Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
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).
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 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 23% and life-threatening (NCI-CTC grade 4) skin reactions in <1% of patients who received Vectibix monotherapy and in combination with chemotherapy (n=2,224) (see section 4.8). If a patient develops dermatologic reactions that are grade 3 (CTCAE v 4.0) 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, sun screen (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.
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.
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.
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 severe infusion-related reactions (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 sections 4.3 and 4.8).
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 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.
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).
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).
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, 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.
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.
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.
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).
This medicinal product contains 3.45 mg sodium per mL, equivalent to 0.017% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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 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).
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.
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.
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.
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.
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 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%)].
The data in the table below describe adverse reactions reported from clinical studies in patients with mCRC who received panitumumab as a single agent or in combination with chemotherapy (n=2,224) and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common: Conjunctivitis, Paronychia1
Common: Rash pustular, Cellulitis1, Urinary tract infection, Folliculitis, Localised infection
Uncommon: Eye infection, Eyelid infection
Very common: Anaemia
Common: Leucopenia
Common: Hypersensitivity1
Uncommon: Anaphylactic reaction2
Very common: Hypokalaemia, Hypomagnesaemia, Decreased appetite
Common: Hypocalcaemia, Dehydration, Hyperglycaemia, Hypophosphataemia
Very common: Insomnia
Common: Anxiety
Common: Headache, Dizziness
Common: Blepharitis, Growth of eyelashes, Lacrimation increased, Ocular hyperaemia, Dry eye, Eye pruritus, Eye irritation
Uncommon: Ulcerative keratitis1,4, Keratitis1, Eyelid irritation
Common: Tachycardia
Uncommon: Cyanosis
Common: Deep vein thrombosis, Hypotension, Hypertension, Flushing
Very common: Dyspnoea, Cough
Common: Pulmonary embolism, Epistaxis
Uncommon: Interstitial lung disease3, Bronchospasm, Nasal dryness
Very common: Diarrhoea1, Nausea, Vomiting, Abdominal pain, Stomatitis, Constipation
Common: Rectal haemorrhage, Dry mouth, Dyspepsia, Aphthous ulcer, Cheilitis, Gastro-oesophageal reflux disease
Uncommon: Chapped lips, Dry lips
Very common: Dermatitis acneiform, Rash, Erythema, Pruritus, Dry skin, Skin fissures, Acne, Alopecia
Common: 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
Uncommon: Toxic epidermal necrolysis4, Stevens-Johnson syndrome4, Skin necrosis4, Angioedema1, Hirsutism, Ingrowing nail, Onycholysis
Very common: Back pain
Common: Pain in extremity
Very common: Fatigue, Pyrexia, Asthenia, Mucosal inflammation, Oedema peripheral
Common: Chest pain, Pain, Chills
Uncommon: Infusion-related reaction1
Very common: Weight decreased
Common: Blood magnesium decreased
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 Ulcerative keratitis, skin necrosis, Stevens-Johnson syndrome and toxic epidermal necrolysis 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., 3/2,224 (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.
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 section 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 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 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 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 23% and life-threatening (NCI-CTC 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.
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 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 events 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 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 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 the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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