Portrazza

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. 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.

4). Posology adjustments Recommendations for the management of infusion-related and skin reactions are provided in tables 1 and 2. b • Monitor patient for worsening of condition. • For subsequent infusions, please see premedication section.

b • Monitor patient for worsening of condition. • For subsequent infusions, please see premedication section. Grade 3-4 • Immediately and permanently discontinue treatment with necitumumab. 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.

Medicinal product no longer authorised 4 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.

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)Medicinal product no longer authorised 8 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. 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. 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.

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.

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.

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).

4).