Cyramza · 4.3 Contraindications · 1

HOS-096864 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were: Gastrointestinal perforation (see section 4.4) Severe gastrointestinal haemorrhage (see section 4.4) Arterial thromboembolic events (see section 4.4) Posterior reversible encephalopathy syndrome (see section 4.4) The most common adverse reactions observed in patients treated with ramucirumab as monotherapy are: peripheral oedema, hypertension, diarrhoea, abdominal pain, headache, proteinuria and thrombocytopenia. The most common adverse reactions observed in patients treated with ramucirumab in combination with chemotherapy are: fatigue/asthenia, neutropenia, diarrhoea, epistaxis and stomatitis. The most common adverse reactions observed in patients treated with ramucirumab in combination with erlotinib are: infections, diarrhoea, hypertension, stomatitis, proteinuria, alopecia and epistaxis. Tabulated list of adverse reactions Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens or erlotinib for the treatment of gastric cancer, mCRC and NSCLC. ADRs are listed below by MedDRA body system organ class. The following convention has been used for classification of frequency for ADR tables: 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) 12 Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Table 6: ADRs reported in patients treated with ramucirumab as monotherapy in phase 3 clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml) System Organ Very Common Common Uncommon Class (MedDRA) Blood and Thrombocytopeniaa Neutropeniaa lymphatic system disorders Metabolism and Hypokalaemiaa,b nutrition disorders Hyponatraemiaa Hypoalbuminaemiaa Nervous system Headache

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HOS-096860 · has-contraindication-information · PDF-Seite 8

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. For patients with NSCLC, ramucirumab is contraindicated where there is tumour cavitation or tumour involvement of major vessels (see section 4.4).

HOS-096859 · has-indication-information · PDF-Seite 2

Gastric cancer Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy (see section 5.1). Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate (see section 5.1). Colorectal cancer Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine. 2 Non-small cell lung cancer Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutations (see section 5.1). Cyramza in combination with docetaxel is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with disease progression after platinum-based chemotherapy. Hepatocellular carcinoma Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have been previously treated with sorafenib.

HOS-096862 · has-interaction-information · PDF-Seite 11

No drug-drug interactions were observed between ramucirumab and paclitaxel. The pharmacokinetics of paclitaxel were not affected when co-administered with ramucirumab and the pharmacokinetics of ramucirumab were not affected when co-administered with paclitaxel. The pharmacokinetics of irinotecan and its active metabolite, SN-38, were not affected when co-administered with ramucirumab. The pharmacokinetics of docetaxel or erlotinib were not affected when co-administered with ramucirumab.

HOS-096863 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential/Contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while on Cyramza and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should use effective contraception during and up to 3 months after the last dose of ramucirumab treatment. Pregnancy There are no data from the use of ramucirumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). As angiogenesis is critical to maintenance of pregnancy and to foetal development, the inhibition of angiogenesis following ramucirumab administration may result in adverse events on pregnancy, including the foetus. Cyramza should only be used if the potential benefit to the mother justifies the potential risk during pregnancy. If the patient becomes pregnant while being treated with ramucirumab, she should be informed of the potential risk 11 to the maintenance of pregnancy and the risk to the foetus. Cyramza is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low. As a risk to breast-fed newborns/infants cannot be excluded, breast-feeding should be discontinued during treatment with Cyramza and for at least 3 months after the last dose. Fertility There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to be compromised during treatment with ramucirumab based on studies in animals (see section 5.3).

HOS-096861 · has-warning-information · PDF-Seite 8

Traceability In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Arterial thromboembolic events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia have been reported in clinical studies. Ramucirumab should be permanently discontinued in patients who experience a severe ATE (see section 4.2). Gastrointestinal perforations Ramucirumab is an antiangiogenic therapy and may increase the risk of gastrointestinal perforations. Cases of gastrointestinal perforation have been reported in patients treated with ramucirumab. Ramucirumab should be permanently discontinued in patients who experience gastrointestinal perforations (see section 4.2). Severe bleeding Ramucirumab is an antiangiogenic therapy and may increase the risk of severe bleeding. Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding (see section 4.2). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. For HCC patients with evidence of portal hypertension or prior history of oesophageal variceal bleeding, screening for and treatment of oesophageal varices should be performed as per standard of care before starting ramucirumab treatment. Severe gastrointestinal haemorrhage, including fatal events, were reported in patients with gastric cancer treated with ramucirumab in combination with paclitaxel, and in patients with mCRC treated with ramucirumab in combination with FOLFIRI. 8 Pulmonary haemorrhage in NSCLC Patients with squamous histology are at higher risk of developing serious pulmonary bleeding, however, no excess of Grade 5 pulmonary haemorrhage was observed in ramucirumab treated patients with squamous histology in REVEL. NSCLC patients with recent pulmonary bleeding (> 2.5 ml or bright red blood) as well as patients with evidence of baseline tumour cavitation, regardless of histology, or those with any evidence of tumour invasion or encasement of major blood vessels have been excluded from clinical trials (see section 4.3). Patients receiving any kind of therapeutic anticoagulation were excluded from the

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