Portrazza

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Portrazza 800 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 50 mL vial contains 800 mg of necitumumab. 
Each mL of concentrate for solution for infusion contains 16 mg of necitumumab. 
The concentrate must be diluted before use (see section 6.6). 
 
Necitumumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant 
DNA technology. 
 
Excipient with known effect 
Each 50 mL vial contains approximately 76 mg sodium. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear to slightly opalescent and colourless to slightly yellow liquid, with pH 6.0. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Portrazza in combination with gemcitabine and cisplatin chemotherapy is indicated for the treatment 
of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) 
expressing squamous non-small cell lung cancer who have not received prior chemotherapy for this 
condition. 
 
4.2 Posology and method of administration 
 
Necitumumab therapy must be administered under the supervision of a physician qualified in the use 
of anti-cancer chemotherapy. 
Appropriate medical resources for the treatment of severe infusion reactions should be available 
during necitumumab infusions. Availability of resuscitation equipment must be ensured. 
 
Posology 
 
Portrazza is administered in addition to gemcitabine and cisplatin-based chemotherapy for up to 
6 cycles of treatment followed by Portrazza as a single agent in patients whose disease has not 
progressed, until disease progression or unacceptable toxicity. 
 
The recommended dose of Portrazza is 800 mg (flat dose) administered as an intravenous infusion 
over 60 minutes on Days 1 and 8 of each 3-week cycle. If a decreased infusion rate is indicated, the 
infusion duration should not exceed 2 hours. 



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Patients should be monitored during infusion for signs of infusion-related reactions (see section 4.4). 
 
Premedication 
In patients who have experienced a previous Grade 1-2 hypersensitivity or infusion-related reaction to 
Portrazza, premedication with a corticosteroid and an antipyretic in addition to an antihistamine is 
recommended. 
 
Prior to each necitumumab infusion, premedication for possible skin reactions must be considered (see 
section 4.4). 
 
Posology adjustments 
Recommendations for the management of infusion-related and skin reactions are provided in tables 1 
and 2. 
 
Hypersensitivity/Infusion-related reactions 
 

Table 1 – Management recommendations for hypersensitivity/infusion-related 
reactions 

 
Toxicity 
gradea 

Management recommendations 
(any occurrence) 

Grade 1 • Decrease infusion rate by 50  % for the duration of infusion.b 
• Monitor patient for worsening of condition. 
• For subsequent infusions, please see premedication section. 

Grade 2 • Stop the infusion; when the reaction has resolved to Grade 
≤ 1, resume infusion at a 50  % decreased infusion rate.b 

• Monitor patient for worsening of condition. 
• For subsequent infusions, please see premedication section. 

Grade 3-4 • Immediately and permanently discontinue treatment with 
necitumumab. 

a Grade per NCI-CTCAE, Version 3.0 
b Once the infusion rate has been reduced for a Grade 1 or 2 hypersensitivity/infusion-related 
reaction, it is recommended that the lower infusion rate be utilized for all subsequent infusions. 
The infusion duration should not exceed 2 hours. 

 



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Skin reactions 
 
Table 2 – Management recommendations for skin reactions 

 
Toxicity 
gradea 

Management recommendations 
(any occurrence) 

Grades 1 and 2 • No dose adjustment necessary 
Grade 3 • Temporarily withhold, for a maximum of 6 weeks following 

Day 1 of the most recent treatment cycle, until symptoms resolve 
to Grade ≤ 2. Permanently discontinue if symptoms do not 
resolve to Grade ≤ 2 after holding for 2 consecutive cycles 
(6 weeks) 

• Following improvement to Grade ≤ 2, resume at reduced dose of 
400 mg. If symptoms worsen at 400 mg, permanently 
discontinue. 

• If symptoms do not worsen at 400 mg for at least 
1 treatment cycle, the dose may be increased to 600 mg If 
symptoms worsen at 600 mg, temporarily withhold, for a 
maximum of 6 weeks following Day 1 of the most recent 
treatment cycle, until symptoms resolve to Grade ≤ 2. Following 
improvement to Grade ≤ 2, resume at reduced dose of 400 mg. 

• If symptoms do not worsen at 600 mg for another 
treatment cycle, the dose may be further increased to 800 mg. 

• Permanently discontinue if patients experience Grade 3 skin 
induration/fibrosis. 

Grade 4 • Immediately and permanently discontinue treatment with 
necitumumab. 

a Grade per NCI-CTCAE, Version 3.0 
 
 

 
Special populations 
 
Paediatric population 
There is no relevant use of necitumumab in the paediatric population in the non-small cell lung cancer 
indication. 
 
Elderly  
No dose reductions other than those recommended for all patients are necessary (see sections 4.4 and 
5.1). 
 
Renal impairment 
No dose adjustments are required in patients with mild or moderate renal impairment (see section 5.2). 
There are no data regarding necitumumab administration in patients with severe renal impairment. No 
dose reductions are recommended.  
 
Hepatic impairment 
There are no data regarding necitumumab administration in patients with moderate or severe hepatic 
impairment (see section 5.2). No dose reductions are recommended. 
 
Method of administration  
Portrazza is for intravenous use only. It is administered as an intravenous infusion over approximately 
60 minutes via an infusion pump. Portrazza must not be administered as an intravenous bolus or push. 
In case of previous hypersensitivity or infusion-related reaction, recommendations for management of 
hypersensitivity/infusion-related reactions should be followed, as for Table 1. 
 



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Only sodium chloride 9 mg/mL (0.9 %) solution for injection should be used as a diluent. Portrazza 
infusions should not be administered or mixed with glucose solutions. 
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). 
 
4.4 Special warnings and precautions for use 
 
Thromboembolic events  
Venous thromboembolic events (VTE) and arterial thromboembolic events (ATE), including fatal 
cases, were observed with necitumumab in combination with gemcitabine and cisplatin (see also 
section 4.8).  
Administration of necitumumab should be carefully considered in those patients with a history of 
thromboembolic events (such as pulmonary embolism, deep vein thrombosis, myocardial infarction, 
stroke) or preexisting risk factors for thromboembolic events (such as advanced age, patients with 
prolonged periods of immobilisation, severely hypovolemic patients, patients with acquired or 
inherited thrombophilic disorders). The relative risk of VTE or ATE was approximately three-fold 
higher in patients with a reported history of VTE or ATE. 
Necitumumab should not be administered to patients with multiple risk factors for thromboembolic 
events unless the benefits outweigh the risks to the patient. 
Thromboprophylaxis should be considered after careful assessment of a patient's risk factors 
(including the increased risk of serious bleeding in patients with tumour cavitation or tumour 
involvement of large central blood vessels). 
Patients and physicians should be aware of signs and symptoms of thromboembolism. Patients should 
be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, 
arm or leg swelling.  
Discontinuation of necitumumab in patients who experience a VTE or ATE should be considered after 
a thorough benefit risk assessment for the individual patient. 
 
In a clinical trial in advanced non-squamous NSCLC, patients experienced an increased rate of serious 
thromboembolic events (including fatal events) in the necitumumab plus pemetrexed and cisplatin arm 
as compared to the pemetrexed and cisplatin arm (see also section 4.8). The addition of necitumumab 
did not improve the efficacy outcome over pemetrexed and cisplatin alone in advanced non-squamous 
NSCLC. 
 
Cardiorespiratory disorders 
An increased frequency of cardiorespiratory arrest or sudden death was observed with necitumumab. 
Cardiorespiratory arrest or sudden death was reported in 2.8% (15/538) of patients treated with 
necitumumab in combination with gemcitabine and cisplatin compared to 0.6% (3/541) of patients 
treated with chemotherapy alone. Twelve of the fifteen patients died within 30 days of the last dose of 
necitumumab and had comorbid conditions including history of coronary artery disease (n=3), 
hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven 
of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, 
myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart 
failure were not enrolled in the pivotal study. The incremental risk of cardiopulmonary arrest or 
sudden death in patients with a history of coronary artery disease, congestive heart failure, or 
arrhythmias as compared to those without these comorbid conditions is not known. 
 
Hypersensitivity/infusion-related reactions 
Hypersensitivity/infusion-related reactions (IRRs) were reported with necitumumab. The onset of 
events usually occurred after the first or second administration of necitumumab. Monitor patients 
during and following the infusion for signs of hypersensitivity and infusion-related reactions with 



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resuscitation equipment and appropriate medical resources readily available. In patients who have 
experienced a previous Grade 1 or 2 hypersensitivity or infusion related reaction to Portrazza, 
premedication with a corticosteroid and an antipyretic in addition to an antihistamine is recommended. 
For management and dose adjustments, see section 4.2.  
 
Skin reactions 
Skin reactions were reported with necitumumab (see section 4.8). The onset of events occurred mainly 
during the first cycle of treatment. For management and dose adjustments, see section 4.2.  
Pre-emptive skin treatment including skin moisturiser, sun screen, topical steroid cream (1 % 
hydrocortisone) and an oral antibiotic (e.g. doxycycline) may be useful in the management of 
dermatologic reactions as clinically appropriate. Patients may be advised to apply moisturiser, 
sunscreen and topical steroid cream to face, hands, feet, neck, back and chest. 
 
Electrolyte abnormalities 
Progressively decreasing serum magnesium levels occur frequently (81.3%) and may lead to severe 
Hypomagnesaemia (18.7%) (see also section 4.8). Hypomagnesaemia may reoccur at the same grade 
or worse after a dose delay. Patients should be carefully monitored for serum electrolytes, including 
serum magnesium, potassium, and calcium, prior to each necitumumab administration and after 
completion of necitumumab treatment, until within normal limits. Prompt electrolyte repletion is 
recommended, as appropriate. 
 
Infections 
In a phase 2 clinical trial investigating necitumumab in combination with paclitaxel and carboplatin 
versus paclitaxel and carboplatin alone as the first-line therapy in patients with Stage IV metastatic 
squamous NSCLC, an increased rate of infections was observed early after start of treatment, which 
led to subsequent infectious complications such as pneumonia and/or sepsis.  A similar observation 
was made in a clinical trial investigating necitumumab in combination with pemetrexed and cisplatin 
versus pemetrexed and cisplatin alone as the first-line therapy in patients with advanced 
non-squamous NSCLC. 
 
Special attention should be given to patients with clinical evidence of concomitant infectious 
conditions including early signs of active infections.  Treatment of any infection should be initiated 
according to local standards. 
 
Elderly 
No overall differences in efficacy between arms were observed in patients above 70 years of age. 
Cardiovascular comorbidities, performance status and the likely tolerability to chemotherapy with 
add-on necitumumab should therefore be thoroughly evaluated prior to the initiation of treatment in 
patients above 70 years of age.  
 
Women of childbearing potential/contraception in females 
Based on its mechanism of action and animal models where EGFR expression is disrupted, 
necitumumab may cause foetal harm or developmental anomalies. Women of childbearing potential 
should be advised to avoid becoming pregnant while on necitumumab. Effective contraception has to 
be used during necitumumab treatment and up to 3 months after last administration of necitumumab 
treatment. Contraceptive measures or abstinence are recommended (see section 4.6). 
 
Sodium restricted diet 
This medicinal product contains 76 mg sodium per dose. To be taken into consideration by patients on 
a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No drug-drug interactions were observed between Portrazza and gemcitabine/cisplatin. The 
pharmacokinetics of gemcitabine/cisplatin were not affected when co-administered with necitumumab 



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and the pharmacokinetics of necitumumab were not affected when co-administered with 
gemcitabine/cisplatin. 
 
No other formal interaction studies with necitumumab have been performed in humans. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception in females 
Women of childbearing potential should be advised to avoid becoming pregnant while on 
necitumumab and should be informed of the potential hazard to the pregnancy and foetus. Women of 
childbearing potential have to use effective contraception during necitumumab treatment and up to 
3 months after last administration of necitumumab treatment. Contraceptive measures or abstinence 
are recommended. 
 
Pregnancy 
There are no data from the use of necitumumab in pregnant women. Animal reproduction studies have 
not been conducted with necitumumab. Based on animal models, epidermal growth factor receptor 
(EGFR) is involved in prenatal development and may be essential for normal organogenesis, 
proliferation, and differentiation in the developing embryo. Portrazza should not be used during 
pregnancy or in women not using effective contraception, unless the potential benefit justifies the 
potential risk to the foetus.  
 
Breast-feeding 
It is unknown whether necitumumab is excreted in human milk. Excretion in milk and oral absorption 
is expected to be low. A risk to newborns/infants cannot be excluded. Breast-feeding should be 
discontinued during treatment with Portrazza and for at least 4 months after the last dose. 
 
Fertility 
There are no data on the effect of necitumumab on human fertility. Animal studies to assess fertility 
directly have not been conducted (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Portrazza has no known influence on the ability to drive and use machines. If patients experience 
treatment-related symptoms affecting their 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  
The most common serious adverse reactions (Grade ≥3) observed in necitumumab-treated patients are 
skin reactions (6.3 %) and venous thromboembolic events (4.3 %). 
 
The most common adverse reactions were skin reactions, venous thromboembolic events and 
laboratory abnormalities (hypomagnesaemia and albumin-corrected hypocalcaemia). 
 
Tabulated list of adverse reactions 
Adverse drug reactions (ADRs) which were reported in patients with squamous non-small cell lung 
cancer are listed below in MedDRA body system organ class, frequency and grade of severity. The 
following convention has been used for classification of frequency: 
Very common (≥1/10) 
Common (≥1/100 to <1/10) 
Uncommon (≥1/1,000 to <1/100) 
Rare (≥1/10,000 to <1/1,000) 
Very rare (<1/10,000) 
 



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Within each frequency grouping, ADRs are presented in order of decreasing seriousness. 
 
The following table provides the frequency and severity of ADRs based on results from SQUIRE, a 
global, multicenter, two-arm, randomized Phase 3 study in adult patients with squamous NSCLC 
randomised to treatment with necitumumab in combination with gemcitabine/cisplatin or 
gemcitabine/cisplatin. 
 
Table 3. ADRs reported in ≥ 1 % of necitumumab treated patients in SQUIRE 

 

System organ 
class Frequency ADR

a 

Portrazza + GCb 

(N=538) 

GC 

(N=541) 

Any 
grade 
(%) 

Grade ≥ 3 
(%) 

Any 
grade 
(%) 

Grade 
≥ 3 
(%) 

Infections and 
infestations 

Common Urinary tract 
infection 

4.1 0.2 1.7 0.2 

Nervous system 
disorders 

 

 

Common Headache 8.6 0 5.7 0.4 

Common Dysgeusia 5.9 0.2 3.3 0 

Eye disorders Common Conjunctivitis 5.6 0 2.2 0 

Vascular disorders Common Venous 
thromboembolic 
events 

8.2 4.3 5.4 2.6 

Common Arterial 
thromboembolic 
events 

4.3 3.0 3.9 2.0 

Common Phlebitis 1.7 0 0.4 0 

Respiratory, 
thoracic and 
mediastinal 
disorders 

Common Haemoptysis 8.2 0.9 5.0 0.9 

Common Epistaxis 7.1 0 3.1 0.2 

Common Oropharyngeal pain 1.1 0 0.7 0 

Gastrointestinal 
disorders 

 

Very 
common 

Vomiting 28.8 2.8 25.0 0.9 

Very 
common 

Stomatitis 10.4 1.1 6.3 0.6 

Common Dysphagia 2.2 0.6 2.2 0.2 

Common Mouth ulceration 1.5 0 0.4 0 

Skin and 
subcutaneous tissue 
disorders 

 

 

Very 
common 

Skin reactions 77.9 6.3 11.8 0.6 

Common Hypersensitivity 
reactions/infusion-
related reactions 

1.5 0.4 2.0 0 



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Musculoskeletal 
and connective 
tissue disorders 

Common Muscle spasms 1.7 0 0.6 0 

Renal and urinary 
disorders 

Common Dysuria 2.4 0 0.9 0 

General disorders 
and administration 
site conditions 

Very 
common 

Pyrexia 12.3 1.1 11.1 0.4 

Investigations Very 
common 

Hypomagnesaemiac 81.3 18.7 70.2 7.2 

Very 
common 

Albumin-corrected 
hypocalcaemiac 

33.0 4.2 22.9 2.3 

Very 
common 

Hypophosphataemiac 28.9 6.3 22.7 5.7 

Very 
common 

Hypokalaemiac 23.6 4.4 17.6 3.2 

Very 
common 

Weight decreased 12.1 0.6 6.3 0.6 

Abbreviations: GC = gemcitabine and cisplatin alone; Portrazza+GC = necitumumab plus gemcitabine 
and cisplatin; MedDRA = Medical Dictionary for Regulatory Activities. 

a MedDRA preferred term (Version 16).  
b The table reflects the frequency of ADRs during the chemotherapy phase of study treatment in 

which Portrazza+GC was directly compared with GC. 
c  Based on laboratory assessments. Only patients with baseline and at least one post-baseline result 

are included. 
 
Description of selected adverse reactions 
 
Thromboembolic events 
Venous thromboembolic events (VTEs) were reported in approximately 8 % of patients and mainly 
present as pulmonary embolism and deep vein thrombosis. Severe VTEs were reported in 
approximately 4 % of patients. The incidence of fatal VTEs was similar between arms (0.2%).  
Arterial thromboembolic events (ATEs) were reported in approximately 4 % of patients and mainly 
present as stroke and myocardial infarction. Severe ATEs were reported in 3 % of patients. The 
incidence of fatal ATEs was 0.6% in the experimental arm versus 0.2% in the control arm (see also 
section 4.4). 
 
In a clinical trial in advanced non-squamous NSCLC, venous thromboembolic events (VTEs) were 
reported in approximately 11 % of patients treated with necitumumab in combination with pemetrexed 
and cisplatin (versus 8 % in the pemetrexed and cisplatin alone arm) and mainly presented as 
pulmonary embolism and deep vein thrombosis. Severe VTEs were reported in approximately 6 % of 
patients treated with necitumumab in combination with pemetrexed and cisplatin (versus 4 % in the 
pemetrexed and cisplatin alone arm).  
Arterial thromboembolic events (ATEs) were reported in approximately 4 % of patients treated with 
necitumumab in combination with pemetrexed and cisplatin (versus 6 % in the pemetrexed and 
cisplatin alone arm) and mainly present as stroke and myocardial infarction. Severe ATEs were 
reported in approximately 3 % of patients treated with necitumumab in combination with pemetrexed 
and cisplatin (versus 4 % in the pemetrexed and cisplatin alone arm). 
 



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Skin reactions 
Skin reactions were reported in approximately 78 % of patients and mainly presented as acneiform 
rash, dermatitis acneiform, dry skin, pruritus, skin fissures, paronychia and palmar-plantar 
erythrodysaesthesia syndrome. Severe skin rections were reported in approximately 6 % of patients 
while 1.7 % of patients discontinued due to skin reactions. The majority of skin reactions developed 
during the first cycle of treatment and resolved within 17 weeks after onset  (see also section 4.4). 
 
Infusion-related reactions 
Infusion-related reactions were reported in 1.5 % of patients and mainly present as chills, fever or 
dyspnoea. Severe infusion-related reactions were reported in 0.4 % of patients. The majority of 
infusion-related reactions developed after the first or second administration of necitumumab. 
 
Toxicity in the elderly or in patients with ECOG PS 2 
Clinically relevant toxicities with respect to the elderly and those patients with Eastern Cooperative 
Oncology Group (ECOG) performance status score 2 (ECOG PS2) were similar to the overall 
population in patients receiving necitumumab plus chemotherapy consisting of gemcitabine and 
cisplatin. 
 
Eyelash trichomegaly 
Isolated cases of Grade 1 trichomegaly have been reported in patients treated with necitumumab. 
 
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 the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There has been limited experience with necitumumab overdose in human clinical trials. The highest 
dose of necitumumab studied clinically in a human dose-escalation Phase 1 study is 1,000 mg once a 
week or once every other week. Adverse events observed included headache, vomiting and nausea and 
were consistent with the safety profile at the recommended dose. There is no known antidote for 
necitumumab overdose. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC22 
 
Mechanism of action 
Necitumumab is a recombinant human IgG1 monoclonal antibody that binds with high affinity and 
specificity to the human epidermal growth factor receptor 1 (EGFR) and blocks the ligand binding 
site, blocking activation by all known ligands and inhibiting relevant biological consequences in vitro. 
Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and 
inhibition of apoptosis or cell death. In addition, necitumumab induces EGFR internalization and 
degradation in vitro. In vivo studies in cell line-derived xenograft models of human cancer, including 
non-small cell lung carcinoma, demonstrate that necitumumab has antitumor activity both in 
monotherapy and in combination with gemcitabine and cisplatin. 
 
Immunogenicity 
As with all therapeutic proteins, there is the potential for immunogenicity.  
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Overall, there was a low incidence of both treatment-emergent anti-drug antibodies and neutralizing 
antibodies among necitumumab-treated patients, and no correlation with safety outcomes in these 
patients. There was no relationship between immunogenicity and IRRs or treatment emergent adverse 
events. 
 
Clinical efficacy 
 
SQUIRE, a global, multicenter, two-arm, randomized study of Portrazza, was conducted in 
1,093 patients with stage IV (American Joint Committee on Cancer Version 7) squamous NSCLC, 
including patients with ECOG PS2, who had received no prior anticancer  therapy for metastatic 
disease. Patients were randomised to receive first-line Portrazza at 800 mg plus chemotherapy 
consisting of gemcitabine at 1,250 mg/m2 and cisplatin at 75 mg/m2 (Portrazza+GC Arm), or 
gemcitabine-cisplatin chemotherapy alone (GC Arm). Portrazza and gemcitabine were administered 
on days 1 and 8 of each 3-week treatment cycle, and cisplatin was administered on day 1 of each 
3-week treatment cycle. There was no premedication for Portrazza mandated by the study. 
Pre-emptive treatment for skin reaction was not permitted prior to the beginning of the second 
treatment cycle. Patients received a maximum of six cycles of chemotherapy in each arm; patients in 
the Portrazza+GC arm who had no progression continued to receive single-agent Portrazza until 
disease progression, unacceptable toxicity, or withdrawal of consent. The major efficacy outcome 
measure was overall survival (OS) and the supportive efficacy outcome measure was progression-free 
survival (PFS). Patients underwent radiographic assessment of disease status every six weeks, until 
radiographic documentation of progressive disease (PD).  
 
Demographics and baseline characteristics were balanced between arms. Median age was 62 (32-86), 
83 % of patients were men; 83.5 % were Caucasian; and 91 % were smokers. The ECOG PS was 0 for 
31.5 %, 1 for 59.7 %, and 2 for 9 % of patients; over 50 % had metastatic disease at more than 2 sites. 
In the Portrazza+GC arm, 51 % of patients continued with single-agent Portrazza after completing 
chemotherapy. Use of post-study systemic therapy was similar in the 2 arms (47.3 % in the 
Portrazza+GC arm and 44.7 % in the GC arm). 
 
Efficacy results are shown in Table 4. 
 



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Table 4. Summary of efficacy data (ITT population) 
 

 Portrazza+GC Arm 

N=545 

GC Arm 

N=548 

Overall survival   

            Number of events (n) 418 442 

 Median – months (95 % CIa) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1) 

    Hazard ratio (95 % CI)b, c 0.84 (0.74, 0.96) 

    Two-sided log-rank p-valuec 0.012 

1-year Overall survival rate (%) 47.7 42.8 

   

Progression free survival   

            Number of events (n) 431 417 

 Median – months (95 % CI) 5.7 (5.6, 6.0) 5.5 (4.8, 5.6) 

    Hazard ratio (95 % CI) b, c 0.85 (0.74, 0.98) 

    Two-sided log-rank p-valuec 0.020 
a Abbreviations: CI = confidence interval 
b Hazard ratio is expressed as treatment/control and estimated from Cox model 
c Stratified by the randomization strata (ECOG PS [0-1 vs. 2], and geographic region [North 

America, Europe, and Australia vs. South America, South Africa, and India vs. Eastern Asia]) 
 
 
Figure 1. Kaplan Meier plot of overall survival (ITT population) 

 

 
 
Abbreviations: C = cisplatin; G = gemcitabine. 
 



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An improvement was observed in subgroups for OS and PFS including the pre-specified stratification 
factors [ECOG PS score (0-1 vs. 2) and geographic region (North America, Europe, and Australia vs. 
South America, South Africa, and India vs. Eastern Asia)]; in patients age 70 and over, the hazard 
ratio for overall survival was 1.03 (0.75, 1.42) (see Figure 2).  
 
Figure 2. Forest plot for subgroup analysis of overall survival (ITT population) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

Abbreviations:  C = cisplatin; G = gemcitabine; ITT = intent-to-treat. 
 
 
A pre-planned exploratory analysis performed after the primary analysis, determined clinical efficacy 
outcome according to the level of tumour EGFR protein expression.  
Of the ITT population, 982 patients (89.8%) were evaluable for an EGFR protein expression analysis 
by immunohistochemistry (IHC) using Dako PharmDx Kit. A tumour was considered to be EGFR-
expressing if at least one stained cell could be identified. The large majority of patients (95.2% of 
evaluable patients; n = 935) had tumor samples expressing EGFR protein; 4.8% (n = 47) were not 
detectable for EGFR protein expression. There were no relevant differences in the distribution of 
demographics, disease characteristics, or the use of post-study systemic therapy between the subset of 
patients with detectable EGFR protein expression and the ITT population.  
 
In patients with detectable EGFR protein expression (indicated patient population), overall survival 
was statistically significantly improved in the Portrazza+GC Arm as compared to the GC Arm with an 
estimated reduction in risk of death of  21% (hazard ratio [HR] = 0.79 [0.69, 0.92]; p = 0.002) and a 
median OS of 11.7 months in the Portrazza+GC Arm and 10.0 months in the GC Arm.   
A statistically significant improvement in progression-free survival was also observed (HR = 0.84 
[0.72, 0.97]; p = 0.018), with a median PFS of 5.7 months in the Portrazza+GC Arm and 5.5 months in 
the GC Arm. 
In patients with detectable EGFR protein expression, there was no trend observed for increased 
efficacy with increasing levels of EGFR expression.  



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In patients with no detectable EGFR protein expression, no improvement in overall survival (hazard 
ratio [HR] = 1.52 [0.74, 3.12]) or progression free survival (hazard ratio [HR] = 1.33 [0.65, 2.70] was 
observed. 
 
In a phase 2 clinical trial investigating necitumumab in combination with paclitaxel and carboplatin 
versus paclitaxel and carboplatin alone (106 versus 55 patients, 2:1 randomisation) as the first-line 
therapy in patients with Stage IV metastatic squamous NSCLC, a higher rate of death, including death 
due to infection, was observed for the necitumumab plus paclitaxel/carboplatin arm during the first 
4 months (see also section 4.4), with a later trend towards improved survival after 4 months.  The 
overall survival hazard ratio [HR] was 0.83 [0.55, 1.52]. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Portrazza in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Following the dose regimen of 800 mg necitumumab on day 1 and day 8 of a 21 day schedule, the 
geometric mean of necitumumab Cmin was 98.5 μg/mL (Coefficient of Variation 80 %) in serum from 
patients with squamous NSCLC after five cycles of treatment in combination with gemcitabine and 
cisplatin. 
 
Absorption 
Portrazza is administered as an intravenous infusion. There have been no studies performed with other 
routes of administration. 
 
Distribution 
Distribution of Portrazza follow a biphasic decline. Based on population pharmacokinetic approach 
(PopPK), the mean volume of distribution at steady state (Vss) for necitumumab was 6.97 L (CV 
31 %). 
 
Elimination 
Necitumumab exhibits concentration-dependent clearance. Mean total systemic clearance (CLtot) at 
steady state following 800 mg on Day 1 and Day 8 of a 21-day cycle was 0.014 l/hr (CV 39 %). This 
corresponds to a half-life of approximately 14 days. The predicted time to reach steady state was 
approximately 70 days. 
 
Special populations 
Population pharmacokinetic analysis suggested age, gender, and race had no effect on the 
pharmacokinetics of necitumumab, while CL and volume of distribution had a less than proportional 
positive correlation with body weight. Although modeling results suggest that the disposition of 
necitumumab was statistically dependent on body weight, simulations indicated that weight-based 
dosing would not significantly decrease PK variability. No dose adjustment is necessary for these sub-
populations. 
 
Elderly 
Based on the results of the population pharamacokinetic analysis, there was no impact of age on 
necitumumab exposure. 
 
Renal impairment 
No formal studies have been conducted to evaluate the effect of renal impairment on the PK of 
necitumumab. Based on the results of the population pharmacokinetic analysis, there was no impact of 
renal function as assessed by creatinine clearance [CrCl] on the pharmacokinetics of necitumumab.  
 



15 

Hepatic impairment 
No formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of 
necitumumab. Based on the results of the population pharmacokinetic analysis, hepatic status (as 
assessed by alanine aminotransferase, aspartate transaminase and total bilirubin) had no significant 
effect on the pharmacokinetics of necitumumab. 
 
5.3 Preclinical safety data 
 
Dose dependent reversible skin toxicity was observed in the 26-week monkey study. The skin effects 
were consistent with the known class effects of EGFR inhibitors.   
 
Specific animal studies to test necitumumab for carcinogenic potential or potential to impair fertility 
have not been performed. The risk of fertility impairment is unknown. However, no adverse effects on 
male or female reproductive organs were observed in monkeys treated for 26 weeks with 
necitumumab. 
 
Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to be 
transmitted from the mother to the developing foetus. No animal studies have been specifically 
conducted to evaluate the effect of necitumumab on reproduction and foetal development; however, 
based on its mechanism of action and animal models where EGFR expression is disrupted, 
necitumumab may cause foetal harm or developmental anomalies. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium citrate dihydrate (E331) 
Citric acid anhydrous (E330)  
Sodium chloride  
Glycine (E640) 
Mannitol (E421) 
Polysorbate 80 (E433) 
Water for injections 
 
6.2 Incompatibilities 
 
Portrazza infusions should not be administered or mixed with glucose solutions. This medicinal 
product must not be mixed with other medicinal products except those mentioned in section 6.6.  
 
6.3 Shelf life 
 
Unopened vial 
2 years. 
 
After dilution 
When prepared as directed, infusion solutions of Portrazza contain no antimicrobial preservatives. 
 
It is recommended that the prepared dosing solution be used immediately in order to minimize the risk 
of microbial contamination. If not used immediately, the prepared necitumumab dosing solution must 
be stored at 2°C to 8°C for a duration not to exceed 24 hours, or may be held at 9°C to 25°C for up to 
4 hours. Store protected from light. Brief exposure to ambient light is acceptable while preparation and 
administration is taking place. 
 



16 

6.4 Special precautions for storage 
 
Store in a refrigator (2˚C - 8˚C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
50 mL solution in a vial (Type I glass) with a chlorobutyl elastomer stopper, an aluminium seal and a 
polypropylene cap. 
 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. 

 
Each vial is intended for single use only. Inspect the contents of the vials for particulate matter and 
discolouration. The concentrate for solution for infusion must be clear to slightly opalescent and 
colourless to slightly yellow prior to dilution. If particulate matter or discolouration is identified, 
discard the vial.  

 
Vials contain 800 mg as a 16 mg/mL solution of necitumumab; one 50 mL vial contains the complete 
dose. Only use sodium chloride 9 mg/mL (0.9 %) solution for injection as a diluent. 

 
To administer using pre-filled intravenous infusion containers 
Aseptically remove 50 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection from the 
prefilled 250 mL container and transfer 50 mL of necitumumab medicinal product into the container to 
bring the final volume in the container back to 250 mL. Gently invert the container to mix. DO NOT 
FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with 
other electrolytes or medicines. 

 
To administer using empty intravenous infusion containers 
Aseptically transfer 50 mL of necitumumab medicinal product into an empty intravenous container 
and add 200 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection to the container to bring 
the total volume to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the 
infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or 
medicines. 

 
Administer via an infusion pump. A separate infusion line must be used and the line must be flushed 
with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion. 
 
Parenteral medicinal products should be inspected visually for particulate matter prior to 
administration. If particulate matter is identified, discard the infusion solution. 

 
Discard any unused portion of necitumumab left in a vial, as the product contains no antimicrobial 
preservatives. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



17 

7. MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V. 
Papendorpseweg 83 
3528 BJ Utrecht 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1084/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 February 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) 
AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 

 



19 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s)  
ImClone Systems LLC 
33 ImClone Drive 
Branchburg 
New Jersey 
NJ 08876 
United States 
 
Name and address of the manufacturer(s) responsible for batch release 
Lilly, S.A. 
Avda. de la Industria, 30 
Alcobendas 
Madrid 
28108 
Spain 

 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 
• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
• Additional risk minimisation measures  

 



20 

Prior to launch of Portrazza (necitumumab) in each Member State the MAH must agree about the 
content and format of the educational material, including communication media, distribution 
modalities, and any other aspects of the programme, with the National Competent Authority.  
The MAH shall ensure that in each Member State where Portrazza (necitumumab) is marketed, all 
physicians (i.e. oncologists) are notified about the key conditions for the safe use of necitumumab. The 
materials will address the risks concerning arterial / venous thromboembolic events and 
cardiorespiratory disorders. 
 
Key elements of the physician educational material: 

o Importance of assessing the risks before starting treatment with necitumumab 
o Description of thromboembolic events including incidence rates from clinical trials 
o Advice that patients and physicians should be aware of signs and symptoms of 

thromboembolism. Patients should be instructed to seek medical care if they develop 
symptoms of thromboembolism such as shortness of breath, chest pain, arm or leg 
swelling. 

o The need to carefully consider use of necitumumab in patients with a history of 
thromboembolic events or pre-existing risk factors for thromboembolic events 

o Information on relative risk of VTE or ATE in patients with a history of VTE or ATE 
o Advice that necitumumab should not be administered to patients with multiple risk factors 

for thromboembolic events unless the benefits outweigh the risks to the patient 
o The need to consider thromboprophylaxis after careful assessment of a patient’s risk 

factors 
o Discontinuation of necitumumab in patients who experience a VTE or ATE should be 

considered after a thorough benefit risk assessment for the individual patient. 
o Description of cardiorespiratory disorders including incidence rates from clinical trials 
o Information that the incremental risk of cardiopulmonary arrest or sudden death in patients 

with a history of coronary artery disease, congestive heart failure, or arrhythmias as 
compared to those without these comorbid conditions is not known. 

o Instruction for healthcare professionals to read the materials in conjunction with the 
SmPC. 
 

The physician educational material package should also contain: 
o The Summary of Product Characteristics  
o Patient Information Leaflet  

 

 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 

 



23 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Portrazza 800 mg concentrate for solution for infusion  
necitumumab  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial of 50 mL contains 800 mg necitumumab (16 mg/mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium citrate dihydrate, citric acid anhydrous, sodium chloride, glycine, mannitol, 
polysorbate 80 and water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
800 mg/ 50 mL 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
For single use only.  
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
  
Do not shake.  
 
 
8. EXPIRY DATE 
 
EXP 
 



24 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze.  
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V. 
Papendorpseweg 83 
3528 BJ Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1084/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN:  



25 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Portrazza 800 mg sterile concentrate 
necitumumab 
For IV use after dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
800 mg/50 mL  
 
 
6. OTHER 
 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



27 

Package leaflet: Information for the user 
 

Portrazza 800 mg concentrate for solution for infusion 
necitumumab 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Portrazza is and what it is used for  
2. What you need to know before you are given Portrazza  
3. How you are given Portrazza 
4. Possible side effects  
5. How to store Portrazza  
6. Contents of the pack and other information 
 
 
1. What Portrazza is and what it is used for 
 
Portrazza contains the active substance necitumumab, which belongs to a group of substances called 
monoclonal antibodies.  
 
Necitumumab recognises and binds specifically to a protein on the surface of some cancer cells. The 
protein is known as epidermal growth factor receptor (EGFR). Other body proteins (called growth 
factors) can attach to the EGFR and stimulate the cancer cell to grow and divide. Necitumumab 
hinders other proteins from binding  to the EGFR and thus prevents the cancer cell from growth and 
division.  
 
Portrazza is used in combination with other anti-cancer medicines for the treatment of adults with 
certain type of lung cancer at an advanced stage (squamous non-small cell lung cancer), whose cancer 
cells have the EGFR protein on their surface. The anti-cancer medicines it is combined with are 
gemcitabine and cisplatin. 
 
 
2. What you need to know before you are given Portrazza  
 
You must not be given Portrazza 
- if you have ever had a severe allergic reaction to necitumumab or any of the other ingredients of 

this medicine (listed in section 6). 
 
Warnings and precautions  
Talk to your doctor or nurse immediately if any of the following applies to you (or you are not sure) 
during or after treatment with Portrazza: 
 
– Blood clots in the arteries or the veins 

Portrazza can cause blood clots in your arteries or your veins. Symptoms may include swelling, 
pain and tenderness of the limb, difficulty breathing, chest pain, or an abnormal heartbeat and 



28 

discomfort. Your doctor will discuss with you whether you need any preventive measures. See 
also section 4 for the symptoms of blood clots. 

 
– Cardiorespiratory disorders 

Cases of cardiorespiratory disorders and unexplained death were observed in patients treated 
with Portrazza in combination with  gemcitabine and cisplatin and in patients treated  with 
gemcitabine and cisplatin alone. The causes of these deaths and their relationship to treatment 
were not always known. Portrazza may increase this risk. Your doctor will discuss this with 
you. 
 

– Infusion-related reaction 
Infusion-related reactions may occur during treatment with Portrazza. Such reactions may be 
allergic. Your doctor will discuss with you whether you need any preventive measures or early 
treatment. Your doctor or nurse will check for side effects during your infusion. If you have a 
severe infusion-related reaction, your doctor may recommend adjusting the dose of Portrazza, or 
stop your treatment with Portrazza. See section 4 for more details about infusion-related 
reactions which may occur during or after the infusion. 

 
– Skin reactions 

Portrazza may cause side effects involving the skin. Your doctor will discuss with you whether 
you need any preventive measures or early treatment. If you have a severe skin reaction, your 
doctor may recommend adjusting the dose of Portrazza, or stop your treatment with Portrazza. 
See section 4 for more details about skin reactions. 

 
– Blood levels of magnesium, calcium, potassium and phosphate 

During treatment, your  doctor will check your blood periodically for levels of several 
substances such as magnesium, calcium, potassium and phosphate. If these levels are too low, 
your doctor may prescribe appropriate supplements. 
 

– Infections 
If you have signs of infection before start of treatment please tell your doctor.  

 
Children and adolescents 
Portrazza should not be given to patients under the age of 18 years because there is no information 
about how it works in this age group. 
 
Other medicines and Portrazza 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This 
includes medicines obtained without a prescription and herbal medicines. 
 
Pregnancy and breast-feeding 
Before starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you 
may be pregnant or are planning to have a baby. 
 
Avoid getting pregnant while receiving this medicine and for at least 3 months after the last dose of 
Portrazza as this medicine may potentially cause harm to your unborn child. Talk to your doctor about 
the best contraception for you. 
 
Do not breast-feed your baby during treatment with Portrazza and for at least 4 months after you 
receive the last dose, as this medicine may harm the growth and development of your baby. 
 
Driving and using machines 
If you experience any symptoms affecting your ability to concentrate and react, do not drive or use 
machines until the effect goes away. 
 



29 

Portrazza contains sodium 
This medicine contains 76 mg sodium per dose. This should be taken into consideration by patients on 
a controlled sodium diet. 
 
 
3. How you are given Portrazza 
 
A doctor experienced in the use of anti-cancer medicines will supervise your Portrazza therapy. 
 
Premedication 
You may be given medicines to reduce the risk of an infusion-related reaction or a skin reaction before 
you receive Portrazza.  
 
Dose and administration 
The recommended dose of Portrazza is 800 mg on days 1 and 8 of each 3-week cycle. Portrazza is 
given in combination with the medicines gemcitabine and cisplatin for up to 6 cycles and then it is 
given on its own. The number of infusions that you receive will depend on how and for how long you 
respond to treatment with Portrazza. Your doctor will discuss this with you. 
 
This medicine is given as an intravenous (into a vein) infusion via a drip. The drip lasts about 
60 minutes. 
 
Detailed instructions for your doctor or your nurse on how to prepare Portrazza infusion are included 
at the end of this package leaflet (see ‘Handling instructions’). 
 
Dose adjustments 
During each infusion, your doctor or nurse will check for side effects. If you have an infusion-related 
reaction during treatment, your drip will be slowed down and future doses will also be given more 
slowly. The infusion duration should not exceed 2 hours. See also section 2 under “Warnings and 
precautions”. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The important side effects of Portrazza are skin reactions and blood clots in the veins. 
 
Seek medical help immediately if you experience any of the following: 
 
Blood clots in the veins 
Venous blood clots are likely to occur in approximately 8 out of 100 patients. In approximately 4 out 
of 100 patients these side effects are likely to be severe. They can lead to a blockage of a blood vessel 
in the leg. Symptoms may include swelling, pain and tenderness of the limb. Blood clots can also lead 
to a blockage in the blood vessels of the lung. Symptoms may include difficulty breathing, chest pain, 
or an abnormal heartbeat and discomfort.  
 
Skin reactions 
Skin reactions may occur in approximately 80 out of 100 patients who take Portrazza and are usually 
mild to moderate. In approximately 5 out of 100 patients these skin reactions are likely to be severe. 
Symptoms of severe skin reactions may include acne-like skin conditions and skin rash. The skin rash 
commonly resembles acne and often involves the face, upper chest and back, but can affect any area of 
the body. Most of these side effects usually disappear over time after the end of Portrazza therapy. 
 



30 

Other side effects include: 
 
Very common (may affect more than 1 in 10 people): 
– itching; dry skin; scaling; nail disorders (skin reactions) 
– vomiting  
– fever or high temperature (pyrexia) 
– decreased weight 
– mouth ulcers and cold sores (stomatitis) 

 
Common (may affect up to 1 in 10 people) 
– headache 
– coughing up blood (haemoptysis) 
– nosebleed (epistaxis) 
– strange tastes; metallic taste (dysgeusia) 
– eye inflammation (conjunctivitis)  
– blood clots in the arteries 
– urinary tract infection (bladder and/or kidneys) 
– pain when passing urine (dysuria) 
– difficulty in swallowing (dysphagia) 
– muscle spasms 
– inflammation of veins in the legs (phlebitis) 
– allergic reactions 
– pain in your mouth and throat (oropharyngeal pain)  
 
Portrazza may also cause changes in the results of blood tests. These include low blood levels of 
magnesium, calcium, potassium or phosphate.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Portrazza 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
Infusion solution: After dilution and preparation, the medicine must be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 to 8 ºC, or up to 4 hours at 9  ºC to 25 ºC. Do not 
freeze or shake the infusion solution. Do not administer the solution if you notice any particulate 
matter or discoloration. 
 
This medicine is for single use only.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


31 

6. Contents of the pack and other information 
 
What Portrazza contains  
- The active substance is necitumumab. Each millilitre of the concentrate for solution for infusion 

contains 16 mg of necitumumab. 
Each 50 mL vial contains 800 mg of necitumumab. 

- The other ingredients are sodium citrate dihydrate (E331), citric acid anhydrous (E330), sodium 
chloride (see section 2 “Portrazza contains sodium”), glycine (E640), mannitol (E421), 
polysorbate 80 (E433) and water for injections.  

 
What Portrazza looks like and contents of the pack 
Portrazza 800 mg concentrate for solution for infusion (sterile concentrate) is a clear to slightly 
opalescent and colourless to slightly yellow liquid in a glass vial with a rubber stopper. 
 
It is available in packs of:  
- 1 vial of 50 mL 
 
Marketing Authorisation Holder  
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands 
 
Manufacturer  
Lilly S.A., Avda de la Industria, 30, Alcobendas, Madrid, 28108, Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32-(0)2 548 84 84 
 

Lietuva 
Eli Lilly Holdings Limited atstovybė 
Tel. +370 (5) 2649600 
 

България 
ТП "Ели Лили Недерланд" Б.В. - България 
тел. + 359 2 491 41 40 
 

Luxembourg/Luxemburg 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32-(0)2 548 84 84 

Česká republika 
ELI LILLY ČR, s.r.o. 
Tel: + 420 234 664 111 
 

Magyarország 
Lilly Hungária Kft. 
Tel: + 36 1 328 5100 

Danmark 
Eli Lilly Danmark A/S  
Tlf: +45 45 26 60 00 
 

Malta 
Charles de Giorgio Ltd. 
Tel: + 356 25600 500 

Deutschland 
Lilly Deutschland GmbH 
Tel. + 49-(0) 6172 273 2222 
 

Nederland 
Eli Lilly Nederland B.V.  
Tel: + 31-(0) 30 60 25 800 

Eesti 
Eli Lilly Holdings Limited Eesti filiaal  
Tel: +372 6 817 280 
 

Norge 
Eli Lilly Norge A.S.  
Tlf: + 47 22 88 18 00 

Ελλάδα 
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.  
Τηλ: +30 210 629 4600 
 

Österreich 
Eli Lilly Ges.m.b.H.  
Tel: + 43-(0) 1 711 780 

España 
Lilly S.A. 
Tel: + 34-91 663 50 00 

Polska 
Eli Lilly Polska Sp. z o.o. 
Tel: +48 22 440 33 00 



32 

 
France 
Lilly France SAS 
Tél: +33-(0) 1 55 49 34 34 
 

Portugal 
Lilly Portugal Produtos Farmacêuticos, Lda 
Tel: + 351-21-4126600 

Hrvatska 
Eli Lilly Hrvatska d.o.o. 
Tel: +385 1 2350 999 
 

România 
Eli Lilly România S.R.L. 
Tel: + 40 21 4023000 

Ireland 
Eli Lilly and Company (Ireland) Limited 
Tel: + 353-(0) 1 661 4377 
 

Slovenija 
Eli Lilly farmacevtska družba, d.o.o. 
Tel: +386 (0)1 580 00 10 

Ísland 
Icepharma hf. 
Sími + 354 540 8000 
 

Slovenská republika 
Eli Lilly Slovakia, s.r.o. 
Tel: + 421 220 663 111 

Italia 
Eli Lilly Italia S.p.A. 
Tel: + 39- 055 42571 
 

Suomi/Finland 
Oy Eli Lilly Finland Ab  
Puh/Tel: + 358-(0) 9 85 45 250 

Κύπρος 
Phadisco Ltd  
Τηλ: +357 22 715000 
 

Sverige 
Eli Lilly Sweden AB 
Tel: + 46-(0) 8 7378800 

Latvija 
Eli Lilly Holdings Limited pārstāvniecība Latvijā 
Tel: +371 67364000 
 

United Kingdom 
Eli Lilly and Company Limited 
Tel: + 44-(0) 1256 315000 

 
This leaflet was last revised in <{month YYYY}>. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
--------------------------------------------------------------------------------------------------------------------------- 

Handling instructions 
Portrazza 800 mg 

concentrate for solution for infusion 
necitumumab 

 
 
The following information is intended for healthcare professionals only: 
 
Prepare the infusion solution using the aseptic technique to ensure the sterility of the prepared 
solution. 

 
Each vial is intended for single use only. Inspect the contents of the vials for particulate matter and 
discolouration. The concentrate for solution for infusion must be clear to slightly opalescent and 
colourless to slightly yellow prior to dilution. If particulate matter or discolouration is identified, 
discard the vial.  

 
Vials contain 800 mg as a 16 mg/mL solution of necitumumab; one 50 mL vial contains the complete 
dose. Only use sodium chloride 9 mg/mL (0.9%) solution for injection as a diluent. 

 

http://www.ema.europa.eu/


33 

To administer using pre-filled intravenous infusion containers   
Aseptically remove 50 mL of sodium chloride 9 mg/mL (0.9%) solution for injection from the 
prefilled 250 mL container and transfer 50 mL of necitumumab medicine into the container to bring 
the final volume in the container back to 250 mL. Gently invert the container to mix. DO NOT 
FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with 
other electrolytes or medicines. 

 
To administer using empty intravenous infusion containers 
Aseptically transfer 50 mL of necitumumab medicine into an empty intravenous container and add 
200 mL of sterile sodium chloride 9 mg/mL (0.9%) solution for injection to the container to bring the 
total volume to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the 
infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or 
medicines. 

 
Administer via an infusion pump. A separate infusion line must be used and the line must be flushed 
with sodium chloride 9 mg/mL (0.9%) solution for injection at the end of the infusion. 

 
Parenteral medicines should be inspected visually for particulate matter prior to administration. If 
particulate matter is identified, discard the infusion solution. 

 
Discard any unused portion of necitumumab left in a vial, as the product contains no antimicrobial 
preservatives. 
 
 
Any unused medicines or waste material should be disposed of in accordance with local requirements. 
  
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET