Portrazza - summary of medicine characteristics

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).

.............­....... TT_

Clear to slightly opalescent and colourless to slightly yellow liquid, with pH 6.0.

4. CLINICAL PARTICULARS

4 1 Th f • d- f

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.

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 table and 2.

Hypersensitivi­ty/Infusion-related reactions

Decrease infusion rate by 50 % for the duration of infusion.b

Monitor patient for worsening o For subsequent infusions, please

ced for a Grade 1 or 2 hypersensiti­vity/infusion-related t the lower infusion rate be utilized for all subsequent infusions. not exceed 2 hours.

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), includin g 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.

uency of cardiorespiratory arrest or sudden death was observed with necitumumab. 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 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 thera squamous NSCLC, an increased rate of infections was obser led to subsequent infectious complications such as pneumon

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 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 i cacy between arms were observed in patients above 70 years of age.

Cardiovascular comorb     s, 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.

aring potential/con­traception in females

chanism of action and animal models where EGFR expression is disrupted, necitum 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 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 an

on the ability to drive and use machines. If patients experience ing their ability to concentrate and react, it is recommended that s until the effect subsides.

4.8 Undesirable

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 %).

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)

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

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).

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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).

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 Oncology Group (ECOG) performance status score 2 (ECOG PS2) were similar to the population in patients receiving necitumumab plus chemotherapy consisting of gemcit cisplatin.

Eyelash trichomegaly

Isolated cases of Grade 1 trichomegaly have been reported in patients tre

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

4.9 Overdose

umab overdose in human clinical trials. The highest an dose-escalation Phase 1 study is 1,000 mg once a

events observed included headache, vomiting and nausea and the recommended dose. There is no known antidote for

5.1 Pharmaco

ic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC22

Mec f action

N mab 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.

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 administ on days 1 and 8 of each 3-week treatment cycle, and cisplatin was administered on day 1 of eac 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      re was progression-free

survival (PFS). Patients underwent radiographic assessment of disease s very 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. Summary of efficacy data (ITT population)

Abbreviations: CI = confidence interval

Hazard ratio is expressed as treatment/control and estimated from Cox model

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])

Time Since Randomization (Months)

545   496  450  407  358  291  243  208  176   130  101  84   61   42   32   20   11    3    3     0    0

548  494  435  379  308  254  219  182  153   115   80   63   49   33   27   19   9    7    3     1    0

Abbreviations: C = cisplatin; G = gemcitabine.

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)

0.4 K. X           1                    24

*------------ ------------>

Fa^ffî PDRTRAZZA*GC Arm Favors GC Arm

Abbreviations: C = cisplatin; G = gemcitabine; ITT = intent-to-treat.

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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.

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. 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 pg/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 routes of administration.

Distribution

Distribution of Portrazza follow a b (PopPK), the mean volume of distri 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 subpopulations.

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.

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. ♦.w-'

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 PARTICULARS6.1 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        ot be administered or mixed with glucose solutions. This medicinal

product must not ixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf

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.

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

Each vial is intended for single use only. Inspect the contents of the vials fo iculate 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 ’ ’to 250 mL._Gently invert the container to mix. DO NOT FREEZE OR SHAKE the infusion s DO NOT dilute with other solutions or co-infuse with other electrolytes or medicines.

To administer using empty ini

L of necitumumab medicinal product into an empty intravenous container hloride 9 mg/mL (0.9 %) solution for injection to the container to bring. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the

T dilute with other solutions or co-infuse with other electrolytes or

Administer 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.

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