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: 100 mg (5 mL vial) of panitumumab (20 mg/mL).
When prepared according to the instructions given in Instructions for Use/Handling under Cautions for Usage, the final panitumumab concentration should not exceed 10 mg/mL.
Panitumumab is a fully human monoclonal IgG2 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.
Excipient with known effect: Each mL of concentrate contains 0.150 mmol sodium, which is 3.45 mg sodium.
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: Mechanism of action: Panitumumab is a recombinant fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and HER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle, and is expressed on a variety of tumour cells.
Panitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation induced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation of the receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular endothelial growth factor production.
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 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.
Pharmacodynamic effects: 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.
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 (with cross-reference to Dosage & Administration and Adverse Reactions).
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Data on the development of anti-panitumumab antibodies has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies (an ELISA which detects high-affinity antibodies, and a Biosensor Immunoassay which detects both high and low-affinity antibodies) 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%.
Compared with patients who did not develop antibodies, no relationship between the presence of anti-panitumumab antibodies and pharmacokinetics, efficacy and safety has been observed. In combination with irinotecan- or oxaliplatin-based chemotherapy: The incidence of binding antibodies (excluding predose positive patients) was 1.0% as detected by the acid-dissociation ELISA and < 1% as detected by the Biacore assay.
The incidence of neutralising antibodies (excluding predose positive patients) was < 1%.
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. The observed incidence of 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, therefore, comparison of the incidence of antibodies to other products may be misleading.
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) and open-label, single-arm trials (384 patients).
A multinational, randomised, controlled trial was conducted in 463 patients 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. Four hundred and twenty seven (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.
PFS - Patients with mutant and wild-type KRAS: (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 randomised, controlled trial of 1,183 patients with mCRC with the primary endpoint of progression-free survival (PFS). 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 (exon 2) status which was evaluable in 93% of the patients.
Primary analysis: The efficacy results in patients with wild-type KRAS (exon 2) mCRC and mutant KRAS mCRC are presented in Table 2 as follows.

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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 4 as follows.

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The results of an exploratory covariate analysis according to ECOG status in patients with wildtype 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) tumour status reported OS with an event rate of 54% of patients in the primary analysis and 68% of patients in the final analysis. 535/656 patients (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 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 the Table 7 as follows.

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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). 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 table as previously mentioned.
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]). 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.
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 (± Standard Deviation [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.
Toxicology: Pre-clinical safety data: Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Skin rash and diarrhoea were the major findings observed in repeat-dose toxicity studies of up to 26 weeks duration in cynomolgus monkeys. These findings were observed at doses approximately equivalent to the recommended human dose and were reversible upon termination of administration of panitumumab. The skin rash and diarrhoea observed in monkeys are considered related to the pharmacological action of panitumumab and are consistent with the toxicities observed with other anti-EGFR inhibitors.
Studies to evaluate the mutagenic and carcinogenic potential of panitumumab have not been performed.
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.
Formal male fertility studies have not been conducted; however, microscopic evaluation of male reproductive organs from repeat-dose toxicity studies in cynomolgus monkeys at doses up to approximately 5-fold the human dose on a mg/kg basis, revealed no differences compared to control male monkeys. Fertility studies conducted in female cynomolgus monkeys showed that panitumumab may produce prolonged menstrual cycle and/or amenorrhea and reduced pregnancy rate which occurred at all doses evaluated.
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 is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC): In first-line in combination with FOLFOX.
In second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
As monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
Dosage/Direction for Use
Vectibix treatment should be supervised by a physician experienced in the use of anti-cancer therapy.
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.
Posology: The recommended dose of Vectibix is 6 mg/kg of bodyweight given once every two 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 Instructions for Use/Handling under Cautions for Usage).
Modification of the dose of Vectibix may be necessary in cases of severe (≥ grade 3) dermatological reactions (see Precautions).
Special populations: The safety and efficacy of Vectibix have not been studied in patients with renal or hepatic impairment. There is no clinical data to support dose adjustments in the elderly.
Paediatric population: There is no relevant use of Vectibix in the paediatric population in the indication treatment of colorectal cancer.
Method of administration: Vectibix must be administered as an intravenous 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. If the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes. Doses higher than 1,000 mg should be infused over approximately 90 minutes (for handling instructions, Instructions for Use/Handling under Cautions for Usage).
The infusion line should be flushed with sodium chloride solution before and after Vectibix administration to avoid mixing with other medicinal products or intravenous solutions.
A reduction in the rate of infusion of Vectibix may be necessary in cases of infusion-related reactions (see Precautions).
Vectibix must not be administered as an intravenous push or bolus.
For instructions on dilution of the medicinal product before administration, see Instructions for Use/Handling under Cautions for Usage.
Overdosage
Symptoms of overdose: Doses up to 9 mg/kg have been tested in clinical trials. There have been reports of overdose at doses up to approximately twice the recommended therapeutic dose (12 mg/kg). Adverse events observed included skin toxicity, diarrhoea, dehydration and fatigue and were consistent with the safety profile at the recommended dose.
Treatment of overdose: Further management should be as clinically indicated or as recommended by the national poisons centre.
Contraindications
Patients with a history of severe or life-threatening hypersensitivity to the active substance or to any of the excipients listed in Description (see Precautions).
Patients with interstitial pneumonitis or pulmonary fibrosis (see Precautions).
The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown (see Precautions).
Special Precautions
Dermatologic reactions and soft tissue toxicity: Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 94%) treated with Vectibix. Severe (NCI-CTC grade 3) skin reactions were reported in 32% and life-threatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received Vectibix in combination with chemotherapy (n = 1,172) (see Adverse Reactions). If a patient develops dermatologic reactions that are grade 3 (CTCAE v 4.0) or higher, or that are considered intolerable, the following dose modification is recommended: (See Table 8.)

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In clinical studies, subsequent to the development of severe dermatologic reactions (including stomatitis), infectious complications including sepsis and necrotising fasciitis, in rare cases leading to death, and local abscesses requiring incisions and drainage were reported. Patients who have severe dermatologic reactions or soft tissue toxicity or who develop worsening reactions whilst receiving Vectibix should be monitored for the development of inflammatory or infectious sequelae (including cellulitis and necrotising fasciitis), and appropriate treatment promptly initiated. Life threatening and fatal infectious complications including necrotising fasciitis and sepsis have been observed in patients treated with Vectibix. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix in the post-marketing setting. Withhold or discontinue Vectibix in the event of dermatologic or soft tissue toxicity associated with severe or life threatening inflammatory or infectious complications.
Treatment of dermatologic reactions should be based on severity and may include a moisturiser, sun screen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics. It is also recommended that patients experiencing rash/dermatological toxicities wear sunscreen and hats and limit sun exposure as sunlight can exacerbate any skin reactions that may occur.
Proactive skin treatment including skin moisturiser, sun screen (SPF > 15 UVA and UVB), topical steroid cream (not stronger than 1% hydrocortisone) and an oral antibiotic (e.g. doxycycline) may be useful in the management of dermatologic reactions. 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 during treatment.
Pulmonary complications: Patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded from clinical studies. Cases of interstitial lung disease (ILD), both fatal and non-fatal, have been reported, mainly from the Japanese population. In the event of acute onset or worsening pulmonary symptoms, Vectibix treatment should be interrupted and a prompt investigation of these symptoms should occur. If ILD is diagnosed, Vectibix should be permanently discontinued and the patient should be treated appropriately. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with panitumumab versus the risk of pulmonary complications must be carefully considered.
Electrolyte disturbances: Progressively decreasing serum magnesium levels leading to severe (grade 4) hypomagnesaemia have been observed in some patients. Patients should be periodically monitored for hypomagnesaemia and accompanying hypocalcaemia prior to initiating Vectibix treatment, and periodically thereafter for up to 8 weeks after the completion of treatment (see Adverse Reactions). Magnesium repletion is recommended, as appropriate.
Other electrolyte disturbances, including hypokalaemia, have also been observed. Monitoring as above and repletion as appropriate of these electrolytes is also recommended.
Infusion related reactions: Across monotherapy and combination mCRC clinical studies (n = 2,224), infusion-related reactions (occurring within 24 hours of an infusion) were reported in approximately 5% of Vectibix-treated patients, of which 1% were severe (NCI-CTC grade 3 and grade 4).
In the post-marketing setting, serious infusion-related reactions have been reported, including rare post-marketing reports with a fatal outcome. If a severe or life-threatening reaction occurs during an infusion or at any time post-infusion [e.g. presence of bronchospasm, angioedema, hypotension, need for parenteral treatment, or anaphylaxis], Vectibix should be permanently discontinued (see Contraindications and Adverse Reactions).
In patients experiencing a mild or moderate (CTCAE v 4.0 grades 1 and 2) infusion-related reaction the infusion rate should be reduced for the duration of that infusion. It is recommended to maintain this lower infusion rate in all subsequent infusions.
Hypersensitivity reactions occurring more than 24 hours after infusion have been reported including a fatal case of angioedema that occurred more than 24 hours after the infusion. Patients should be informed of the possibility of a late onset reaction and instructed to contact their physician if symptoms of a hypersensitivity reaction occur.
Acute renal failure: Acute renal failure has been observed in patients who develop severe diarrhoea and dehydration. Patients who experience severe diarrhoea should be instructed to consult a healthcare professional urgently.
Vectibix in combination with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapy: Patients receiving Vectibix in combination with the IFL regimen [bolus 5-fluorouracil (500 mg/m2), leucovorin (20 mg/m2) and irinotecan (125 mg/m2)] experienced a high incidence of severe diarrhoea (see Adverse Reactions). Therefore administration of Vectibix in combination with IFL should be avoided (see Interactions).
Vectibix in combination with bevacizumab and chemotherapy regimens: 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. Shortened progression-free survival time and increased deaths were observed in the patients receiving Vectibix in combination with bevacizumab and chemotherapy. A greater frequency of pulmonary embolism, infections (predominantly of dermatologic origin), diarrhoea, electrolyte imbalances, nausea, vomiting and dehydration was also observed in the treatment arms using Vectibix in combination with bevacizumab and chemotherapy. An additional analysis of efficacy data by KRAS status did not identify a subset of patients who benefited from Vectibix in combination with oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. A trend towards worse survival was observed with Vectibix in the wild-type KRAS subset of the bevacizumab and oxaliplatin cohort, and a trend towards worse survival was observed with Vectibix in the bevacizumab and irinotecan cohort regardless of KRAS mutational status. Therefore, Vectibix should not be administered in combination with bevacizumab containing chemotherapy (see Interactions and Pharmacology: Pharmacodynamics under Actions).
Vectibix in combination with oxaliplatin-based chemotherapy in patients with mutant RAS mCRC or for whom RAS tumour status is unknown: The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown (see Contraindications and Pharmacology: Pharmacodynamics under Actions).
In the primary analysis of a study (n = 1,183, 656 patients with wild-type KRAS (exon 2) and 440 patients with mutant KRAS tumours) evaluating panitumumab in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, a shortened progression-free survival (PFS) and overall survival (OS) time were observed in patients with mutant KRAS tumours who received panitumumab and FOLFOX (n = 221) versus FOLFOX alone (n = 219).
A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) tumours from this 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 tumours who received panitumumab and FOLFOX (n = 51) versus FOLFOX alone (n = 57).
RAS mutational status should be determined using a validated test method by an experienced laboratory (see Dosage & Administration).
Ocular toxicities: Serious cases of keratitis and ulcerative keratitis have been rarely reported in the post-marketing setting. Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.
If a diagnosis of ulcerative keratitis is confirmed, treatment with Vectibix should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered.
Vectibix should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Patients with ECOG 2 performance status treated with Vectibix in combination with chemotherapy: For patients with ECOG 2 performance status, assessment of benefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy for treatment of mCRC. A positive benefitrisk balance has not been documented in patients with ECOG 2 performance status.
Other precautions: This medicinal product contains 0.150 mmol sodium (which is 3.45 mg sodium) per mL of concentrate. To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines: 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 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 FOLFIRI or FOLFOX chemotherapy compared to chemotherapy alone (see Adverse Reactions).
Use In Pregnancy & Lactation
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.
Pregnancy: There are no adequate data from the use of Vectibix 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 prenatal 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, appropriate contraceptive measures must be used during treatment with Vectibix, and for 2 months following the last dose.
If Vectibix is used during pregnancy or if the patient becomes pregnant while receiving Vectibix, she should be advised of the potential risk for loss of the pregnancy or potential hazard to the foetus.
Breast-feeding: It is unknown whether panitumumab is excreted in human breast 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 do not breast-feed 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 = 2,224), the most commonly reported adverse reactions are skin reactions occurring in approximately 94% of patients. These reactions are related to the pharmacologic effects of Vectibix, and the majority are mild to moderate in nature with 23% 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).
Very commonly reported adverse reactions occurring in ≥ 20% of patients were gastrointestinal disorders [diarrhoea (46%), nausea (39%), vomiting (26%), constipation (23%) and abdominal pain (23%)]; general disorders [fatigue (35%), pyrexia (21%)]; metabolism and nutrition disorders [decreased appetite (30%)]; infections and infestations [paronychia (20%)]; and skin and subcutaneous disorders [rash (47%), dermatitis acneiform (39%), pruritus (36%), erythema (33%) and dry skin (21%)].
Tabulated summary of adverse reactions: The data in the table as follows 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) and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 9.)

Click on icon to see table/diagram/image

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 16% 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: Across monotherapy and combination mCRC clinical studies (n = 2,224), infusion-related reactions (occurring within 24 hours of any infusion), which may include symptoms/signs such as chills, fever or dyspnoea, were reported in approximately 5% of Vectibix-treated patients, of which 1% were severe (NCI-CTC grade 3 and grade 4).
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 31 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 approximately 94% of patients receiving Vectibix as monotherapy or in combination with chemotherapy (n = 2,224). 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 32% and life-threatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received Vectibix in combination with chemotherapy (n = 1,172). Life - threatening and fatal infectious complications including necrotising fasciitis and sepsis have been observed in patients treated with Vectibix (see Precautions).
For clinical management of dermatological reactions, including dose modification recommendations, see Precautions.
In the post-marketing setting, rare cases of skin necrosis, Stevens-Johnson syndrome and toxic epidermal necrolysis (see Precautions) have been reported.
Ocular toxicities: Non-serious cases of keratitis have been observed in 0.3% of clinical trial patients. In the post marketing setting, serious cases of keratitis and ulcerative keratitis have been rarely reported (see Precautions).
Other special populations: 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 FOLFIRI (45% versus 37%) or FOLFOX (52% versus 37%) chemotherapy compared to chemotherapy alone (see Precautions). The most increased serious adverse events included diarrhoea in patients treated with Vectibix in combination with either FOLFOX or FOLFIRI, and dehydration and pulmonary embolism when patients were treated with Vectibix in combination with FOLFIRI.
The safety of Vectibix has not been studied in patients with renal or hepatic impairment.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Drug Interactions
Data from an interaction study involving Vectibix and irinotecan in patients with mCRC indicated that the pharmacokinetics of irinotecan and its active metabolite, SN-38, are not altered when the medicinal products 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.
Vectibix should not be administered in combination with IFL chemotherapy or with bevacizumabcontaining chemotherapy. A high incidence of severe diarrhoea was observed when panitumumab was administered in combination with IFL (see Precautions), and increased toxicity and deaths were seen when panitumumab was combined with bevacizumab and chemotherapy (see Precautions and Pharmacology: Pharmacodynamics under Actions).
The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown. A shortened progression-free survival and overall survival time were observed in a clinical study in patients with mutant RAS tumours who received panitumumab and FOLFOX (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Caution For Usage
Instructions for Use/Handling: Vectibix is intended for single use only. Vectibix should be diluted in sodium chloride 9 mg/mL (0.9%) solution for injection by healthcare professional using aseptic technique. Do not shake or vigorously agitate the vial. Vectibix should be inspected visually prior to administration. The solution should be colourless 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.Using only a 21-gauge or smaller diameter hypodermic needle, 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 a total volume of 100 mL. The final concentration should not exceed 10 mg/mL. Doses higher than 1,000 mg should be diluted in 150 mL sodium chloride 9 mg/mL (0.9%) solution for injection (see Dosage & Administration). The 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.
No incompatibilities have been observed between Vectibix and sodium chloride 9 mg/mL (0.9%) solution for injection in polyvinyl chloride bags or polyolefin bags.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities:
This medicinal product must not be mixed with other medicinal products except those previously mentioned in Instructions for Use/Handling.
Storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from direct light.
Do not shake.
For storage conditions after dilution of the medicinal product, see Shelf-Life.
Shelf-Life: Vial: The expiry date is indicated on the packaging.
Diluted solution: 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-8 °C. The diluted solution must not be frozen.
ATC Classification
L01XC08 - panitumumab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Soln for infusion 20 mg/mL (sterile concentrate, colourless solution which may contain visible, translucent to white, amorphous, proteinaceous particles in vial) x 5 mL.
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