4.1. Therapeutic indications

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

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

• 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.

4.2. Posology and method of administration

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 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.

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

Occurrence of skin symptom(s):

≥ grade 31

Administration of Vectibix

Outcome

Dose regulation

Initial occurrence

Withhold 1 or 2 doses

Improved (< grade 3)

Continuing infusion at 100% of original dose

Not recovered

Discontinue

At the second occurrence

Withhold 1 or 2 doses

Improved (< grade 3)

Continuing infusion at 80% of original dose

Not recovered

Discontinue

At the third occurrence

Withhold 1 or 2 doses

Improved (< grade 3)

Continuing infusion at 60% of original dose

Not recovered

Discontinue

At the fourth occurrence

Discontinue

-

-

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

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.

Prior to infusion, Vectibix should be diluted in sodium chloride 9 mg/mL (0.9%) solution for injection to 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 approximately 60 minutes. If the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes. Doses higher than 1000 mg should be infused over approximately 90 minutes (for handling instructions, see section 6.6).

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 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.

4.3. Contraindications

Patients with a history of severe or life-threatening hypersensitivity to the active substance or to any of the 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 patients with mutant RAS mCRC or for whom RAS mCRC status is unknown (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

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

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, where grading is defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)) skin reactions were reported in 23% and life-threatening (grade 4) skin reactions in < 1% of patients who received Vectibix monotherapy and in combination with chemotherapy (n = 2224) (see section 4.8). If a patient develops dermatologic reactions that are grade 3 (CTCAE v5.0) or higher, or that are considered intolerable, see the recommendation for dose modification in section 4.2.

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 and management of dermatologic reactions should be based on severity and may include a moisturiser, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics (e.g. doxycycline). 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. 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 section 4.8). 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 = 2224), infusion-related reactions (occurring within 24 hours of an infusion) were reported in Vectibix-treated patients, including severe infusion-related reactions (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 sections 4.3 and 4.8).

In patients experiencing a mild or moderate (grade 1 and grade 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 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 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. Vectibix should not be administered in combination with bevacizumab containing chemotherapy (see sections 4.5 and 5.1).

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 sections 4.3 and 5.1).

A shortened progression-free survival (PFS) and overall survival (OS) time were observed in patients with 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 experienced laboratory (see section 4.2). If Vectibix is to be used in combination with FOLFOX then it is recommended 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.

Ocular toxicities

Serious cases of keratitis and ulcerative keratitis, which may lead to corneal perforation, have been reported . 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 (Eastern Cooperative Oncology Group) performance status, assessment of benefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy for treatment of mCRC. A positive benefit-risk balance has not been documented in patients with ECOG 2 performance status.

Elderly patients

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 were reported in elderly patients treated with Vectibix in combination with FOLFIRI or FOLFOX chemotherapy 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 WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

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 bevacizumab‑containing chemotherapy. A high incidence of severe diarrhoea was observed when panitumumab was administered in combination with IFL (see section 4.4), and increased toxicity and deaths were seen when panitumumab was combined with bevacizumab and chemotherapy (see sections 4.4 and 5.1).

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 sections 4.4 and 5.1).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Vectibix in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 this medicinal product, 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, panitumumab 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.

Fertility

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

4.7. Effects on ability to drive and use machines

Vectibix may have a minor influence on the 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 effect subsides.

4.8. Undesirable effects

Summary of the 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) and < 1% life‑threatening (grade 4). For clinical management of skin reactions, including dose modification recommendations, see section 4.4.

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 list of adverse reactions

The data in the table below describe adverse reactions reported from clinical studies in patients with mCRC who received panitumumab as a single agent or in combination with chemotherapy (n = 2224) and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions

MedDRA system organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1000 to < 1/100)

Infections and infestations

Conjunctivitis

Paronychia1

Rash pustular

Cellulitis1

Urinary tract infection

Folliculitis

Localised infection

Eye infection

Eyelid infection

Blood and lymphatic system disorders

Anaemia

Leucopenia

Immune system disorders

Hypersensitivity1

Anaphylactic reaction2

Metabolism and nutrition disorders

Hypokalaemia

Hypomagnesaemia

Decreased appetite

Hypocalcaemia

Dehydration

Hyperglycaemia

Hypophosphataemia

Psychiatric disorders

Insomnia

Anxiety

Nervous system disorders

Headache

Dizziness

Eye disorders

Blepharitis

Growth of eyelashes

Lacrimation increased

Ocular hyperaemia

Dry eye

Eye pruritus

Eye irritation

Ulcerative keratitis1,4

Keratitis1

Eyelid irritation

Cardiac disorders

Tachycardia

Cyanosis

Vascular disorders

Deep vein thrombosis

Hypotension

Hypertension

Flushing

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

Pulmonary embolism

Epistaxis

Interstitial lung disease3

Bronchospasm

Nasal dryness

Gastrointestinal disorders

Diarrhoea1

Nausea

Vomiting

Abdominal pain

Stomatitis

Constipation

Rectal haemorrhage

Dry mouth

Dyspepsia

Aphthous ulcer

Cheilitis

Gastro-oesophageal reflux disease

Chapped lips

Dry lips

Skin and subcutaneous tissue disorders1

Dermatitis acneiform

Rash

Erythema

Pruritus

Dry skin

Skin fissures

Acne

Alopecia

Skin ulcer

Skin exfoliation

Exfoliative rash

Dermatitis

Rash papular

Rash pruritic

Rash erythematous

Rash generalised

Rash macular

Rash maculo-papular

Skin lesion

Skin toxicity

Scab

Hypertrichosis

Onychoclasis

Nail disorder

Hyperhidrosis

Palmar-plantar erythrodysaesthesia syndrome

Toxic epidermal necrolysis,1,4

Stevens-Johnson syndrome,1,4

Skin necrosis,1,4

Angioedema1

Hirsutism

Ingrowing nail

Onycholysis

Musculoskeletal and connective tissue disorders

Back pain

Pain in extremity

General disorders and administration site conditions

Fatigue

Pyrexia

Asthenia

Mucosal inflammation

Oedema peripheral

Chest pain

Pain

Chills

Investigations

Weight decreased

Blood magnesium decreased

Injury, poisoning and procedural complications

Infusion-related reaction1

1 See section “Description of selected adverse reactions” below

2 See section 4.4 Infusion-related reactions

3 See section 4.4 Pulmonary complications

4 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 was estimated from the upper limit of 95% confidence interval for the point estimate based on regulatory guidelines for estimation of the frequency of adverse reactions from spontaneous reporting. The maximum frequency estimated from the upper limit of 95% confidence interval for the point estimate, i.e., 3/2224 (or 0.13%).

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 (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 section 4.4).

Infusion-related reactions

Across monotherapy and combination mCRC clinical studies (n = 2224), 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 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 sections 4.3 and 4.4). 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 section 4.4.

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 = 2224). These reactions consisted predominantly 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% of patients. Life‑threatening and fatal infectious complications including necrotising fasciitis and sepsis have 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 toxic epidermal necrolysis (see section 4.4) have been reported.

Ocular toxicities

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

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 reactions were reported 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). The most increased serious adverse reactions 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 via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. 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 reactions observed included skin toxicity, diarrhoea, dehydration and fatigue and were consistent with the safety profile at the recommended dose.