VECTIBIX 20mg / ml perfusive solution concentrate medication leaflet

Vectibix 20 mg/mL concentrate for solution for infusion.

Each mL of concentrate contains 20 mg panitumumab.

Each vial contains either 100 mg of panitumumab in 5 mL, or 400 mg of panitumumab in 20 mL.

When prepared according to the instructions given in section 6.6, the final panitumumab concentrationshould not exceed 10 mg/mL.

Panitumumab is a fully human monoclonal IgG2 antibody produced in a mammalian cell line (Chinesehamster ovary cell) by recombinant DNA technology.

Each mL of concentrate contains 0.150 mmol sodium, which is 3.45 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless, pH 5.6 to 6.0 solution that may contain translucent to white, visible amorphous,proteinaceous panitumumab particles.

Vectibix is indicated for the treatment of adult patients with wild-type RAS metastatic colorectalcancer (mCRC):

* in first-line in combination with FOLFOX or FOLFIRI.

* in second-line in combination with FOLFIRI for patients who have received first-linefluoropyrimidine-based chemotherapy (excluding irinotecan).

* as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containingchemotherapy regimens.

Vectibix treatment should be supervised by a physician experienced in the use of anti-cancer therapy.

Evidence of wild-type RAS (KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS(neuroblastoma RAS viral oncogene homologue)) status is required before initiating treatment with

Vectibix. Mutational status should be determined by an experienced laboratory using validated testmethods for detection of KRAS (exons 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutations.

The recommended dose of Vectibix is 6 mg/kg of bodyweight given once every two weeks.

Modification of the dose of Vectibix may be necessary in cases of severe (≥ grade 3) dermatologicalreactions as follows:

Occurrence of

Administrationskin symptom(s): Outcome Dose regulationof Vectibix≥ grade 31

Continuing infusion

Withhold 1 or Improved (< grade 3)

Initial occurrence at 100% of original dose2 doses

Not recovered Discontinue

Continuing infusion at 80%

At the second Withhold 1 or Improved (< grade 3)of original doseoccurrence 2 doses

Not recovered Discontinue

Continuing infusion at 60%

At the third Withhold 1 or Improved (< grade 3)of original doseoccurrence 2 doses

Not recovered Discontinue

At the fourth

Discontinue - -occurrence1 Greater than or equal to grade 3 is defined as severe or life-threatening

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.

There is no relevant use of Vectibix in the paediatric population in the indication treatment ofcolorectal cancer.

Vectibix must be administered as an intravenous infusion via an infusion pump.

Prior to infusion, Vectibix should be diluted in sodium chloride 9 mg/mL (0.9%) solution for injectionto a final concentration not to exceed 10 mg/mL (for preparation instructions, see section 6.6).

Vectibix must be administered 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 approximately60 minutes. If the first infusion is tolerated, then subsequent infusions may be administered over30 to 60 minutes. Doses higher than 1 000 mg should be infused over approximately 90 minutes (forhandling instructions, see section 6.6).

The infusion line should be flushed with sodium chloride solution before and after Vectibixadministration 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 section 4.4).

Vectibix must not be administered as an intravenous push or bolus.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Patients with a history of severe or life-threatening hypersensitivity to the active substance or to any ofthe excipients listed in section 6.1 (see section 4.4).

Patients with interstitial pneumonitis or pulmonary fibrosis (see section 4.4).

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patientswith mutant RAS mCRC or for whom RAS mCRC status is unknown (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Dermatologic reactions and soft tissue toxicity

Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factorreceptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 94%) treated with

Vectibix. Severe (NCI-CTC grade 3, where grading is defined by National Cancer Institute Common

Terminology Criteria for Adverse Events (NCI CTCAE)) skin reactions were reported in 23% andlife-threatening (grade 4) skin reactions in < 1% of patients who received Vectibix monotherapy andin combination with chemotherapy (n = 2 224) (see section 4.8). If a patient develops dermatologicreactions that are grade 3 (CTCAE v5.0) or higher, or that are considered intolerable, see therecommendation for dose modification in section 4.2.

In clinical studies, subsequent to the development of severe dermatologic reactions (includingstomatitis), infectious complications including sepsis and necrotising fasciitis, in rare cases leading todeath, and local abscesses requiring incisions and drainage were reported. Patients who have severedermatologic reactions or soft tissue toxicity or who develop worsening reactions whilst receiving

Vectibix should be monitored for the development of inflammatory or infectious sequelae (includingcellulitis and necrotising fasciitis), and appropriate treatment promptly initiated. Life-threatening andfatal infectious complications including necrotising fasciitis and sepsis have been observed in patientstreated with Vectibix. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis havebeen 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-threateninginflammatory or infectious complications.

Treatment and management of dermatologic reactions should be based on severity and may include amoisturiser, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1%hydrocortisone) applied to affected areas, and/or oral antibiotics (e.g. doxycycline). It is alsorecommended that patients experiencing rash/dermatological toxicities wear sunscreen and hats andlimit sun exposure as sunlight can exacerbate any skin reactions that may occur. Patients may beadvised to apply moisturiser and sunscreen to face, hands, feet, neck, back and chest every morningduring treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every nightduring treatment.

Pulmonary complications

Patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excludedfrom clinical studies. Cases of interstitial lung disease (ILD), both fatal and non-fatal, have beenreported, mainly from the Japanese population. In the event of acute onset or worsening pulmonarysymptoms, Vectibix treatment should be interrupted and a prompt investigation of these symptomsshould occur. If ILD is diagnosed, Vectibix should be permanently discontinued and the patient shouldbe treated appropriately. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, thebenefits of therapy with panitumumab versus the risk of pulmonary complications must be carefullyconsidered.

Progressively decreasing serum magnesium levels leading to severe (grade 4) hypomagnesaemia havebeen observed in some patients. Patients should be periodically monitored for hypomagnesaemia andaccompanying hypocalcaemia prior to initiating Vectibix treatment, and periodically thereafter for upto 8 weeks after the completion of treatment (see section 4.8). Magnesium repletion is recommended,as appropriate.

Other electrolyte disturbances, including hypokalaemia, have also been observed. Monitoring as aboveand repletion as appropriate of these electrolytes is also recommended.

Across monotherapy and combination mCRC clinical studies (n = 2 224), infusion-related reactions(occurring within 24 hours of an infusion) were reported in Vectibix-treated patients, including severeinfusion-related reactions (grade 3 and grade 4).

In the post-marketing setting, serious infusion-related reactions have been reported, including rarepost-marketing reports with a fatal outcome. If a severe or life-threatening reaction occurs during aninfusion or at any time post-infusion [e.g. presence of bronchospasm, angioedema, hypotension, needfor parenteral treatment, or anaphylaxis], Vectibix should be permanently discontinued (seesections 4.3 and 4.8).

In patients experiencing a mild or moderate (grade 1 and grade 2) infusion-related reaction theinfusion rate should be reduced for the duration of that infusion. It is recommended to maintain thislower infusion rate in all subsequent infusions.

Hypersensitivity reactions occurring more than 24 hours after infusion have been reported including afatal case of angioedema that occurred more than 24 hours after the infusion. Patients should beinformed of the possibility of a late onset reaction and instructed to contact their physician ifsymptoms of a hypersensitivity reaction occur.

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 professionalurgently.

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 section 4.8). Therefore, administration of Vectibix in combination with IFL should be avoided(see section 4.5).

Vectibix in combination with bevacizumab and chemotherapy regimens

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 pulmonaryembolism, infections (predominantly of dermatologic origin), diarrhoea, electrolyte imbalances,nausea, vomiting and dehydration was also observed in the treatment arms using Vectibix incombination with bevacizumab and chemotherapy. Vectibix should not be administered incombination with bevacizumab containing chemotherapy (see sections 4.5 and 5.1).

Vectibix in combination with oxaliplatin-based chemotherapy in patients with mutant RAS mCRC orfor whom RAS tumour status is unknown

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patientswith mutant RAS mCRC or for whom RAS mCRC status is unknown (see sections 4.3 and 5.1).

A shortened progression-free survival (PFS) and overall survival (OS) time were observed in patientswith mutant KRAS (exon 2) tumours and additional RAS mutations (KRAS [exons 3 and 4] or NRAS[exons 2, 3 and 4]) who received panitumumab in combination with infusional 5-fluorouracil,leucovorin, and oxaliplatin (FOLFOX) versus FOLFOX alone (see section 5.1).

RAS mutational status should be determined using a validated test method by an experiencedlaboratory (see section 4.2). If Vectibix is to be used in combination with FOLFOX then it isrecommended that mutational status be determined by a laboratory that participates in a RAS External

Quality Assurance programme or wild-type status be confirmed in a duplicate test.

Serious cases of keratitis and ulcerative keratitis, which may lead to corneal perforation, have beenreported. Patients presenting with signs and symptoms suggestive of keratitis such as acute orworsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eyeshould be referred promptly to an ophthalmology specialist.

If a diagnosis of ulcerative keratitis is confirmed, treatment with Vectibix should be interrupted ordiscontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should becarefully considered.

Vectibix should be used with caution in patients with a history of keratitis, ulcerative keratitis orsevere 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 (Eastern Cooperative Oncology Group) performance status, assessment ofbenefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy fortreatment of mCRC. A positive benefit-risk balance has not been documented in patients with ECOG 2performance status.

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 reactions werereported in elderly patients treated with Vectibix in combination with FOLFIRI or FOLFOXchemotherapy compared to chemotherapy alone (see section 4.8).

Warnings for excipients

This medicinal product contains 3.45 mg sodium per mL, equivalent to 0.17% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Data from an interaction study involving Vectibix and irinotecan in patients with mCRC indicated thatthe pharmacokinetics of irinotecan and its active metabolite, SN-38, are not altered when themedicinal products are co-administered. Results from a cross-study comparison indicated thatirinotecan-containing regimens (IFL or FOLFIRI) have no effect on the pharmacokinetics ofpanitumumab.

Vectibix should not be administered in combination with IFL chemotherapy or withbevacizumab-containing chemotherapy. A high incidence of severe diarrhoea was observed whenpanitumumab was administered in combination with IFL (see section 4.4), and increased toxicity anddeaths were seen when panitumumab was combined with bevacizumab and chemotherapy (seesections 4.4 and 5.1).

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patientswith mutant RAS mCRC or for whom RAS mCRC status is unknown. A shortened progression-freesurvival and overall survival time were observed in a clinical study in patients with mutant RAStumours who received panitumumab and FOLFOX (see sections 4.4 and 5.1).

There are no adequate data from the use of Vectibix in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. EGFR hasbeen 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 tocause foetal harm when administered to pregnant women.

Human IgG is known to cross the placental barrier, and panitumumab may therefore be transmittedfrom the mother to the developing foetus. In women of childbearing potential, appropriatecontraceptive measures must be used during treatment with Vectibix, and for 2 months following thelast dose. If Vectibix is used during pregnancy or if the patient becomes pregnant while receiving thismedicinal product, she should be advised of the potential risk for loss of the pregnancy or potentialhazard to the foetus.

It is unknown whether panitumumab is excreted in human breast milk. Because human IgG is secretedinto human milk, panitumumab might also be secreted. The potential for absorption and harm to theinfant after ingestion is unknown. It is recommended that women do not breast-feed during treatmentwith Vectibix and for 2 months after the last dose.

Animal studies have shown reversible effects on the menstrual cycle and reduced female fertility inmonkeys (see section 5.3). Panitumumab may impact the ability of a woman to become pregnant.

Vectibix may have a minor influence on the ability to drive and use machines. If patients experiencetreatment-related symptoms affecting their vision and/or ability to concentrate and react, it isrecommended that they do not drive or use machines until the effect subsides.

Based on an analysis of all mCRC clinical trial patients receiving Vectibix monotherapy and incombination with chemotherapy (n = 2 224), the most commonly reported adverse reactions are skinreactions occurring in approximately 94% of patients. These reactions are related to the pharmacologiceffects of Vectibix, and the majority are mild to moderate in nature with 23% severe (grade 3)and < 1% life-threatening (grade 4). For clinical management of skin reactions, including dosemodification recommendations, see section 4.4.

Very commonly reported adverse reactions occurring in ≥ 20% of patients were gastrointestinaldisorders [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 subcutaneousdisorders [rash (47%), dermatitis acneiform (39%), pruritus (36%), erythema (33%) and dry skin(21%)].

The data in the table below describe adverse reactions reported from clinical studies in patients withmCRC who received panitumumab as a single agent or in combination with chemotherapy (n = 2 224)and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in orderof decreasing seriousness.

Adverse reactions

MedDRA Very common Common Uncommonsystem organ (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 toclass < 1/100)

Infections and Conjunctivitis Rash pustular Eye infectioninfestations Paronychia1 Cellulitis1 Eyelid infection

Folliculitis

Localised infection

Blood and Anaemia Leucopenialymphaticsystemdisorders

Immune system Hypersensitivity1 Anaphylacticdisorders reaction2

Metabolism and Hypokalaemia Hypocalcaemianutrition Hypomagnesaemia Dehydrationdisorders Decreased appetite Hyperglycaemia

Hypophosphataemia

Psychiatric Insomnia Anxietydisorders

Nervous system Headachedisorders Dizziness

Eye disorders Blepharitis Ulcerative

Growth of eyelashes keratitis1,4

Lacrimation increased Keratitis1

Ocular hyperaemia Eyelid irritation

Dry eye

Eye pruritus

Eye irritation

Cardiac Tachycardia Cyanosisdisorders

Vascular Deep vein thrombosisdisorders Hypotension

Flushing

Respiratory, Dyspnoea Pulmonary embolism Interstitial lungthoracic and Cough Epistaxis disease3mediastinal Bronchospasmdisorders Nasal dryness

Adverse reactions

MedDRA Very common Common Uncommonsystem organ (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 toclass < 1/100)

Gastrointestinal Diarrhoea1 Rectal haemorrhage Chapped lipsdisorders Nausea Dry mouth Dry lips

Vomiting Dyspepsia

Abdominal pain Aphthous ulcer

Stomatitis Cheilitis

Constipation Gastro-oesophageal refluxdisease

Skin and Dermatitis acneiform Skin ulcer Toxic epidermalsubcutaneous Rash Skin exfoliation necrolysis1,4tissue disorders1 Erythema Exfoliative rash Stevens-Johnson

Pruritus Dermatitis syndrome1,4

Dry skin Rash papular Skin necrosis1,4

Skin fissures Rash pruritic Angioedema1

Acne Rash erythematous Hirsutism

Alopecia Rash generalised Ingrowing nail

Rash macular Onycholysis

Rash maculo-papular

Skin lesion

Skin toxicity

Scab

Hypertrichosis

Onychoclasis

Nail disorder

Hyperhidrosis

Palmar-plantarerythrodysaesthesia syndrome

Musculoskeletal Back pain Pain in extremityand connectivetissue disorders

General Fatigue Chest paindisorders and Pyrexia Painadministration Asthenia Chillssite conditions Mucosal inflammation

Oedema peripheral

Investigations Weight decreased Blood magnesium decreased

Injury, Infusion-relatedpoisoning and reaction1proceduralcomplications1 See section “Description of selected adverse reactions” below2 See section 4.4 Infusion-related reactions3 See section 4.4 Pulmonary complications4 Skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis and ulcerative keratitis are panitumumab

ADRs that were reported in the post-marketing setting. For these ADRs the maximum frequency category wasestimated from the upper limit of 95% confidence interval for the point estimate based on regulatory guidelinesfor estimation of the frequency of adverse reactions from spontaneous reporting. The maximum frequencyestimated from the upper limit of 95% confidence interval for the point estimate, i.e., 3/2 224 (or 0.13%).

The safety profile of Vectibix in combination with chemotherapy consisted of the reported adversereactions 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 additiveeffects were observed. Skin reactions were the most frequently occurring adverse reactions in patientsreceiving panitumumab in combination with chemotherapy. Other toxicities that were observed with agreater frequency relative to monotherapy included hypomagnesaemia, diarrhoea, and stomatitis.

These toxicities infrequently led to discontinuation of Vectibix or of chemotherapy.

Diarrhoea when reported was mainly mild or moderate in severity. Severe diarrhoea (grade 3 and 4)was reported in 2% of patients treated with Vectibix as a monotherapy and in 16% of patients treatedwith Vectibix in combination with chemotherapy.

There have been reports of acute renal failure in patients who develop diarrhoea and dehydration (seesection 4.4).

Across monotherapy and combination mCRC clinical studies (n = 2 224), infusion-related reactions(occurring within 24 hours of any infusion), which may include signs and symptoms such as chills,fever or dyspnoea, were reported in approximately 1% of Vectibix-treated patients, of which 0.3%were severe (grade 3 and 4).

A case of fatal angioedema occurred in a patient with recurrent and metastatic squamous cellcarcinoma of the head and neck treated with Vectibix in a clinical trial. The fatal event occurred afterre-exposure following a prior episode of angioedema; both episodes occurred greater than 24 hoursafter administration (see sections 4.3 and 4.4). Hypersensitivity reactions occurring more than24 hours after infusion have also been reported in the post-marketing setting.

For clinical management of infusion-related reactions, see section 4.4.

Skin rash most commonly occurred on the face, upper chest, and back, but could extend to theextremities. Subsequent to the development of severe skin and subcutaneous reactions, infectiouscomplications including sepsis, in rare cases leading to death, cellulitis and local abscesses requiringincisions and drainage were reported. The median time to first symptom of dermatologic reaction was10 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 Vectibixas monotherapy or in combination with chemotherapy (n = 2 224). These reactions consistedpredominantly of rash and dermatitis acneiform and were mostly mild to moderate in severity. Severe(grade 3) skin reactions were reported in 23% and life-threatening (grade 4) skin reactions in < 1% ofpatients. Life-threatening and fatal infectious complications including necrotising fasciitis and sepsishave been observed in patients treated with Vectibix (see section 4.4).

For clinical management of dermatological reactions, including dose modification recommendations,see section 4.4.

In the post-marketing setting, rare cases of skin necrosis, Stevens-Johnson syndrome and toxicepidermal necrolysis (see section 4.4) have been reported.

Serious cases of keratitis and ulcerative keratitis, which may lead to corneal perforation, have beenreported (see section 4.4).

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 reactions werereported in elderly patients treated with Vectibix in combination with FOLFIRI (45% versus 32%) or

FOLFOX (52% versus 37%) chemotherapy compared to chemotherapy alone (see section 4.4). Themost increased serious adverse reactions included diarrhoea in patients treated with Vectibix incombination with either FOLFOX or FOLFIRI, and dehydration and pulmonary embolism whenpatients were treated with Vectibix in combination with FOLFIRI.

The safety of Vectibix has not been studied in patients with renal or hepatic impairment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 9 mg/kg have been tested in clinical trials. There have been reports of overdose at dosesup to approximately twice the recommended therapeutic dose (12 mg/kg). Adverse reactions observedincluded skin toxicity, diarrhoea, dehydration and fatigue and were consistent with the safety profile atthe recommended dose.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, ATC code: L01FE02

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinityand specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of asubfamily 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 autophosphorylationinduced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation ofthe receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascularendothelial growth factor production.

KRAS and NRAS are highly related members of the RAS oncogene family. KRAS and NRAS genesencode small, GTP-binding proteins involved in signal transduction. A variety of stimuli, includingthat from the EGFR activate KRAS and NRAS which in turn stimulate other intracellular proteins topromote cell proliferation, cell survival and angiogenesis.

Activating mutations in the RAS genes occur frequently in a variety of human tumours and have beenimplicated in both oncogenesis and tumour progression.

In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth andsurvival of tumour cells expressing EGFR. No anti-tumour effects of panitumumab were observed inhuman tumour xenografts lacking EGFR expression. The addition of panitumumab to radiation,chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase inanti-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 (seesections 4.2 and 4.8).

As with all therapeutic proteins, there is potential for immunogenicity. Data on the development ofanti-panitumumab antibodies has been evaluated using two different screening immunoassays for thedetection 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 patientswhose sera tested positive in either screening immunoassay, an in vitro biological assay wasperformed 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 presenceof 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% as detectedby 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 antibodiesto Vectibix.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Theobserved incidence of antibody positivity in an assay may be influenced by several factors includingassay methodology, sample handling, timing of sample collection, concomitant medicinal productsand underlying disease, therefore, comparison of the incidence of antibodies to other products may bemisleading.

Clinical efficacy as monotherapy

The efficacy of Vectibix as monotherapy in patients with metastatic colorectal cancer (mCRC) whohad disease progression during or after prior chemotherapy was studied in open-label, single-arm trials(585 patients) and in two randomised controlled trials versus best supportive care (463 patients) andversus cetuximab (1 010 patients).

A multinational, randomised, controlled trial was conducted in 463 patients with EGFR-expressingmetastatic carcinoma of the colon or rectum after confirmed failure of oxaliplatin andirinotecan-containing regimens. Patients were randomised 1:1 to receive Vectibix at a dose of 6 mg/kggiven once every two weeks plus best supportive care (not including chemotherapy) (BSC) or BSCalone. Patients were treated until disease progression or unacceptable toxicity occurred. Upon diseaseprogression BSC alone patients were eligible to crossover to a companion study and receive Vectibixat a dose of 6 mg/kg given once every two weeks.

The primary endpoint was PFS. The study was retrospectively analysed by wild-type KRAS (exon 2)status versus mutant KRAS (exon 2) status. Tumour samples obtained from the primary resection ofcolorectal cancer were analysed for the presence of the seven most common activating mutations inthe codons 12 and 13 of the KRAS gene. Patients (427 (92%)) were evaluable for KRAS status ofwhich 184 had mutations. The efficacy results from an analysis adjusting for potential bias fromunscheduled assessments are shown in the table below. There was no difference in overall survival(OS) seen in either group.

Wild-type KRAS (exon 2) Mutant KRAS (exon 2) populationpopulation

Vectibix plus BSC BSC Vectibix plus BSC BSC(n = 124) (n = 119) (n = 84) (n = 100)

ORR n (%) 17% 0% 0% 0%

Response rate (investigator 22% 0%assessed)a (95% CI) (14, 32) (0, 4)

Stable disease 34% 12% 12% 8%

PFS

Hazard ratio (95% CI) 0.49 (0.37, 0.65), p < 0.0001 1.07 (0.77, 1.48), p = 0.6880

Median (weeks) 16.0 8.0 8.0 8.0

BSC = best supportive care

CI = confidence interval

ORR = objective response rate

PFS = progression-free survivala In patients that crossed over to panitumumab after progression on BSC alone (95% CI)

In an exploratory analysis of banked tumour specimens from this study, 11 of 72 patients (15%) withwild-type RAS tumours receiving panitumumab had an objective response compared to only 1 of95 patients (1%) with mutant RAS tumour status. Moreover, panitumumab treatment was associatedwith improved PFS compared to BSC in patients with wild-type RAS tumours (HR = 0.38[95% CI: 0.27, 0.56]), but not in patients with tumours harbouring a RAS mutation (HR = 0.98[95% CI: 0.73, 1.31]).

The efficacy of Vectibix was also evaluated in an open-label trial in patients with wild-type KRAS(exon 2) mCRC. A total of 1 010 patients refractory to chemotherapy were randomised 1:1 to receive

Vectibix or cetuximab to test whether Vectibix is non-inferior to cetuximab. The primary endpointwas OS. Secondary endpoints included PFS and objective response rate (ORR).

The efficacy results for the study are presented in the table below.

Wild-type KRAS (exon 2) Vectibix Cetuximabpopulation (n = 499) (n = 500)

OS

Median (months) (95% CI) 10.4 (9.4, 11.6) 10.0 (9.3, 11.0)

Hazard ratio (95% CI) 0.97 (0.84, 1.11)

PFS

Median (months) (95% CI) 4.1 (3.2, pct. 4.8) 4.4 (3.2, pct. 4.8)

Hazard ratio (95% CI) 1.00 (0.88, 1.14)

ORRn (%) (95% CI) 22% (18%, 26%) 20% (16%, 24%)

Odds ratio (95% CI) 1.15 (0.83, 1.58)

ORR = objective response rate

CI = confidence interval

OS = overall survival

PFS = progression-free survival

Overall, the safety profile of panitumumab was similar to that of cetuximab, in particular regardingskin toxicity. However, infusion reactions were more frequent with cetuximab (13% versus 3%) butelectrolyte disturbances were more frequent with panitumumab, especially hypomagnesaemia(29% versus 19%).

Clinical efficacy in combination with chemotherapy

Among patients with wild-type RAS mCRC, PFS, OS, and ORR were improved for subjects receivingpanitumumab plus chemotherapy (FOLFOX or FOLFIRI) compared with those receivingchemotherapy alone. Patients with additional RAS mutations beyond KRAS exon 2 were unlikely tobenefit from the addition of panitumumab to FOLFIRI and a detrimental effect was seen with theaddition of panitumumab to FOLFOX in these patients. BRAF mutations in exon 15 were found to beprognostic of worse outcome. BRAF mutations were not predictive of the outcome for panitumumabtreatment in combination with FOLFOX or FOLFIRI.

First-line combination with FOLFOX

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 theprimary endpoint of PFS. Other key endpoints included the OS, ORR, time to response, time toprogression (TTP), and duration of response. The study was prospectively analysed by tumour KRAS(exon 2) status which was evaluable in 93% of the patients.

A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS(exon 2) mCRC was performed. Patient tumour samples with wild-type KRAS exon 2 (codons 12/13)status were tested 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)and BRAF exon 15 (codon 600). The incidence of these additional RAS mutations in the wild-type

KRAS exon 2 population was approximately 16%.

Results in patients with wild-type RAS mCRC and mutant RAS mCRC are presented in the tablebelow.

Vectibix plus

FOLFOX

FOLFOX Difference Hazard ratio(months)(months) (months) (95% CI)

Median (95% CI)

Median (95% CI)

Wild-type RAS population10.1 7.9 0.72

PFS 2.2(9.3, 12.0) (7.2, 9.3) (0.58, 0.90)26.0 20.2 0.78

OS 5.8(21.7, 30.4) (17.7, 23.1) (0.62, 0.99)

Mutant RAS population7.3 8.7 1.31

PFS -1.4(6.3, 7.9) (7.6, 9.4) (1.07, 1.60)15.6 19.2 1.25

OS -3.6(13.4, 17.9) (16.7, 21.8) (1.02, 1.55)

CI = confidence interval

OS = overall survival

PFS = progression-free survival

Additional mutations in KRAS and NRAS at exon 3 (codon 59) were subsequently identified (n = 7).

An exploratory analysis showed similar results to those in the previous table.

Combination with FOLFIRI

The efficacy of Vectibix in second-line in combination with irinotecan, 5-fluorouracil (5-FU) andleucovorin (FOLFIRI) was evaluated in a randomised, controlled trial of 1 186 patients with mCRCwith the primary endpoints of OS and PFS. Other key endpoints included the ORR, time to response,

TTP, and duration of response. The study was prospectively analysed by tumour KRAS (exon 2) statuswhich was evaluable in 91% of the patients.

A predefined retrospective subset analysis of 586 patients of the 597 patients with wild-type KRAS(exon 2) mCRC was performed, where tumour samples from these patients were tested for additional

RAS and BRAF mutations as previously described. The RAS/BRAF ascertainment was 85% (1 014 of1 186 randomised patients). The incidence of these additional RAS mutations (KRAS exons 3, 4 and

NRAS exons 2, 3 and 4) in the wild-type KRAS (exon 2) population was approximately 19%. Theincidence of BRAF exon 15 mutation in the wild-type KRAS (exon 2) population wasapproximately 8%. Efficacy results in patients with wild-type RAS mCRC and mutant RAS mCRC areshown in the below table.

Vectibix plus FOLFIRI Hazard ratio

FOLFIRI (months) (95% CI)(months) Median (95% CI)

Median (95% CI)

Wild-type RAS population

PFS 6.4 4.6 0.70(5.5, 7.4) (3.7, 5.6) (0.54, 0.91)

OS 16.2 13.9 0.81(14.5, 19.7) (11.9, 16.0) (0.63, 1.02)

Mutant RAS population

PFS 4.8 4.0 0.86(3.7, 5.5) (3.6, 5.5) (0.70, 1.05)

OS 11.8 11.1 0.91(10.4, 13.1) (10.2, 12.4) (0.76, 1.10)

CI = confidence interval

OS = overall survival

PFS = progression-free survival

The efficacy of Vectibix in first-line in combination with FOLFIRI was evaluated in a single-armstudy of 154 patients with the primary endpoint of objective response rate (ORR). Other key endpointsincluded the PFS, time to response, TTP, and duration of response.

A predefined retrospective subset analysis of 143 patients of the 154 patients with wild-type KRAS(exon 2) mCRC was performed, where tumour samples from these patients were tested for additional

RAS mutations. The incidence of these additional RAS mutations (KRAS exons 3, 4 and NRAS exons 2,3 and 4) in the wild-type KRAS (exon 2) population was approximately 10%.

Results in patients with wild-type RAS mCRC and mutant RAS mCRC from the primary analysis arepresented in the table below.

Panitumumab + FOLFIRI

Wild-type RAS (n = 69) Mutant RAS (n = 74)

ORR (%) 59 41(95% CI) (46, 71) (30, 53)

Panitumumab + FOLFIRI

Wild-type RAS (n = 69) Mutant RAS (n = 74)

Median PFS (months) 11.2 7.3(95% CI) (7.6, 14.8) (5.8, 7.5)

Median duration of response (months) 13.0 5.8(95% CI) (9.3, 15.7) (3.9, 7.8)

Median TTP (months) 13.2 7.3(95% CI) (7.8, 17.0) (6.1, 7.6)

CI = confidence interval

ORR = objective response rate

PFS = progression-free survival

TTP = time to progression

First-line combination with bevacizumab and oxaliplatin or irinotecan-based chemotherapy

In a randomised, open-label, controlled clinical trial, chemotherapy (FOLFOX or FOLFIRI) andbevacizumab were given with and without panitumumab in the first-line treatment of patients withmetastatic 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 patientsreceiving panitumumab observed in an interim analysis.

The major study objective was comparison of PFS in the oxaliplatin cohort. In the final analysis, thehazard ratio for PFS was 1.27 (95% CI: 1.06, 1.52). Median PFS was 10.0 (95% CI: 8.9, 11.0) and11.4 (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 survivalwas 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 (exon 2) status did not identify a subset of patientswho benefited from panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapyand bevacizumab. For the wild-type KRAS subset of the oxaliplatin cohort, the hazard ratio for PFSwas 1.36 with 95% CI: 1.04-1.77. For the mutant KRAS subset, the hazard ratio for PFS was 1.25 with95% CI: 0.91-1.71. A trend for OS favouring the control arm was observed in the wild-type KRASsubset of the oxaliplatin cohort (hazard ratio = 1.89; 95% CI: 1.30, 2.75). A trend towards worsesurvival was also observed with panitumumab in the irinotecan cohort (hazard ratio = 1.42;95% CI: 0.77, 2.62) regardless of KRAS mutational status. Overall, panitumumab treatment combinedwith chemotherapy and bevacizumab is associated with an unfavourable benefit- risk profileirrespective of tumour KRAS mutational status.

The European Medicines Agency has waived the obligation to submit the results of studies with

Vectibix in all subsets of the paediatric population in colorectal cancer (see section 4.2 for informationon paediatric use).

Vectibix administered as a single agent or in combination with chemotherapy exhibits nonlinearpharmacokinetics.

Following a single-dose administration of panitumumab as a 1-hour infusion, the area under theconcentration-time curve (AUC) increased in a greater than dose-proportional manner and clearance(CL) of panitumumab decreased from 30.6 to 4.6 mL/kg/day as the dose increasedfrom 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increases in anapproximately 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 mcg/mL, respectively. Themean (± SD) AUC0-tau and CL were 1 306 ± 374 mcg*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 selectedcovariates on panitumumab pharmacokinetics. Results suggest that age (21-88), gender, race, hepaticfunction, 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 patientswith renal or hepatic impairment.

Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and withpossible relevance to clinical use were as follows:

Skin rash and diarrhoea were the major findings observed in repeat-dose toxicity studies of up to26 weeks duration in cynomolgus monkeys. These findings were observed at doses approximatelyequivalent to the recommended human dose and were reversible upon termination of administration ofpanitumumab. The skin rash and diarrhoea observed in monkeys are considered related to thepharmacological action of panitumumab and are consistent with the toxicities observed with otheranti-EGFR inhibitors.

Studies to evaluate the mutagenic and carcinogenic potential of panitumumab have not beenperformed.

Animal studies are insufficient with respect to embryo-foetal development since foetal panitumumabexposure levels were not examined. Panitumumab has been shown to cause foetal abortions and/orfoetal deaths in cynomolgus monkeys when administered during the period of organogenesis at dosesapproximately equivalent to the recommended human dose.

Formal male fertility studies have not been conducted; however, microscopic evaluation of malereproductive organs from repeat-dose toxicity studies in cynomolgus monkeys at doses up toapproximately 5-fold the human dose on a mg/kg basis, revealed no differences compared to controlmale monkeys. Fertility studies conducted in female cynomolgus monkeys showed that panitumumabmay produce prolonged menstrual cycle and/or amenorrhea and reduced pregnancy rate whichoccurred at all doses evaluated.

No pre- and post-natal development animal studies have been conducted with panitumumab. Allpatients should be advised regarding the potential risk of panitumumab on pre- and post-nataldevelopment prior to initiation of Vectibix therapy.

Sodium chloride

Sodium acetate trihydrate

Acetic acid, glacial (for pH-adjustment)

Water for injections.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Vial3 years.

Vectibix does not contain any antimicrobial preservative or bacteriostatic agent. The product should beused immediately after dilution. If not used immediately, in-use storage times and conditions prior touse are the responsibility of the user and should be no longer than 24 hours at 2°C - 8°C. The dilutedsolution must not be frozen.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I glass vial with an elastomeric stopper, aluminium seal and flip-off plastic cap.

One vial contains either 100 mg of panitumumab in 5 mL, or 400 mg panitumumab in 20 mL ofconcentrate for solution for infusion.

Pack of 1 vial.

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 orvigorously agitate the vial. Vectibix should be inspected visually prior to administration. The solutionshould be colourless and may contain visible translucent-to-white, amorphous, proteinaceousparticulates (which will be removed by in-line filtration). Do not administer Vectibix if its appearanceis not as described above. Using only a 21-gauge or smaller diameter hypodermic needle, withdrawthe necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g. vialadapters) to withdraw vial contents. Dilute in a total volume of 100 mL. The final concentrationshould not exceed 10 mg/mL. Doses higher than 1 000 mg should be diluted in 150 mL sodiumchloride 9 mg/mL (0.9%) solution for injection (see section 4.2). The diluted solution should be mixedby gentle inversion, do not shake.

Vectibix must be administered using a low protein binding 0.2 or 0.22 micrometre in-line filter,through a peripheral line or indwelling catheter.

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.

Discard the vial and any liquid remaining in the vial after the single-use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

EU/1/07/423/001

EU/1/07/423/003

Date of first authorisation: 3 December 2007

Date of latest renewal: 23 September 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.