of age. The safety and effectiveness of VECTIBIX in paediatric patients has not been established.
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.
Renal impairment: The safety and efficacy of VECTIBIX have not been studied in patients with renal impairment.
Hepatic impairment: The safety and efficacy of VECTIBIX have not been studied in patients with hepatic impairment.
Overdosage
Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhoea, dehydration, and fatigue.
Contraindications
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).
Special Precautions
RAS mutations: In patients with mutant RAS (exons 2,3,4 of KRAS and NRAS) mCRC or for whom RAS status is unknown, VECTIBIX should not be used in combination with oxaliplatin-based chemotherapy.
In other treatment settings (2nd and 3rd line) of mutant RAS mCRC, use of VECTIBIX should be considered with caution.
Dermatologic and soft tissue toxicity: Skin and subcutaneous tissue disorders, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, were frequently reported [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 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 post-marketing setting.
Stop or discontinue VECTIBIX for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications.
Eye toxicity: Very rarely (0.008%), serious cases of keratitis and/or ulcerative keratitis have been reported.
Patients who develop eye toxicities while receiving VECTIBIX should be monitored for evidence of keratitis or ulcerative keratitis.
Infusion reactions: Infusion reactions, including anaphylactic reactions, bronchospasm, and hypotension, have been reported in clinical trials and post-marketing 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.
From post-marketing experience, serious infusion reactions have been reported in < 1% of patients, very rarely with a fatal outcome (less than 1 in 10,000).
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 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, 5-fluorouracil, and leucovorin (IFL) chemotherapy: In a single-arm study (n = 19), patients receiving VECTIBIX in combination with irinotecan, 5-fluorouracil, and leucovorin administered as the IFL regimen experienced a high incidence of severe diarrhoea (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 randomised, open-label, multicentre study of 1,053 patients evaluated the efficacy 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 panitumumab 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 panitumumab group versus 37% in the Control group, with higher incidences in the panitumumab group of dehydration, diarrhoea, 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 panitumumab experienced a serious event that was considered related to panitumumab, the most common of which were diarrhoea, dehydration, and vomiting.
This study did not demonstrate an improvement in progression-free survival (the primary endpoint) by the addition of panitumumab 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. 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 panitumumab 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 panitumumab 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 16% (n = 108) of patients. A shortening of PFS and OS was observed in patients with mutant RAS mCRC who received panitumumab and FOLFOX (n = 51) versus FOLFOX alone (n = 57).
Acute renal failure: Acute renal failure has been observed in patients who develop severe diarrhoea 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 panitumumab in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy, patients with ECOG 2 (Eastern Cooperative Oncology Group) performance status (n = 40) were observed to have increased toxicity and significant shortening of progression-free survival (PFS) relative to ECOG 0 or 1 performance status (n = 616). 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.
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.
RAS tumour genetic marker testing: Mutational status should be determined by an experienced laboratory using a validated test method.
Determination of mutational status before initiation of VECTIBIX. (See Table 9.)

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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.
Fertility: Animal studies have shown reversible effects on the menstrual cycle and reduced female fertility in monkeys (see Pharmacology: Toxicology: Preclinical safety data under Actions). Panitumumab may impact the ability of a woman to become pregnant.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate studies in pregnant women.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. EGFR has been implicated in the control of pre-natal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Therefore, VECTIBIX has the potential to cause foetal harm when administered to pregnant women.
Human IgG is known to cross the placental barrier, and panitumumab may therefore be transmitted from the mother to the developing foetus. In women of childbearing potential, 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 foetus.
Use in Lactation: It is unknown whether panitumumab is excreted in human milk. 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.
Adverse Reactions
Summary of safety profile: Based on an analysis of all mCRC clinical trial patients receiving VECTIBIX monotherapy and in combination with chemotherapy (n = 2,588), the most commonly reported adverse reactions are skin reactions occurring in 93% of patients. These reactions are related to the pharmacologic effects of VECTIBIX, and the majority are mild to moderate in nature with 25% severe (grade 3 NCI-CTC) and < 1% life threatening (grade 4 NCI-CTC). For clinical management of skin reactions, including dose modification recommendations, see Precautions.
Commonly reported adverse reactions occurring in ≥20% of patients were gastrointestinal disorders [diarrhoea (50%), nausea (41%), vomiting (27%), constipation (23%) and abdominal pain (23%)]; general disorders [fatigue (37%), pyrexia (20%)]; metabolism and nutrition disorders [anorexia (27%)]; infections and infestations [paronychia (20%)]; and skin and subcutaneous disorders [rash (45%), dermatitis acneiform (39%), pruritus (35%), erythema (30%) and dry skin (22%)].
Tabulated summary of adverse reactions: The data in the table below describe adverse reactions reported from clinical studies in patients with mCRC who received panitumumab as a single agent or in combination with chemotherapy (n = 2,588). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 10.)

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The safety profile of VECTIBIX in combination with chemotherapy consisted of the reported adverse reactions of VECTIBIX (as a monotherapy) and the toxicities of the background chemotherapy regimen. No new toxicities or worsening of previously recognised toxicities beyond the expected additive effects were observed. Skin reactions were the most frequently occurring adverse reactions in patients receiving panitumumab in combination with chemotherapy. Other toxicities that were observed with a greater frequency relative to monotherapy included hypomagnesaemia, diarrhoea, and stomatitis. These toxicities infrequently led to discontinuation of VECTIBIX or of chemotherapy.
Description of selected adverse reactions: Gastrointestinal disorders: Diarrhoea when reported was mainly mild or moderate in severity. Severe diarrhoea (NCI-CTC grade 3 and 4) was reported in 2% of patients treated with VECTIBIX as a monotherapy and in 17% of patients treated with VECTIBIX in combination with chemotherapy.
There have been reports of acute renal failure in patients who develop diarrhoea and dehydration (see Precautions).
Infusion-related reactions: In the setting of infusion-related reactions occurring within 24 hours of infusion, adverse reactions including abdominal pain, anaphylactic reactions, angioedema, back pain, bronchospasm, cardiorespiratory arrest, chest pain, chills, cyanosis, dyspnoea, flushing, hypertension, hypotension, pyrexia, tachycardia and vomiting have been reported in clinical trials and in the post-marketing setting. Across all monotherapy mCRC clinical trials infusion-related reactions occurring within 24 hours of any infusion were reported in 3% of VECTIBIX-treated patients, of which 0.5% were severe (NCI-CTC grade 3 and 4). In clinical studies with irinotecan-based chemotherapy, severe infusion reactions (NCI-CTC grade 3 and 4) occurred in 0.1% of patients administered VECTIBIX in combination with irinotecan-based chemotherapy (n = 951) and in 0.2% of patients administered only irinotecan-based chemotherapy (n = 594). In clinical studies with oxaliplatin-based chemotherapy, severe infusion reactions (NCI-CTC grade 3 and 4) occurred in 2.4% of patients administered VECTIBIX in combination with oxaliplatin-based chemotherapy (n = 585) and 2.4% of patients administered only oxaliplatin-based chemotherapy (n = 584). In the post-marketing setting, serious infusion reactions have been reported, including rare reports with a fatal outcome.
A case of fatal angioedema occurred in a patient with recurrent and metastatic squamous cell carcinoma of the head and neck treated with VECTIBIX in a clinical trial. The fatal event occurred after re-exposure following a prior episode of angioedema; both episodes occurred greater than 24 hours after administration (see Contraindications and Precautions). Hypersensitivity reactions occurring more than 24 hours after infusion have also been reported in the post-marketing setting.
For clinical management of infusion-related reactions, see Precautions.
Skin and subcutaneous tissue disorders: Skin rash most commonly occurred on the face, upper chest, and back, but could extend to the extremities. Subsequent to the development of severe skin and subcutaneous reactions, infectious complications including sepsis, in rare cases leading to death, cellulitis and local abscesses requiring incisions and drainage were reported. The median time to first symptom of dermatologic reaction was 10 days, and the median time to resolution after the last dose of VECTIBIX was 28 days.
Paronychial inflammation was associated with swelling of the lateral nail folds of the toes and fingers.
Dermatological reactions (including nail effects), observed in patients treated with VECTIBIX or other EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy.
Across all clinical trials, skin reactions occurred in 93% of patients receiving VECTIBIX as monotherapy or in combination with chemotherapy (n = 2,588). These events consisted predominantly of rash and dermatitis acneiform and were mostly mild to moderate in severity. Severe (NCI-CTC grade 3) skin reactions were reported in 34% and life-threatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received VECTIBIX in combination with chemotherapy (n = 1,536).
For clinical management of dermatological reactions, including dose modification recommendations, see Precautions.
Post-marketing data: Skin necrosis has been reported very rarely.
Serious cases of keratitis/ulcerative keratitis have been reported very rarely.
Stevens-Johnson syndrome.
Toxic epidermal necrolysis.
Drug Interactions
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.
Caution For Usage
Instructions for use/handling: VECTIBIX must be administered using a low-protein binding 0.2 or 0.22 micrometre in-line filter.
DO NOT ADMINISTER VECTIBIX AS AN IV PUSH OR BOLUS.
Do not administer VECTIBIX if discolouration is observed.
VECTIBIX MUST BE ADMINISTERED BY IV INFUSION PUMP: Withdraw the necessary amount of VECTIBIX for a dose of 6 mg/kg or 2.5 mg/kg as appropriate.
Dilute in 100 mL of 0.9% sodium chloride USP. Final concentration should not exceed 10 mg/mL.
Diluted solution should be mixed by gentle inversion. DO NOT SHAKE.
Infuse over approximately 60 minutes through a peripheral line or indwelling catheter*. If the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes.
Flush line before and after VECTIBIX administration with 0.9% sodium chloride USP to avoid mixing with other drug products or IV solutions.
*If a patient's actual body weight requires a volume greater than 150 mL infusion, VECTIBIX may be administered over approximately 90 minutes.
Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Storage
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.
ATC Classification
L01XC08 - panitumumab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Infusion conc (vial, sterile, colourless solution which may contain visible translucent to white, amorphous, proteinaceous particles) 100 mg/5 mL x 1's.
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