Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.3 · PDF-Seite 5

HOS-215760 · Präparat HOS-155534

Hypersensitivity to aflibercept or to any of the excipients listed in section 6.1.

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Gegenanzeigen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.3 · PDF-Seite 5

HOS-215761 · Präparat HOS-155534

Ophthalmic / intravitreal use due to hyperosmotic properties of ZALTRAP (see section 4.4).

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Gegenanzeigen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.3 · PDF-Seite 5

HOS-215762 · Präparat HOS-155534

For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to the current respective summary of product characteristics.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): irinotecan (HOS-112102)

Wechselwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 8

HOS-215764 · Präparat HOS-155534

Population pharmacokinetics analysis and inter study comparisons did not reveal any pharmacokinetic drug-drug interaction between aflibercept and the FOLFIRI regimen.

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9

HOS-215765 · Präparat HOS-155534

Summary of the safety profile The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1,216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP 4 mg/kg every two weeks (one cycle) and 605 patients were treated with placebo/FOLFIRI in a phase III study. Patients received a median number of 9 cycles of the ZALTRAP/FOLFIRI regimen.

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9

HOS-215766 · Präparat HOS-155534

The most common adverse reactions (all grades, ≥ 20 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache (see Table 1).

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9

HOS-215767 · Präparat HOS-155534

The most common reported grades 3-4 reactions ( ≥5 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9

HOS-215768 · Präparat HOS-155534

The most frequent adverse reactions leading to permanent discontinuation in ≥ 1 % of patients treated with the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8 %) including hypertension (2.3 %), infections (3.4 %), asthenia/fatigue (1.6 %, 2.1 %),diarrhoea (2.3 %), dehydration (1 %), stomatitis (1.1 %), neutropenia (1.1 %), proteinuria (1.5 %), and pulmonary embolism (1.1 %).

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9

HOS-215769 · Präparat HOS-155534

Tabulated summary of adverse reactions Adverse reactions and laboratory abnormalities reported in patients treated with the ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed in Table 1 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 1 are defined as either any adverse clinical reaction or laboratory abnormality

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 9–10

HOS-215770 · Präparat HOS-155534

9 having ≥ 2 % greater incidence (all grades) in the aflibercept treatment group in comparison to the placebo treatment group in the MCRC study including those that do not meet this threshold but were consistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of the adverse reactions is graded according to NCI CTC version 3.0 (grade ≥ 3 = G ≥ 3). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies are based on all grades and defined as: 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); not known (cannot be estimated from the available data).

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-215771 · Präparat HOS-155534

Table 1 - Adverse reactions reported in patients treated with the ZALTRAP/FOLFIRI regimen from the MCRC study

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-215772 · Präparat HOS-155534

System Organ Class Adverse Reaction Frequency Category All grades Grades ≥3 Infections and infestations Very common Infection (1) Infection (1) Common Neutropenic infection/sepsis (1) Neutropenic infection/sepsis (1) Urinary tract infection Nasopharyngitis Uncommon Urinary tract infection Blood and lymphatic system disorders Very common Leucopenia (2) Leucopenia (2) Neutropenia (1),(2) Neutropenia (2) Thrombocytopenia (2) Common Febrile neutropenia Febrile neutropenia Thrombocytopenia (2) Immune system disorders Common Hypersensitivity (1) Uncommon Hypersensitivity (1) Metabolism and nutrition disorders Very common Decreased appetite Weight loss Common Dehydration (1) Dehydration (1) Decreased appetite Weight loss Cardiac disorders Uncommon Cardiac failure

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-215773 · Präparat HOS-155534

Rare Ejection fraction decreased Nervous system disorders Very common Headache Common Headache Uncommon PRES (1),(4) PRES (1),(4) Vascular disorders Very common Hypertension (1) Hypertension Haemorrhage (1)

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10–11

HOS-215774 · Präparat HOS-155534

10 System Organ Class Adverse Reaction Frequency Category All grades Grades ≥3 Common Arterial thromboembolism (1) Arterial thromboembolism (1) Venous thromboembolism (1) Venous thromboembolism (1) Haemorrhage (1) Not known Aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Very common Dyspnoea Epistaxis Dysphonia Common Oropharyngeal pain Rhinorrhoea Uncommon Dyspnoea Epistaxis Dysphonia Oropharyngeal pain Gastrointestinal disorders Very common Diarrhoea (1) Diarrhoea (1) Stomatitis Stomatitis Abdominal pain Abdominal pain upper Common Rectal haemorrhage Abdominal pain Fistula (1) Abdominal pain upper Aphthous stomatitis Haemorrhoids Proctalgia Toothache Uncommon GI perforation (1) GI perforation (1) Rectal haemorrhage Fistula (1) Aphthous stomatitis Proctalgia Hepatobiliary disorders Very common Increased AST (2) Increased ALT (2) Common Increased AST (2) Increased ALT (2)

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-215775 · Präparat HOS-155534

Skin and subcutaneous tissue disorders Very common Palmar-Plantar Erythrodysaesthesia syndrome Common Skin hyperpigmentation Palmar-Plantar Erythrodysaesthesia syndrome Uncommon Compromised wound healing (1) Compromised wound healing (1)

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11–12

HOS-215776 · Präparat HOS-155534

11  System Organ Class Adverse Reaction Frequency Category All grades Grades ≥3 Musculoskeletal and connective tissue disorders Uncommon Osteonecrosis of the Jaw (ONJ) Renal and urinary disorders Very common Proteinuria (1),(3) Increased serum creatinine Common Proteinuria (1),(3) Uncommon Nephrotic syndrome (1) Nephrotic syndrome (1) Thrombotic microangiopathy (1) Thrombotic microangiopathy (1) General disorders and administration site conditions Very common Asthenic conditions Asthenic conditions Note: Adverse reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 (1) See “Description of selected adverse reactions” in this section (2) Based on laboratory values (percentages done on patients with laboratory assessments) (3) Compilation of clinical and laboratory data (4) Not reported in MCRC study; however, PRES was reported in patients from other studies treated with aflibercept as monotherapy and in combination with chemotherapies other than FOLFIRI

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 12

HOS-215777 · Präparat HOS-155534

In the pivotal MCRC study, anaemia, nausea, vomiting, constipation, alopecia, increased alkaline phosphatase, and hyperbilirubinaemia occurred in ≥ 20 % of patients. These were comparable between groups, and the difference between groups did not exceed ≥ 2 % incidence for the ZALTRAP/FOLFIRI regimen.

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 12

HOS-215778 · Präparat HOS-155534

Description of selected adverse reactions

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 12

HOS-215779 · Präparat HOS-155534

Haemorrhage Patients treated with ZALTRAP have an increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events. In the pivotal study of MCRC patients, episodes of bleeding/haemorrhage (all grades) was reported in 37.8 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 19.0 % of patients treated with the placebo/FOLFIRI regimen. The most common reported form of bleeding was minor (grade 1-2) epistaxis occurring in 27.7 % of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 3-4 haemorrhage including GI haemorrhage, haematuria, and post-procedural haemorrhage was reported in 2.9 % of patients receiving the ZALTRAP/FOLFIRI regimen compared with 1.7 % of patients receiving the placebo/FOLFIRI regimen. In other studies, severe intracranial haemorrhage and pulmonary haemorrhage/haemoptysis including fatal events have occurred in patients receiving ZALTRAP (see section 4.4).

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Nebenwirkungen · Zaltrap

ZALTRAP 25 mg/ml concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 12

HOS-215780 · Präparat HOS-155534

Gastrointestinal perforation GI perforation including fatal GI perforation has been reported in patients treated with ZALTRAP. In the pivotal study of MCRC patients, GI perforation (all grades) was reported in 3 of 611 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5 %) treated with the placebo/FOLFIRI regimen. Grade 3-4 GI perforation events occurred in all 3 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and in 2 patients (0.3 %) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8 % for patients treated with ZALTRAP and 0.3 % for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8 % of patients treated with ZALTRAP and 0.2 % of patients treated with placebo (see section 4.4).

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